- Insights into Thiourea-Based Bifunctional Catalysts for Efficient Conversion of CO2to Cyclic Carbonates
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The bifunctional thiourea catalyst system with both electrophilic and nucleophilic centers has been certified to be effective for fixing CO2 under mild reaction conditions; however, many questions remain, especially concerning the relationship between str
- Li, Zhuo-Qun,Zhang, Yao-Yao,Zheng, Yu-Jia,Li, Bo,Wu, Guang-Peng
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p. 3145 - 3155
(2022/02/14)
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- Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents
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The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Patel, Sagar P.,Sinha, Anshuman,Kansara, Deep D.,Mecwan, Annie R.,Patel, Sarvangee B.,Upadhyay, Pragnesh N.,Patel, Kishan B.,Shah, Dharti B.,Prajapati, Navnit K.,Murumkar, Prashant R.,Patel, Kirti V.,Yadav, Mange Ram
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p. 3635 - 3661
(2019/08/20)
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- Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma
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Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 μM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.
- Ghedira, Donia,Voissière, Aurélien,Peyrode, Caroline,Kraiem, Jamil,Gerard, Yvain,Maubert, Elise,Vivier, Magali,Miot-Noirault, Elisabeth,Chezal, Jean-Michel,Farhat, Farhat,Weber, Valérie
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supporting information
p. 51 - 67
(2018/09/13)
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- Transition state modeling and catalyst design for hydrogen bond-stabilized enolate formation
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A catalyst for enolate formation was designed that incorporates an amine base along with a thiourea to bind to the oxygen atom of the substrate and enolate through hydrogen bonding. A computational model of the transition state was developed in which the thiourea (modeled initially as a urea) and amine were separate molecules. This model and models incorporating one or two methanol molecules in place of the urea showed an out-of-plane hydrogen bond, apparently to the carbonyl π-bond, in addition to an in-plane hydrogen bond to an unshared electron pair. In contrast, optimized complexes of the ketone and the fully formed enolate showed only in-plane hydrogen bonding. The transition state model with the urea and amine was used to define a database search with the computer program CAVEAT to identify structures suitable for linking the amine and urea/thiourea moieties in the transition state. On the basis of a group of structures identified from this search, a flexible but conformationally biased linker was designed to connect the two catalytic moieties. The molecule having the amine and thiourea moieties connected by this linker was synthesized and was shown to catalyze proton exchange between methanol and deuterated acetone. The catalyst was about 5-fold more efficient than the amine and thiourea as separate molecules and relative to a similar but less conformationally biased catalyst.
- Zhu, Yimin,Drueckhammer, Dale G.
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p. 7755 - 7760
(2007/10/03)
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- Continuous chemoselective methylation of functionalized amines and diols with supercritical methanol over solid acid and acid-base bifunctional catalysts
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The selective N-methylation of bifunctionalized amines with supercritical methanol (scCH3OH) promoted by the conventional solid acids (H-mordenite, β-zeolite, amorphous silica-alumina) and acid-base bifunctional catalysts (Cs-P-Si mixed oxide and γ-alumina) was investigated in a continuous-flow, fixed-bed reactor. The use of scCH 3OH in the reaction of 2-aminoethanol with methanol (amine/CH 3OH = 1/10.8) over the solid catalysts led to a significant improvement in the chemoselectivity of the N-methylation. Among the catalysts examined, the Cs-P-Si mixed oxide provided the most efficient catalyst performance in terms of selectivity and reactivity at 300 °C and 8.2 MPa; the N-methylation selectivity in the products reaching up to 94% at 86% conversion. The present selective methylation was successfully applied to the synthesis of N-methylated amino alcohols and diamines as well as O-methylated ethylene glycol. Noticeably, ethoxyethylamine was less reactive, suggesting that the hydroxy group of the amino alcohols is a crucial structural factor in determining high reactivity and selectivity, possibly because of the tethering effect of another terminus, a hydroxo group, to the catalyst surface. The magic-angle-spinning NMR spectroscopy and X-ray diffraction analysis of the Cs-P-Si mixed oxide catalyst revealed that the acidic and basic sites originate from P2O5/SiO2 and Cs/SiO2, respectively, and the weak acid-base paired sites are attributed to three kinds of cesium phosphates on SiO2. The weak acid-base sites on the catalyst surface might be responsible for the selective dehydrative methylation.
- Oku, Tomoharu,Arita, Yoshitaka,Tsuneki, Hideaki,Ikariya, Takao
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p. 7368 - 7377
(2007/10/03)
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- Regioselective covalent modification of hemoglobin in search of antisickling agents
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Although the molecular defect in sickle hemoglobin that produces sickle cell disease has been known for decades, there is still no effective drug treatment that acts on hemoglobin itself. In this work, a series of diversely substituted isothiocyanates (R-NCS) were examined for their regioselective reaction with hemoglobin in an attempt to alter the solubility properties of sickle hemoglobin. Electrospray mass spectrometry, molecular modeling, X-ray crystallography, and conventional protein chemistry were used to study this regioselectivity and the resulting increase in solubility of the modified hemoglobin. Depending on the attached R-group, the isothiocyanates were found to react either with the Cysβ93 or the N-terminal amine of the α-chain. One of the most effective compounds in the series, 2-(N,N-dimethylamino)ethyl isothiocyanate, selectively reacts with the thiol of Cysβ93 which, in conjunction with the cationic group, was seen to perturb the local hemoglobin structure. This modified HbS shows an approximately 30% increase in solubility for the fully deoxygenated state, along with a significant increase in oxygen affinity. This compound and a related analogue appear to readily traverse the erythrocyte membrane. A discussion of the relation of these structural changes to inhibition of gelation is presented. The dual activities of increasing HbS oxygen affinity and directly inhibiting deoxy HbS polymerization, in conjunction with facile membrane traversal, suggest that these cationic isothiocyanates show substantial promise as lead compounds for development of therapeutic agents for sickle cell disease.
- Park, Soobong,Hayes, Brittany L.,Marankan, Fatima,Mulhearn, Debbie C.,Wanna, Linda,Mesecar, Andrew D.,Santarsiero, Bernard D.,Johnson, Michael E.,Venton, Duane L.
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p. 936 - 953
(2007/10/03)
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- Synthesis and screening of conformationally restricted and conformationally free N-(tertiary aminoalkyl)dithiocarbamic acids and esters as inhibitors of neuronal nitric oxide synthase
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N-(Tertiary aminoalkyl)dithiocarbamic acids and esters were synthesized and evaluated for their ability to inhibit neuronal nitric oxide synthase. Preliminary results show these compounds are able to act at the binding site for l-arginine and the conformationally restricted esters may have a second site of activity involving the cofactor (6R)-5,6,7,8-tetrahydro-l-biopterin. Copyright (C) 1997 Elsevier Science Ltd.
- Sassaman, Mark B.,Giovanelli, John,Sood, Virendar K.,Eckelman, William C.
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p. 1759 - 1766
(2007/10/03)
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- Long-range anisotropic effects of long chain amides
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In 1H-NMR spectra of amids with long-chain aliphatic N-substituents one observes - despite of the free mobility of the aliphatic chain - splitting of the signals of the terminal methyl groups which is caused by the hindered rotation of the amide bond. - Keywords: Amides; Hindered rotation; 1H-NMR
- Budzikiewicz, Herbert,Vieth, Peter-Eric,Krueger, Uwe
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p. 825 - 840
(2007/10/02)
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