- In vitro and in vivo evaluation of 99mTc-DO3A-EA-Folate for receptor-mediated targeting of folate positive tumors
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Background: The cell membrane folate receptor is a potential molecular target for tumor selective drug delivery via receptor-mediated endocytosis, including delivery of radiolabeled folate-chelate conjugates for diagnostic imaging. Method: A new radiopharmaceutical, 99mTc-1,4,7-tris (carboxymethyl)-10-(4-aminoethyl)-1,4,7,10-tetraazacyclododecane (DO3A-EA)-Folate has been synthesized introducing DO3A-EA to the γ-carboxyl group of folic acid and was characterized by different spectroscopic techniques. Cytotoxicity was determined by macrocolony and MTT assay on three different cell lines. Cell uptake studies and receptor binding assay were performed using 99mTc-DO3A-EA-Folate. Tumor imaging was performed in KB cell line implanted tumor bearing nude mice, and uptake of the radiotracer was estimated. Results: The synthesized conjugate binds with 99mTc at high efficiency at ambient temperature. The resulting conjugate is stable under physiological conditions for 24h after radiocomplexation. Using an in vitro receptor binding assay, the conjugate showed Kd in μM range on human tumor cell lines (KB, U-87MG and OAW). The pharmacokinetic data revealed rapid wash out of the more than 75% activity within 5min from the circulation with hepato-biliary clearance. Data from γ scintigraphic and biodistribution studies performed in KB tumor bearing nude mice revealed major accumulation of radiotracer at tumor site. High tumor uptake was shown in the tumor bearing mice; tumor to blood ratios reached 2.27±0.32 and 6.05±1.02 at 1 and 4h after post injection, respectively. Conclusion: These results suggest that 99mTc-DO3A-EA- Folate may be clinically useful as a noninvasive radiodiagnostic imaging agent for the detection of FR-positive human cancers.
- Mishra, Gauri,Hazari, Puja Panwar,Kumar, Nitin,Mishra, Anil K.
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- Manganese Complex of a Rigidified 15-Membered Macrocycle: A Comprehensive Study
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Owing to the increasing importance of manganese(II) complexes in the field of magnetic resonance imaging (MRI), large efforts have been devoted to find an appropriate ligand for Mn(II) ion encapsulation by providing balance between the seemingly contradictory requirements (i.e., thermodynamic stability and kinetic inertness vs low ligand denticity enabling water molecule(s) to be coordinated in its metal center). Among these ligands, a large number of pyridine or pyridol based open-chain and macrocyclic chelators have been investigated so far. As a next step in the development of these chelators, 15-pyN3O2Ph and its transition metal complexes were synthesized and characterized using established methods. The 15-pyN3O2Ph ligand incorporates both pyridine and ortho-phenylene units to decrease ligand flexibility. The thermodynamic properties, protonation and stability constants, were determined using pH-potentiometry; the solid-state structures of two protonation states of the free ligand and its manganese complex were obtained by single crystal X-ray diffractometry. The results show a seven-coordinate metal center with two water molecules in the first coordination sphere. The longitudinal relaxivity of [Mn(15-pyN3O2Ph)]2+ was found to be 5.16 mM-1 s-1 at 0.49 T (298 K). Furthermore, the r2p value of 11.72 mM-1 s-1 (0.49 T), which is doubled at 1.41 T field, suggests that design of this Mn(II) complex does achieve some characteristics required for contrast imaging. In addition, 17O NMR measurements were performed in order to access the microscopic parameters governing this key feature (e.g., water exchange rate). Finally, manganese complexes of ligands with analogous polyaza macrocyclic scaffold have been investigated as low molecular weight Mn(CAT) mimics. Here, we report the H2O2 disproportionation study of [Mn(15-pyN3O2Ph)]2+ to demonstrate the versatility of this ligand scaffold as well.
- Freire, David M.,Green, Kayla N.,Kálmán, Ferenc Krisztián,Molnár, Enik?,Pota, Kristof,Tircsó, Gyula
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- Silver-guided excimer emission in an adenine-pyrene conjugate: fluorescence lifetime and crystal studies
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This Communication describes a novel adenine-pyrene conjugate (1) and its solid-state structure with silver and copper ions. Singlecrystal studies of metal complexes of 1 offer insight into molecular interactions and provide a basis to rationalize possible interactions in the solution state, leading to excimer formation. The robust nature of this interaction was further confirmed by deposition of the silver complex on a graphite surface, which exhibited a remarkable resemblance to its solid-state structure. The structural basis of selective excimer formation in the presence of Ag+ ions presents a viable approach for ratiometric detection of these ions.
- Pandey, Mrituanjay D.,Mishra, Ashutosh Kumar,Chandrasekhar, Vadapalli,Verma, Sandeep
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- Tetrazole-based trans-translation inhibitors kill Bacillus anthracis spores to protect host cells
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Bacillus anthracis, the causative agent of anthrax, remains a significant threat to humans, including potential use in bioterrorism and biowarfare. The capacity to engineer strains with increased pathogenicity coupled with the ease of disseminating lethal
- Alumasa, John N.,Goralski, Tyler D. P.,Keiler, Kenneth C.
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- Enhanced Out-of-Plane Conductivity and Photovoltaic Performance in n = 1 Layered Perovskites through Organic Cation Design
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Layered perovskites with the formula (R-NH3)2PbI4 have excellent environmental stability but poor photovoltaic function due to the preferential orientation of the semiconducting layer parallel to the substrate and the typically insulating nature of the R-NH3+ cation. Here, we report a series of these n = 1 layered perovskites with the form (aromatic-O-linker-NH3)2PbI4 where the aromatic moiety is naphthalene, pyrene, or perylene and the linker is ethyl, propyl, or butyl. These materials achieve enhanced conductivity perpendicular to the inorganic layers due to better energy level matching between the inorganic layers and organic galleries. The enhanced conductivity and visible absorption of these materials led to a champion power conversion efficiency of 1.38%, which is the highest value reported for any n = 1 layered perovskite, and it is an order of magnitude higher efficiency than any other n = 1 layered perovskite oriented with layers parallel to the substrate. These findings demonstrate the importance of leveraging the electronic character of the organic cation to improve optoelectronic properties and thus the photovoltaic performance of these chemically stable low n layered perovskites.
- Passarelli, James V.,Fairfield, Daniel J.,Sather, Nicholas A.,Hendricks, Mark P.,Sai, Hiroaki,Stern, Charlotte L.,Stupp, Samuel I.
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- Bioinspired adenine-dopamine immobilized polymer hydrogel adhesives for tissue engineering
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Nontoxic adhesive hydrogels are of great importance in tissue engineering. Herein, we report a simple synthesis of a few biocompatible hydrogels from adenine and dopamine immobilized polyacrylic acid (PAA) and alginic acid (Alg) polymers. The adenine-dopamine adduct incorporated hydrogels showed enhanced adhesiveness, transparency and biocompatibility, and induced cell proliferation in 2D and 3D-cell culture models within 24 h. Moreover, blending the modifiedPAAand Alg polymers (P2P4) further increased the stability and bioactivity of the hydrogel. Such biogels can be developed as smart materials for biomedical applications.
- Joshi, Saurabh,Mahadevan, Gomathi,Verma, Sandeep,Valiyaveettil, Suresh
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- Exploring hydrogen bonding and weak aromatic interactions induced assembly of adenine and thymine functionalised naphthalenediimides
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Adenine and thymine functionalised naphthalenediimide (NDI) conjugates and complementary peptide nucleic acid (PNA) dimers are designed to exploit complementary hydrogen bonding and aromatic interactions for controllable molecular organization. These nucleobase appended NDIs organized into well-defined fibers, nanoribbons, porous spheres, belts and petal-like 2D sheets.
- Narayanaswamy, Nagarjun,Avinash,Govindaraju
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- Synthesis of novel conjugates of a saccharide, amino acids,nucleobase and the evaluation of their cell compatibility
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This article reports the synthesis of a novel type of conjugate of three fundamental biological build blocks (i.e., saccharide, amino acids, and nucleobase) and their cell compatibility. The facile synthesis starts with the synthesis of nucleobase and saccharide derivatives, then uses solid-phase peptide synthesis (SPPS) to build the peptide segment (Phe-Arg-Gly-Asp or naphthAla-Phe-Arg- Gly-Asp with fully protected groups), and later, an amidation reaction in liquid phase connects these three parts together. The overall yield of these multiple step synthesis is about 34%. Besides exhibiting excellent solubility, these conjugates of saccharide-amino acids-nucleobase (SAN), like the previously reported conjugates of nucleobase-amino acids-saccharide (NAS) and nucleobase-saccharide-amino acids (NSA), are mammalian cell compatible.
- Yuan, Dan,Du, Xuewen,Shi, Junfeng,Zhou, Ning,Baoum, Abdulgader Ahmed,Xu, Bing
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- Purine-Based Fluorescent Sensors for Imaging Zinc Ions in HeLa Cells
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We synthesized three chelate-tethered purine ligands, having a Schiff base linkage at the N9 position, which resulted in the dipolar imine-methoxyphenol adenine Schiff base HL1, the 2-aminopurine Schiff base HL2, and the 2,6-diaminopurine Schiff base HL3. These ligands selectively showed enhancement of the fluorescence of the zinc ions. The imine-based compound HL1 chelated with zinc ions to give the discrete dimeric structure 1, a green fluorescent complex, which was again stabilized by purine–purine interactions to give a 1D polymeric structure. The ligands having a 6-amino group, HL1 and HL3, have high quantum yield, which gives higher fluorescence enhancement of the free zinc ions in the HeLa cells. HL1 was localized in the cytoplasm and the nucleoli of the HeLa cells, which was confirmed by an RNase digestion test.
- Pratibha,Singh, Swati,Sivakumar, Sri,Verma, Sandeep
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- Synthesis and biological evaluation of newly designed phosphonate based bone-seeking agent
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A cyclic tetraaza based bifunctional triphosphonate ligand 10-(2-aminoethyl)-1,4,7,10-tetraaza cyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3MP-EA) was synthesized as bone-seeking theranostic agent. The compound was characterized by spectroscopic techniques and labelled with 99mTc with more than 97% purity. Blood clearance of 99mTc labelled compound a quick wash out from the circulation. The compound was excreted mainly via kidneys and accumulation of 99mTc-DO3MP-EA in bone was 9.53 ± 1.06% of injected dose per gram of bone at 1 h. The preliminary CADD analysis confirms the efficacy of DO3MP-EA (G Score -7.005) as better binding agent for osteocalcin (pdb 1Q8H) rather than other known clinical agents. Subsequently stability constant of chelate with Ga(III) was found to be 18.6 which confirms its efficacy as 68Ga labelled PET radiopharmaceutical for bone.
- Srivastava, Pooja,Tiwari, Anjani K.,Chadha, Nidhi,Chuttani, Krishna,Mishra, Anil K.
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- Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors
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We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low-nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved
- Clima, Lilia,Craciun, Bogdan Florin,Angeli, Andrea,Petreni, Andrea,Bonardi, Alessandro,Nocentini, Alessio,Carta, Fabrizio,Gratteri, Paola,Pinteala, Mariana,Supuran, Claudiu T.
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- Novel PHD2/HDACs hybrid inhibitors protect against cisplatin-induced acute kidney injury
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Acute kidney injury (AKI) is associated with high morbidity and mortality. Cisplatin is a common chemotherapeutic, but its nephrotoxicity-driven AKI limits its clinical application. Currently, there are no specific and satisfactory therapies in the clinic for AKI. Inhibitors of hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PHD2) or histone deacetylase (HDACs) had shown renoprotective effects against AKI in preclinical studies. This study aimed to develop a novel therapeutic to prevent AKI progression by targeting PHD2 and HDACs simultaneously. We designed and synthesized a series of PHD2/HDACs hybrid inhibitors. The initial drug activity screening identified a candidate compound 31c, which exhibited potent inhibitory activities against PHD2 and HDAC1/2/6. Cellular analyses further showed that 31c did not affect cisplatin's antitumor activity in cancer cells but strongly protected cisplatin-induced toxicity on HK-2 cells. In vivo studies with the cisplatin-induced AKI mouse model demonstrated that 31c remarkably alleviated kidney dysfunction with suppressed plasma BUN/SCr and increased EPO levels. The potent renoprotective effects of 31c on AKI were confirmed by significant improvements in pathological kidney conditions in the mouse model. These results suggest that the novel PHD2/HDACs hybrid inhibitor, 31c, has a clinical potential as the renoprotective agent for the treatment/prevention of cisplatin-induced AKI for various cancers.
- Gao, Jun,Gou, Wenfeng,Hou, Wenbin,Li, Deguan,Li, Yiliang,Ning, Hongxin,Qin, Yong,Song, Yang,Wei, Huiqiang
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- Pd(II)-Mediated C?H Activation for Cysteine Bioconjugation
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Selective bioconjugation remains a significant challenge for the synthetic chemist due to the stringent reaction conditions required by biomolecules coupled with their high degree of functionality. The current trailblazer of transition-metal mediated bioconjugation chemistry involves the use of Pd(II) complexes prepared via an oxidative addition process. Herein, the preparation of Pd(II) complexes for cysteine bioconjugation via a facile C?H activation process is reported. These complexes show bioconjugation efficiency competitive with what is seen in the current literature, with a user-friendly synthesis, common Pd(II) sources, and a more cost-effective ligand. Furthermore, these complexes need not be isolated, and still achieve high conversion efficiency and selectivity of a model peptide. These complexes also demonstrate the ability to selectively arylate a single surface cysteine residue on a model protein substrate, further demonstrating their utility.
- Tilden, James A. R.,Lubben, Anneke T.,Reeksting, Shaun B.,Kociok-K?hn, Gabriele,Frost, Christopher G.
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supporting information
(2022/01/19)
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- Application of bioorthogonal hetero-Diels-Alder cycloaddition of 5-arylidene derivatives of 1,3-dimethylbarbituric acid and vinyl thioether for imaging inside living cells
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New bioorthogonal cycloaddition of 5-arylidene derivatives of 1,3-dimethylbarbituric acid as 1-oxa-1,3-butadienes and vinyl thioether as a dienophile has been applied to imaging inside living cells. The reaction is high yielding, selective, and fast in aqueous media. The proposed 1-oxa-1,3-butadiene derivative conjugated to a FITC fluorochrome selectively and rapidly labels the cancer cells pretreated with the dienophile-taxol. The second order rate constants k2 for various proposed bioorthogonal cycloadditions were estimated to be in the range from 0.9 × 10-2 M-1 s-1 to 1.4 M-1 s-1, which is much better than in the case of the first generation TQ-ligation (o-quinolinone quinone methide and vinyl thioether ligation, k2 = 1.5 × 10-3 M-1 s-1) and comparable or better to that for the second generation TQ-ligation (k2 = 2.8 × 10-2 M-1 s-1). The reaction rate constants k2 of proposed ligation reactions are in the range of the rate constants k2 for tetrazines and norbornenes or tetrazines and cyclopropenes. These findings indicate that this chemistry is suitable for in vitro imaging experiments.
- Bazan, Bart?omiej,Pa?asz, Aleksandra,Skalniak, ?ukasz,Cie?, Dariusz,Buda, Szymon,J?drzejowska, Katarzyna,G?omb, Sonia,Kamzol, Daniel,Czarnota, Kinga,Latos, Krystian,Kozie?, Krzysztof,Musielak, Bogdan
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supporting information
p. 6045 - 6058
(2021/07/25)
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- Ni-Catalyzed Formal Cross-Electrophile Coupling of Alcohols with Aryl Halides
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Direct coupling of unactivated alcohols remains a challenge in current synthetic chemistry. We herein demonstrate a strategy building upon in situ halogenation/reductive coupling of alcohols with aryl halides to forge Csp2-Csp3 bonds. The combination of 2-chloro-3-ethylbenzo[d]oxazol-3-ium salt (CEBO) and TBAB as the mild bromination reagents enables rapid transformation of a wide range of alcohols to their bromide counterparts within one to 5 min in CH3CN and DMF, which is compatible with the Ni-catalyzed cross-electrophile coupling conditions in the presence of a chemical reductant. The present method is suitable for arylation of a myriad of structurally complex alcohols with no need for prepreparation of alkyl halides. More importantly, the mild and kinetically rapid bromination process has shown good selectivity in the bromination/arylation of symmetric diols and less sterically hindered hydroxyl groups in polyols, thus offering promise for selective functionalization of diols and polyols without laborious protecting/deprotecting operations. The practicality of this work is also evident in the arylation of a number of carbohydrates, drug compounds, and naturally occurring alcohols.
- Lin, Quan,Ma, Guobin,Gong, Hegui
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p. 14102 - 14109
(2021/11/20)
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- Pyrimidine ring-containing substituted five-membered heterocyclic compound as well as preparation method and application thereof
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The invention discloses a substituted five-membered heterocyclic compound containing pyrimidine rings. The structure is shown in a formula I: (the formula I is shown in the description), and the definition of each substation group is shown in the descript
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Paragraph 0342-0345
(2021/02/06)
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- Preparation and application of substituted pyrazole compound containing pyriminostrobin
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The invention discloses a substituted pyrazole compound containing pyrimidine amine as shown in a general formula I. The definition of each substituent in the formula is described in the description. The compounds of the invention have a broad spectrum of sterilization. The insecticidal acaricidal activity has an excellent control effect on cucumber downy mildew, wheat powdery mildew, corn rust, rice blast, cucumber anthracnose and the like. The compounds of the invention exhibit good insecticidal activity at the same time.
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Paragraph 0452-0455
(2021/10/20)
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- Anti-tumor metastasis effect of 2, 4, 7-trisubstituted pyrimidino indole compound
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The invention relates to a compound with a 2, 4, 7-trisubstituted pyrimidino indole structure. The compound can inhibit tumor cell migration and invasion at a very low concentration, and has an effect superior to that of a clinically common drug cis-platinum. In addition, the compound can also inhibit the expression of matrix metalloproteinase related protein which plays an important role in tumor migration and invasion processes. The invention also relates to a preparation method of the compound and application of the compound in marking, diagnosis, prevention and treatment or adjuvant therapy of tumors.
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Paragraph 0068; 0097-0099
(2021/05/29)
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- Antitumor effect of 2, 4, 7-trisubstituted pyrimidino indole compound
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The invention relates to a series of compounds with 2, 4, 7-trisubstituted pyrimidino indole structures, and the compounds can inhibit the growth of various tumor cells, and particularly, the compounds can efficiently inhibit the proliferation of breast cancer, cervical cancer, gastric adenocarcinoma and liver cancer cells. In addition, the compound can inhibit tumor cell clone formation at a very low concentration and promote tumor cell apoptosis. The invention also relates to a preparation method of the compound and application of the compound in marking, diagnosis, prevention and treatment or adjuvant therapy of tumors.
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Paragraph 0091; 0120-0122
(2021/05/29)
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- Preparation and application of Sigma-2 fluorescent ligand
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The invention mainly relates to synthesis of a series of sigma-2 fluorescent ligands and application of the sigma-2 fluorescent ligands in the fields of pharmacy and medicine, specifically to a series of compounds containing benzopyran structures, wherein the compounds have high affinity activity and selectivity to a sigma-2 receptor, have good affinity activity to the sigma-2 receptor, and have diagnosis and treatment effects on tumor cells, brain cells of patients with Alzheimer's disease, and other cells highly expressing the sigma-2 receptor.
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Paragraph 0070; 0075-0077
(2021/06/06)
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- 2, 4, 7 -substituted pyrimido indole compound antitumor drug resistance effect
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The invention relates to 2, 4 and 7 - tri-substituted pyrimido-indole structural compounds which can inhibit the growth of various drug-resistant tumor cells, and in particular, can efficiently inhibit doxorubicin resistant breast cancer. Cisplatin-resistant lung cancer and cisplatin liver cancer cell proliferation. In addition, the compounds of the present invention can inhibit the formation of drug-resistant tumor cell clones at very low concentrations and inhibit P glycoprotein and ABCG2 transport in vitro functions. The invention also relates to a preparation method of the compound and an application of the compound in tumor treatment or adjuvant therapy.
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Paragraph 0027; 0056-0058
(2021/09/08)
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- A novel H2S releasing-monastrol hybrid (MADTOH) inhibits L-type calcium channels
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A new alleged monastrol-H2S releasing hybrid, named MADTOH, was designed based on the structure of monastrol (M) and 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) and synthesized in 7.8% overall yield. MADTOH was shown to be an H2S donor under physiological conditions. In addition, the hybrid causes a decrease in global calcium transient in cardiomyocytes similar to nifedipine (NIFE), taken as a positive control. Whole-cell voltage-clamp showed that MADTOH decreases L-type Ca2+ current in isolated ventricular cardiomyocytes.
- Braga, Taniris Cafiero,De Jesus, Itamar Couto Guedes,Soares, Kathleen Viveiros,Guatimosim, Silvia,Da Silva Neto, Leonardo,Da-Silva, Cristiane Jovelina,Modolo, Luzia Valentina,Menezes Filho, José Evaldo Rodrigues,Rhana, Paula,Cruz, Jader Santos,De Fátima, ?ngelo
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p. 671 - 678
(2021/01/25)
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- Self-Assembly of Stimuli-Responsive [2]Rotaxanes by Amidinium Exchange
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Advances in supramolecular chemistry are often underpinned by the development of fundamental building blocks and methods enabling their interconversion. In this work, we report the use of an underexplored dynamic covalent reaction for the synthesis of stimuli-responsive [2]rotaxanes. The formamidinium moiety lies at the heart of these mechanically interlocked architectures, because it enables both dynamic covalent exchange and the binding of simple crown ethers. We demonstrated that the rotaxane self-assembly follows a unique reaction pathway and that the complex interplay between crown ether and thread can be controlled in a transient fashion by addition of base and fuel acid. Dynamic combinatorial libraries, when exposed to diverse nucleophiles, revealed a profound stabilizing effect of the mechanical bond as well as intriguing reactivity differences between seemingly similar [2]rotaxanes.
- Borodin, Oleg,Richter, Stefan,Robertson, Craig C.,Shchukin, Yevhenii,Von Delius, Max
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supporting information
p. 16448 - 16457
(2021/10/12)
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- Oxygen-release microspheres capable of releasing oxygen in response to environmental oxygen level to improve stem cell survival and tissue regeneration in ischemic hindlimbs
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Stem cell transplantation has been extensively explored to promote ischemic limb vascularization and skeletal muscle regeneration. Yet the therapeutic efficacy is low due to limited cell survival under low oxygen environment of the ischemic limbs. Therefore, continuously oxygenating the transplanted cells has potential to increase their survival. During tissue regeneration, the number of blood vessels are gradually increased, leading to the elevation of tissue oxygen content. Accordingly, less exogenous oxygen is needed for the transplanted cells. Excessive oxygen may induce reactive oxygen species (ROS) formation, causing cell apoptosis. Thus, it is attractive to develop oxygen-release biomaterials that are responsive to the environmental oxygen level. Herein, we developed oxygen-release microspheres whose oxygen release was controlled by oxygen-responsive shell. The shell hydrophilicity and degradation rate decreased as the environmental oxygen level increased, leading to slower oxygen release. The microspheres were capable of directly releasing molecular oxygen, which are safer than those oxygen-release biomaterials that release hydrogen peroxide and rely on its decomposition to form oxygen. The released oxygen significantly enhanced mesenchymal stem cell (MSC) survival without inducing ROS production under hypoxic condition. Co-delivery of MSCs and microspheres to the mouse ischemic limbs ameliorated MSC survival, proliferation and paracrine effects under ischemic conditions. It also significantly accelerated angiogenesis, blood flow restoration, and skeletal muscle regeneration without provoking tissue inflammation. The above results demonstrate that the developed microspheres have potential to augment cell survival in ischemic tissues, and promote ischemic tissue regeneration in a safer and more efficient manner.
- Guan, Ya,Gao, Ning,Niu, Hong,Dang, Yu,Guan, Jianjun
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p. 376 - 389
(2021/02/03)
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- Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases
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Chlamydia trachomatis is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen. Herein, we present a SAR of the sulfonylpyridine molecule by introducing substituents on the aromatic regions. Biological evaluation studies showed that several analogues can impair the growth of C. trachomatis without affecting host cell viability. The compounds did not kill other bacteria, indicating selectivity for Chlamydia. The compounds presented mild toxicity toward mammalian cell lines. The compounds were found to be nonmutagenic in a Drosophila melanogaster assay and exhibited a promising stability in both plasma and gastric fluid. The presented results indicate this scaffold is a promising starting point for the development of selective antichlamydial drugs.
- Seleem, Mohamed A.,Rodrigues De Almeida, Nathalia,Chhonker, Yashpal Singh,Murry, Daryl J.,Guterres, Zaira Da Rosa,Blocker, Amanda M.,Kuwabara, Shiomi,Fisher, Derek J.,Leal, Emilse S.,Martinefski, Manuela R.,Bollini, Mariela,Monge, María Eugenia,Ouellette, Scot P.,Conda-Sheridan, Martin
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p. 4370 - 4387
(2020/05/22)
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- Identification of a Potent and Selective 5-HT1AReceptor Agonist with in Vitro and in Vivo Antinociceptive Activity
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Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.
- Linciano, Pasquale,Sorbi, Claudia,Comitato, Antonella,Lesniak, Anna,Bujalska-Zadro?ny, Magdalena,Paw?owska, Agata,Bielenica, Anna,Orzelska-Górka, Jolanta,K?dzierska, Ewa,Bia?a, Gra?yna,Ronsisvalle, Simone,Limoncella, Silvia,Casarini, Livio,Cichero, Elena,Fossa, Paola,Sata?a, Grzegorz,Bojarski, Andrzej J.,Brasili, Livio,Bardoni, Rita,Franchini, Silvia
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p. 4111 - 4127
(2020/12/21)
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- Construction of pH sensitive smart glutathione peroxidase (GPx) mimics based on pH responsive pseudorotaxanes
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Two organoselenium compounds, both of which were modified with two primary amine groups, were designed and synthesized to mimic the catalytic properties of glutathione peroxidase (GPx). It was demonstrated that the catalytic mechanism of the diselenide organoselenium compound (compound 1) was a ping-pong mechanism while that of the selenide organoselenium compound (compound 2) was a sequential mechanism. The pH-controlled switching of the catalytic activities was achieved by controlling the formation and dissociation of the pseudorotaxanes based on the organoselenium compounds and cucurbit[6]uril (CB[6]). Moreover, the switching was reversible at pH between 7 and 9 for compound 1 or between 7 and 10 for compound 2.
- An, Shaojie,Jia, Wenlong,Li, Jiaxi,Ma, Ganghui,Shi, Shan,Wang, Tao,Zhang, Xiaoyin
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supporting information
p. 3125 - 3134
(2020/05/08)
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- METHOD FOR PRODUCING HETEROCYCLIC COMPOUND
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PROBLEM TO BE SOLVED: To provide a production method suitable for industrial production of a compound (A). SOLUTION: A compound (A) or a salt thereof is produced in an increased total yield and at low cost, with a reduced number of steps, and without requiring cryogenic reaction conditions or complex operation such as column purification or chiral column purification [where each symbol is as described in the specifications]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPO&INPIT
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Paragraph 0145-0147
(2020/10/16)
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- Second-coordination sphere effects on the reactivities of Hoveyda-Grubbs-type catalysts: A ligand exchange study using phenolic moiety-functionalized ligands
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The Hoveyda-Grubbs (HG) second-generation catalyst (HG-II), a Ru complex with a 2-isopropoxybenzylidene ligand, is extensively used for olefin metathesis, the rearrangement of carbon-carbon double bonds. A well-known strategy to control its complex reactivity is to modify the phenyl ring in the ligand, thereby directly influencing the coordination of the phenolic oxygen to the metal center. We, herein, report that a functional group attached to the phenolic moiety in the 2-alkoxybenzylidene ligand can indirectly affect the reactivities of HG-type complexes. In this work, the ligand exchange reactions between HG-II and phenolic moiety-modified 2-alkoxybenzylidene ligands are useful for evaluating the structural effects of the ligands. Specifically, an ethylene amide or an ester group at the terminal phenolic moiety in the benzylidene ligand was found to influence the relative stabilities of HG-type complexes compared to that of the HG-II complex. The structural analyses proved that the observed effects of the functional groups on the complex stabilities originate from the interactions with a chlorido ligand in HG-type complexes without changes in coordination fashions at the metal centers. It was found that the outer-sphere interactions also influence the catalytic activities of HG-type complexes, namely, the properties of HG-type complexes can be controlled by outer-sphere structural factors toward the metal center (i.e., "the second-coordination sphere effect"). In the design of functionalized HG-type complexes, the outer-sphere structural effects need to be considered in addition to the optimization of the metal coordination site.
- Akiyama, Naoki,Goshima, Kenta,Hirota, Shun,Jatmika, Catur,Matsuo, Takashi,Wakabayashi, Kazumo
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supporting information
p. 11618 - 11627
(2020/09/09)
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- Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle “Stitching” by N–H Insertion and Cyclization
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Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, pi
- Boddy, Alexander J.,Affron, Dominic P.,Cordier, Christopher J.,Rivers, Emma L.,Spivey, Alan C.,Bull, James A.
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supporting information
p. 1458 - 1462
(2019/01/04)
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- Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19
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In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.
- Wang, Siwen,Yang, Dazhou,Singh, Mandeep,Joo, Hyun,Rangel, Vanessa M.,Tran, Aaron,Phan, Erich,Xue, Liang
-
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- Synthesis of Peptide–Adenine Conjugates as a New Tool for Monitoring Protease Activity
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We took advantage of the powerful adenine SERS (Surface Enhanced Raman Spectroscopy) probe to design peptide–adenine conjugates as candidates for use as serine protease substrates. Whereas the direct introduction of the peptide sequence on the adenine exocyclic N6 amine gave an imidazopurinone derivative, the introduction of an aminoethyl linker between the adenine group and the peptide chain led to the expected candidate probes. These potential substrates were then evaluated for monitoring the hydrolytic activity of trypsin, used as a model protease, by HPLC and by SERS. We demonstrated that the Boc–VPR–adenine conjugate is a substrate of trypsin and constitutes a good starting point to design optimized substrates to monitor protease activity by SERS.
- Masurier, Nicolas,Soualmia, Feryel,Sanchez, Pierre,Lefort, Valérie,Roué, Mia,Maillard, Ludovic T.,Subra, Gilles,Percot, Aline,El Amri, Chahrazade
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p. 176 - 183
(2019/01/04)
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- Dual inhibitor for prolyl hydroxylase and histone deacetylase, preparation method and application thereof
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The invention discloses a new dual inhibitor for prolyl hydroxylase and histone deacetylase shown as formula I, a preparation method and an application thereof. The new dual inhibitor is capable of selectively promoting the level of hypoxia-inducible fact
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-
Paragraph 0081; 0082; 0083
(2019/02/04)
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- Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion
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The scarcity of hematopoietic stem cells (HSCs)significantly hindered their clinical potentials. Umbilical cord blood (UCB)has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34+ cells and CD34+CD38? cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.
- Feng, Yue,Xie, Xiao-Yang,Yang, Yi-Qiu,Sun, Yu-Tong,Ma, Wen-Hui,Zhou, Peng-Jun,Li, Zi-Yao,Liu, Hui-Qiang,Wang, Yi-Fei,Huang, Yun-Sheng
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p. 181 - 197
(2019/04/30)
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- UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H4 Receptors
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Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH4Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH4Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC50 (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC50 (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([3H]46) at the h/m/rH4Rs revealed comparable Kd values (41/17/22 nM), low nonspecific binding (11-17%, aKd), and fast associations/dissociations (25-30 min) and disclosed [3H]UR-DEBa176 as useful molecular tool to determine h/m/rH4R binding affinities for H4R ligands.
- Bartole, Edith,Littmann, Timo,Tanaka, Miho,Ozawa, Takeaki,Buschauer, Armin,Bernhardt, Günther
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supporting information
p. 8338 - 8356
(2019/10/11)
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- Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4-Dihydropyrazino[1,2-b]indazol-1(2H)-one Derivatives
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Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.
- Furlotti, Guido,Alisi, Maria Alessandra,Cazzolla, Nicola,Ceccacci, Francesca,Garrone, Beatrice,Gasperi, Tecla,La Bella, Angela,Leonelli, Francesca,Loreto, Maria Antonietta,Magarò, Gabriele,Mangano, Giorgina,Bettolo, Rinaldo Marini,Masini, Emanuela,Miceli, Martina,Migneco, Luisa Maria,Vitiello, Marco
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supporting information
p. 1597 - 1607
(2018/07/30)
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- Thieno [3, 2 - c] pyridine compound, its preparation method and application
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The invention relates to a thieno-[3,2-c] pyridine type compound and an application thereof. The compound has a structure shown by a formula (I) in the specification. The compound of which the structure is shown by the formula (I), provided by the invention has a very good effect of inhibiting the activity of Bruton kinase. The invention also relates to the application of the compound in preventing and/or treating diseases which are improved by virtue of BTK (Bruton tyrosine kinase) activity inhibition.
- -
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Paragraph 0184; 0185; 0186
(2018/09/02)
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- Labeling of Hyaluronic Acids with a Rhenium-tricarbonyl Tag and Percutaneous Penetration Studied by Multimodal Imaging
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Hyaluronic acids were labeled with a rhenium-tricarbonyl used as single core multimodal probe for imaging and their penetration into human skin biopsies was studied using IR microscopy and fluorescence imaging (labeled SCoMPI). The penetration was shown to be dependent on the molecular weight of the molecule and limited to the upper layer of the skin.
- Henry, Lucas,Delsuc, Nicolas,Laugel, Cécile,Lambert, Fran?ois,Sandt, Christophe,Hostachy, Sarah,Bernard, Anne-Sophie,Bertrand, Hélène C.,Grimaud, Laurence,Baillet-Guffroy, Arlette,Policar, Clotilde
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p. 987 - 991
(2018/04/23)
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- Substituted Pyrazole Compounds Containing Pyrimidine and Preparation Method and Use Thereof
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Disclosed are substituted pyrazole compounds containing pyrimidinyl as shown in Formula I: The definitions of each of the substituents can be seen in the description. The compounds of present invention have a good spectrum of bactericidal, insecticidal and acaricidal activity,and have good control effect on downy mildew of cucumber, powdery mildew of wheat, corn rust, rice blast, cucumber anthracnosis and the like. The compounds of present invention also show good insecticidal activity.
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Paragraph 0352; 0353
(2018/06/04)
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- Pyrimidine-containing substituted azole compounds and application thereof
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The invention discloses pyrimidine-containing substituted azole compounds with a structure as shown in a formula 1 in the description. In the formula 1, the definition of each substituent is enclosedin the description. The compounds disclosed by the invention have broad-spectrum bactericidal function and insecticidal and acaricidal activities, and have excellent control efficacy on cucumber downymildew, puccinia polysora, cucumber anthracnose and the like, in particular on cucumber downy mildew and puccinia polysora. Part of the compounds show certain insecticidal cavity on myzus persicae and tetranychus cinnabarinus at the same time. The pyrimidine-containing substituted azole compounds can be used for preparing bactericidal, insecticidal and acaricidal agents.
- -
-
Paragraph 0417; 0418; 0419; 0420
(2018/03/24)
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- Substituted pyrazole compound containing pyrimidine, and preparation method and use thereof
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The invention discloses a substituted pyrazole compound containing pyrimidine, wherein the compound has a structure represented by the general formula I, and the definitions of substituents in the formula are defined in the specification. The compound has broad-spectrum bactericidal activity, and has excellent prevention and treatment effects on cucumber downy mildew, corn rust disease, rice blastand the like.
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Paragraph 0284-0287
(2018/06/04)
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- Biguanide derivatives, pharmaceutical composition, preparation method and application
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The invention belongs to the field of medicine and particularly relates to biguanide derivatives, pharmaceutical composition, a preparation method and an application. The biguanide derivatives are compounds with the structure shown in the description, or pharmaceutically acceptable salts, solvates, isomers, esters and predrugs of the compounds. The compounds can remarkably inhibit proliferation and migration of tumor cells, IC50 is greatly lower than that of metformin and phenformin before derivatization, the compound 11 has the highest activity, and activity of the compounds in UMUC3, T24 andA2780 cells is more than 300-800 times that of metformin, and the compounds have good application prospect in antitumor drugs.
- -
-
Paragraph 0045-0047
(2019/01/14)
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- Graphene oxide-phenalenyl composite: transition metal-free recyclable and catalytic C-H functionalization
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An efficient route towards a heterogeneous transition metal-free catalytic C-H functionalization using a covalently linked graphene oxide-phenalenyl conjugate is described herein (28 examples, which include a core of some biologically relevant biaryl and hetero-biaryls). It is an environmentally benign, economical and heterogeneous platform, whose catalytic activity can easily be regenerated through a simple washing-drying technique and the catalytic activity can be retained even after 10 cycles.
- Singh, Bhagat,Paira, Rupankar,Biswas, Goutam,Shaw, Bikash Kumar,Mandal, Swadhin K.
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supporting information
p. 13220 - 13223
(2018/12/10)
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- Bioinspired Amphiphilic Peptide Dendrimers as Specific and Effective Compounds against Drug Resistant Clinical Isolates of E. coli
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Evolution-derived natural compounds have been inspirational for design of numerous pharmaceuticals, e.g., penicillins and tetracyclines. Herein, we present a bioinspired strategy to design peptide dendrimers for the effective therapy of E. coli infections where the selection of appropriate amino acids and the mode of their assembly are based on the information gained from research on membranolytic natural antimicrobial peptides (AMP's). On the molecular level two opposite effects were explored: the effect of multiple positive charges necessary for membrane disintegration was equilibrated by the anchoring role of tryptophanes. Indeed, a series of Trp-terminated dendrimers exhibited high potency against clinical isolates of antibiotic resistant ESBL E. coli strains, stability in human plasma along with very low hemo- and genotoxicity. Investigation of the underlying antimicrobial mechanism indicated that the dendrimers studied at minimal inhibitory concentration showed weak permeability toward membranes. Solid-state 2D NMR studies revealed their presence on and inside the model membranes. Therefore, their biological properties might be explained by targeting of extra- or intracellular receptors. Our results point to a new approach to design novel branched antimicrobials with high therapeutic index.
- Sowińska, Marta,Laskowska, Anna,Gu?piel, Adam,Solecka, Jolanta,Bochynska-Czyz, Marta,Lipkowski, Andrzej W.,Trzeciak, Katarzyna,Urbanczyk-Lipkowska, Zofia
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p. 3571 - 3585
(2018/10/24)
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- Recognition of AMP, ADP and ATP through cooperative binding by Cu(II) and Zn(II) complexes containing urea and/or phenylboronic acid moieties
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We report a series of Cu(II) and Zn(II) complexes with different ligands containing a dipicolyl unit functionalized with urea groups that may contain or not a phenylboronic acid function. These complexes were designed for the recognition of phosphorylated anions through coordination to the metal ion reinforced by hydrogen bonds involving the anion and NH groups of urea. The complexes were isolated and several adducts with pyrophosphate were characterized using X-ray diffraction measurements. Coordination of one of the urea nitrogen atoms to the metal ion promoted the hydrolysis of the ligands containing 1,3-diphenylurea units, while ligands bearing 1-ethyl-3-phenylurea groups did not hydrolyze significantly at room temperature. Spectrophotometric titrations, combined with 1H and 31P NMR studies, were used in investigating the binding of phosphate, pyrophosphate (PPi), and nucleoside 5-polyphosphates (AMP, ADP, ATP, CMP, and UMP). The association constants determined in aqueous solution (pH 7.0, 0.1 M MOPS) point to a stronger association with PPi, ADP, and ATP as compared with the anions containing a single phosphate unit. The [CuL4]2+ complex shows important selectivity for pyrophosphate (PPi) over ADP and ATP.
- Carreira-Barral, Israel,Fernández-Pérez, Isabel,Mato-Iglesias, Marta,de Blas, Andrés,Platas-Iglesias, Carlos,Esteban-Gómez, David
-
-
- Compartmentalized host spaces accommodating guest aromatic molecules in a chiral way in a helix-peptide-aromatic framework
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A novel host molecular assembly of a free-standing flat nanosheet with compartmentalized spaces was prepared using a bolaamphiphilic peptide composed of two amphiphilic helical peptides and an oligo(naphthaleneethynylene) (ONE) unit at the center of the m
- Uji, Hirotaka,Ogawa, Junya,Itabashi, Kenji,Imai, Tomoya,Kimura, Shunsaku
-
supporting information
p. 12483 - 12486
(2018/11/23)
-
- HYALURONIC ACID DERIVATIVE AND DRUG CONTAINING THE SAME
-
The present invention relates to a hyaluronic acid derivative in which an anti-inflammatory drug is bound via a covalent bond, wherein the structure of the hyaluronic acid derivative is represented by following formula (4) or (5): ???????? HA-SP-NSAID?????(4) ???????? HA-SP-DMARD?????(5) wherein HA represents a hyaluronic acid chain; SP represents a spacer residue; NSAID represents a non-steroidal anti-inflammatory drug residue, DMARD represents a disease-modifying anti-rheumatic drug residue, and - represents the covalent bond, wherein the spacer binds to a carboxyl group of the hyaluronic acid via an amide bond and the anti-inflammatory drug selected from non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs binds to the spacer via an ester bond, an amide bond or a thioester bond.
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Paragraph 0176
(2018/09/08)
-
- FLUORESCENT ANTICANCER PLATINUM DRUGS
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The present disclosure is in relation to the field of nanotechnology and cancer therapeutics. In particular, the present disclosure relates to fluorescent platinum based compounds. The disclosure further relates to synthesis of said fluorescent platinum based compounds, nanoparticles and compositions comprising said fluorescent platinum based compounds/nanoparticles. The disclosure also relates to methods of managing cancer by the fluorescence changes between aforesaid platinum based compounds and corresponding free ligands, nanoparticles and compositions.
- -
-
Paragraph 0537; 0538; 0539
(2018/11/21)
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- Preparation method of Lapatinib side chain 2-(methyl sulfonyl) ethylamine salt
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The invention provides a preparation method of Lapatinib side chain 2-(methylsulfonyl) ethylamine salt. The method comprises the following steps: (A) performing reaction on one or two of 2-bromoethylamine and 2-bromoethylamine salt and di-tert-butyl dicarbonate methyl ester under the alkaline condition to obtain N-(Boc)-2-bromoethylamine; (B) performing reaction on the N-(Boc)-2-bromoethylamine and sodium methanesulfinate under the alkaline condition to obtain N-(Boc)-2- methylsulfonyl ethylamine; (C) acidifying the N-(Boc)-2-methylsulfonyl ethaneamine to obtain the Lapatinib side chain 2-(methylsulfonyl) ethylamine salt. The preparation method of the Lapatinib side chain 2-(methylsulfonyl) ethylamine salt, provided by the embodiment of the invention, avoids the occurrence of the problems that when an oxidization method is used for synthesizing a target product, unstable factors are many, and the operation of the obtained product is also unsafe. The preparation method has the advantages that the operation steps are simple and convenient; the molecule utilization degree is high; the reaction conditions can be easily controlled; the operation cost is low; the post treatment operation is simple and convenient; the purity of the obtained product is high.
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Paragraph 0061
(2017/08/28)
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- Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis
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We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KI values in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.
- Bua, Silvia,Di Cesare Mannelli, Lorenzo,Vullo, Daniela,Ghelardini, Carla,Bartolucci, Gianluca,Scozzafava, Andrea,Supuran, Claudiu T.,Carta, Fabrizio
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p. 1159 - 1170
(2017/02/19)
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- Synthesis and Hydrolytic Stability of N- and O-Methyloxyamine Linkers for the Synthesis of GlycoconjugatesSynthesis and Hydrolytic Stability of N- and O-Methyloxyamine Linkers for the Synthesis of Glycoconjugates
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A comparison of the merits of N- and O-methyloxyamines as linkers for carbohydrates is presented for the first time. In particular, optimized synthetic routes for each linker type are given, and the ease of glycan conjugation is described. The hydrolytic stabilities of the respective oxyamine glycoconjugates under a variety of different conditions are reported. This provides insight into the factors that influence hydrolysis rates, and sheds light on the acid-catalysed hydrolysis mechanism.
- Munneke, Stefan,Hill, Jaimé C.,Timmer, Mattie S. M.,Stocker, Bridget L.
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p. 3722 - 3728
(2017/07/22)
-
- Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of DNA (dC5) i-motif structure
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This report describes the synthesis of C-rich sequence, cytosine pentamer, of aep-PNA and its biophysical studies for the formation of hybrid DNA:aep-PNAi-motif structure with DNA cytosine pentamer (dC5) under acidic pH conditions. Herein, the CD/UV/NMR/ESI-Mass studies strongly support the formation of stable hybrid DNA i-motif structure with aep-PNA even near acidic conditions. Hence aep-PNA C-rich sequence cytosine could be considered as potential DNA i-motif stabilizing agents in vivo conditions.
- Gade, Chandrasekhar Reddy,Sharma, Nagendra K.
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supporting information
p. 5424 - 5428
(2017/11/17)
-
- Discovery of uracil-bearing DAPYs derivatives as novel HIV-1 NNRTIs via crystallographic overlay-based molecular hybridization
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A novel series of uracil-bearing DAPYs derivatives were designed and synthesized via structure-based molecular hybridization to discover compounds with improved anti-resistance profiles. Anti-HIV activity of the designed compounds was tested in MT-4 cell
- Zhang, Heng,Tian, Ye,Kang, Dongwei,Huo, Zhipeng,Zhou, Zhongxia,Liu, Huiqing,De Clercq, Erik,Pannecouque, Christophe,Zhan, Peng,Liu, Xinyong
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p. 209 - 222
(2017/03/02)
-
- Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling
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Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-L-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies.
- Yang, Hao,Ouyang, Yifan,Ma, Hao,Cong, Hui,Zhuang, Chunlin,Lok, Wun-Taai,Wang, Zhe,Zhu, Xuanli,Sun, Yutong,Hong, Wei,Wang, Hao
-
supporting information
p. 4635 - 4642
(2017/09/29)
-
- DERIVATIVES OF IMIDAZOLE AND BENZIMIDAZOLE, METHOD OF PREPARATION AND USE THEREOF
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The present invention provides derivatives of imidazole and benzimidazole based thiones and selones used for degrading various toxic heavy metal and salts thereof to a less toxic, stable and insoluble form. The present invention also provides the process of preparation of the said derivatives of imidazole and benzimidazole based thiones and selones and method of detoxification and degradation of various heavy metals including mercury in particular organomercurials, lead, arsenic, cadmium, copper and salts thereof using the said imidazole and benzimidazole-based thione and selone derivatives. The said derivatives have better degradation activity under physiologically and environmentally relevant conditions as well as greater acceptability in a wide range of bases.
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Page/Page column 16
(2017/11/03)
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