- Synthesis and biological evaluation of rigid polycyclic derivatives of the Diels-Alder adduct tricyclo[6.2.1.02,7]undeca-4,9-dien-3,6-dione
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Part of our research program concentrates on the discovery of new bioactive compounds prepared either by total synthesis or molecular transformation of compounds with bioactivity profiles. In this work we have focused our interest on chemical transformati
- Ito, Felicia Megumi,Petroni, Jacqueline Marques,De Lima, Denis Pires,Beatriz, Adilson,Marques, Maria Rita,De Moraes, Manoel Odorico,Costa-Lotufo, Leticia Veras,Montenegro, Raquel Carvalho,Magalhaes, Hemerson Iury Ferreira,Do O Pessoa, Claudia
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- Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors
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Abstract The coagulation factor Xa (FXa) plays a central role in the blood coagulation cascade. Recent studies have shown that FXa is a particularly attractive target for the development of oral antithrombotic agents. In view of the excellent pharmaceutical properties of 1,2-phenylenediamine-based FXa inhibitors and the reported structureeactivity relationship (SAR) analysis of FXa inhibitors, we designed and synthesized a series of 3,4-diaminobenzoyl-based FXa inhibitors. Intensive SAR studies on this new series led to the discovery of 3,4-dimethoxyl substituted compound 7b. 7b is a highly potent, selective, direct FXa inhibitor with excellent in vivo antithrombotic activity.
- Yang, Jiabin,Su, Guoqiang,Ren, Yu,Chen, Yang
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- Unusual C-H...π interactions in the structure of 3,4,5-trimethoxy-N-p-tolylbenzamide
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3,4,5-trimethoxy-N-p-tolylbenzamide, C17H19NO 4, (1), is a benzanilide derivative derived from p-toluidine and 3,4,5-trimethoxybenzoyl chloride. The structure was identified from spectroscopic and elemental analysis data a
- Saeed, Aamer,Simpson, Jim
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- Micellar Catalysis for Sustainable Hydroformylation
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It is here reported a fully sustainable and generally applicable protocol for the regioselective hydroformylation of terminal alkenes, using cheap commercially available catalysts and ligands, in mild reaction conditions (70 °C, 9 bar, 40 min). The process can take advantages from both micellar catalysis and microwave irradiation to obtain the linear aldehydes as the major or sole regioisomers in good to high yields. The substrate scope is largely explored as well as the application of hydroformylation in tandem with intramolecular hemiacetalization thus demonstrating the compatibility with a broad variety of functional groups. The reaction is efficient even in large scale and the catalyst and micellar water phase can be reused at least 5 times without any impact in reaction yields. The efficiency and sustainability of this protocol is strictly related to the in situ transformation of the aldehyde into the corresponding Bertagnini's salt that precipitates in the reaction mixture avoiding organic solvent mediated purification steps to obtain the final aldehydes as pure compounds.
- Calamante, Massimo,Dei, Filippo,Maramai, Samuele,Migliorini, Francesca,Petricci, Elena
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p. 2794 - 2806
(2021/05/03)
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- Tubulin inhibitors: Discovery of a new scaffold targeting extra-binding residues within the colchicine site through anchoring substituents properly adapted to their pocket by a semi-flexible linker
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Bis-hydrazides 13a-h were designed and synthesized as potential tubulin inhibitors selectively targeting the colchicine site between α- and β-tubulin subunits. The newly designed ring-B substituents were assisted at their ends by ‘anchor groups’ which are expected to exert binding interaction(s) with new additional amino acid residues in the colchicine site (beyond those amino acids previously reported to interact with reference inhibitors as CA-4 and colchicine). Conformational flexibility of bis-hydrazide linker assisted these ‘extra-binding’ properties through reliving ligands’ strains in the final ligand-receptor complexes. Compound 13f displayed the most promising computational and biological study results in the series: MM/GBSA binding energy of ?62.362 kcal/mol (extra-binding to Arg α:221, Thr β:353 & Lys β:254); 34% NCI-H522 cells’ death (at 10 μM), IC50 = 0.073 μM (MTT assay); significant cell cycle arrest at G2/M phase; 11.6% preG1 apoptosis induction and 83.1% in vitro tubulin inhibition (at concentration = IC50). Future researchers in bis-hydrazide tubulin inhibitors are advised to consider the 2-chloro-N-(4-substituted-phenyl)acetamide derivatives as compound 13f due to extra-binding properties of their ring B.
- AbdelHafez, El-Shimaa M. N.,Abdelhamid, Dalia,Aly, Omar M.,Maklad, Raed M.
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- Probing the effects of the number and positions of –OCH3 and –CN substituents on color tuning of Ir(III) complex derivatives through a joint computational and experimental study
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We performed a joint theoretical and experimental study on sixteen Ir(III) complexes bearing a similar molecular platform of bis(2-phenylbenzothiozolato-N,C2’) iridium(III) (acetylacetonate) by grafting – OCH3 group and/or – CN group on different positions of the C-related arene moiety of the C^N ligand (Cring). Our results reveal that the introduction of – CN renders an overall drop in the FMO energy levels while a reverse increase is observed for – OCH3. The ortho- and para-sites of the C-ring are more effective substitution positions to modulate the HOMO energy level due to the fact that the electronic density of HOMO mainly locates at them while the meta-site would induce a stronger impact on LUMO since the electronic density of LUMO mainly distributes over the position. Utilizing the synergistic effects of the substituents and the substituted positions, a wide color-tuning range from 479 nm to 637 nm was achieved, which covers nearly the whole window of visible spectrum. In particular, the tri-substituted Ir35mo4cn complex (λemmax=637 nm) may be a potential candidate for high efficiency red OLEDs materials due to its greatly enhanced absorption processes, relatively higher3MLCT (%), lower ΔES1–T1, enlarged separation between3MLCT/π–π* and3MC d–d states, and good hole and particle-transporting performances. Finally, six representative complexes were synthesized and their spectra were determined, which confirm the reliability of our computational strategy.
- Qin, Xiao,Li, Ming,Xiang, Minghui,Luo, Yi,Jiao, Yan,Yuan, Rongao,Wang, Ning,Lu, Zhiyun,Pu, Xumei
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p. 470 - 481
(2019/06/03)
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- Pd(II)-Catalyzed asymmetric oxidative annulation of N-alkoxyheteroaryl amides and 1,3-dienes
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The first Pd(II)-catalyzed asymmetric oxidative annulation of N-alkoxyaryl amides and 1,3-dienes is reported, which features particular applicability for quick assembly of different types of chiral heterocycles with high yields and enantioselectivities. A novel chiral pyridine-oxazoline bearing a methoxyl group at the C-5 position and a gem-dimethyl group on the oxazoline moiety was found to be crucial for conversion.
- Zhang, Tao,Shen, Hong-Cheng,Xu, Jia-Cheng,Fan, Tao,Han, Zhi-Yong,Gong, Liu-Zhu
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p. 2048 - 2051
(2019/03/29)
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- Synthesis, biological evaluation and molecular docking studies of novel trimethoxy-ring derivatives as BRD4 inhibitors
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Background: Bromodomain-containing protein 4 (BRD4) inhibitors synthesized with trimethoxy-ring refer to a new series of small molecular inhibitors. Currently, BRD4 offers the potential for research as a cancer therapeutic target. Based on previous studies, 17 trimethoxy-ring derivatives were designed as novel BRD4 inhibitors. Methods: All these new compounds were synthesized via the amide reaction. Their structures were identified by 1H NRM,13C NRM spectra and HRMS. In vitro antitumor activities of the new compounds were evaluated by MTT. Molecular docking studies were conducted to explain the binding interactions of these compounds with BRD4 protein. Results: A series of novel trimethoxy-ring derivatives were synthesized as BRD4 inhibitors and screened by testing their inhibition against HCT116, MCF-7, K562 and KMS-1 cell lines. Most of the newly synthesized compounds exhibited moderate-to-good inhibitory activity against HCT116, MCF-7, and K562 cell lines, whereas some showed inhibitory activity against the KMS-1 cell line. Conclusion: Compound 3g demonstrated the most potent anti-tumor activity against breast (MCF-7), leukemia (K562), multiple myeloma (KMS-1), and colon cancer (HCT116) cell lines.
- Yang, Yan,Yao, Zhiyi
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p. 1319 - 1328
(2018/11/01)
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- Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents
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A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.
- Semenova, Marina N.,Demchuk, Dmitry V.,Tsyganov, Dmitry V.,Chernysheva, Natalia B.,Samet, Alexander V.,Silyanova, Eugenia A.,Kislyi, Victor P.,Maksimenko, Anna S.,Varakutin, Alexander E.,Konyushkin, Leonid D.,Raihstat, Mikhail M.,Kiselyov, Alex S.,Semenov, Victor V.
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p. 700 - 721
(2019/01/03)
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- Benzoylsalicylic acid derivatives as defense activators in tobacco and Arabidopsis
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Systemic acquired resistance (SAR) is a long lasting inducible whole plant immunity often induced by either pathogens or chemical elicitors. Salicylic acid (SA) is a known SAR signal against a broad spectrum of pathogens in plants. In a recent study, we have reported that benzoylsalicylic acid (BzSA) is a SAR inducer in tobacco and Arabidopsis plants. Here, we have synthesized BzSA derivatives using SA and benzoyl chlorides of various moieties as substrates. The chemical structures of BzSA derivatives were elucidated using Infrared spectroscopy (IR), Nuclear magnetic spectroscopy (NMR) and High-resolution mass spectrometer (HRMS) analysis. The bioefficacy of BzSA derivatives in inducing defense response against tobacco mosaic virus (TMV) was investigated in tobacco and SA abolished transgenic NahG Arabidopsis plants. Interestingly, pre-treatment of local leaves of tobacco with BzSA derivatives enhanced the expression of SAR genes such as NPR1 [Non-expressor of pathogenesis-related (PR) genes 1], PR and other defense marker genes (HSR203, SIPK, WIPK) in systemic leaves. Pre-treatment of BzSA derivatives reduced the spread of TMV infection to uninfected areas by restricting lesion number and diameter both in local and systemic leaves of tobacco in a dose-dependent manner. Furthermore, pre-treatment of BzSA derivatives in local leaves of SA deficient Arabidopsis NahG plants induced SAR through AtPR1 and AtPR5 gene expression and reduced leaf necrosis and curling symptoms in systemic leaves as compared to BzSA. These results suggest that BzSA derivatives are potent SAR inducers against TMV in tobacco and Arabidopsis.
- Kamatham, Samuel,Pallu, Reddanna,Pasupulati, Anil Kumar,Singh, Surya Satyanarayana,Gudipalli, Padmaja
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p. 160 - 169
(2017/08/29)
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- Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate
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A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF-7, and HT-2
- Zhu, Panhu,Ye, Wenfeng,Li, Jiaming,Zhang, Yanchun,Huang, Weijun,Cheng, Mohan,Wang, Yujun,Zhang, Yang,Liu, Huicai,Zuo, Jian
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p. 443 - 455
(2017/04/03)
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- Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor
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Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7?nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35)?=?0.00) among 468 kinases/mutants at the concentration of 1?μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC50: 30?nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology.
- Liang, Qianmao,Chen, Yongfei,Yu, Kailin,Chen, Cheng,Zhang, Shouxiang,Wang, Aoli,Wang, Wei,Wu, Hong,Liu, Xiaochuan,Wang, Beilei,Wang, Li,Hu, Zhenquan,Wang, Wenchao,Ren, Tao,Zhang, Shanchun,Liu, Qingsong,Yun, Cai-Hong,Liu, Jing
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p. 107 - 125
(2017/03/21)
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- General C-H Arylation Strategy for the Synthesis of Tunable Visible Light-Emitting Benzo[a]imidazo[2,1,5-c,d]indolizine Fluorophores
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Herein we report the discovery of the benzo[a]imidazo[2,1,5-c,d]indolizine motif displaying tunable emission covering most of the visible spectrum. The polycyclic core is obtained from readily available amides via a chemoselective process involving Tf2O-mediated amide cyclodehydration, followed by intramolecular C-H arylation. Additionally, these fluorescent heterocycles are easily functionalized using electrophilic reagents, enabling divergent access to varied substitution. The effects of said substitution on the compounds' photophysical properties were rationalized by density functional theory calculations. For some compounds, emission wavelengths are directly correlated to the substituent's Hammett constants. Easily introduced nonconjugated reactive functional groups allow the labeling of biomolecules without modification of emissive properties. This work provides a straightforward platform for the synthesis of new moderately bright fluorescent dyes remarkable for their chemical stability, predictability, and unusually high excitation-emission differential.
- Lévesque, éric,Bechara, William S.,Constantineau-Forget, Léa,Pelletier, Guillaume,Rachel, Natalie M.,Pelletier, Joelle N.,Charette, André B.
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p. 5046 - 5067
(2017/05/24)
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- Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides
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A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resist
- Majellaro, Maria,Stefanachi, Angela,Tardia, Piero,Vicenti, Chiara,Boccarelli, Angelina,Pannunzio, Alessandra,Campanella, Federica,Coluccia, Mauro,Denora, Nunzio,Leonetti, Francesco,de Candia, Modesto,Altomare, Cosimo Damiano,Cellamare, Saverio
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p. 1380 - 1389
(2017/09/01)
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- Structure–Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers
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A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump.
- Teodori, Elisabetta,Dei, Silvia,Bartolucci, Gianluca,Perrone, Maria Grazia,Manetti, Dina,Romanelli, Maria Novella,Contino, Marialessandra,Colabufo, Nicola Antonio
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p. 1369 - 1379
(2017/09/01)
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- Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
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A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
- Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
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p. 40238 - 40249
(2016/05/24)
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- Identification of gallic acid based glycoconjugates as a novel tubulin polymerization inhibitors
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A novel class of gallic acid based glycoconjugates were designed and synthesized as potential anticancer agents. Among all the compounds screened, compound 2a showed potent anticancer activity against breast cancer cells. The latter resulted in tubulin po
- Upadhyaya, Kapil,Hamidullah,Singh, Kartikey,Arun, Ashutosh,Shukla, Mahendra,Srivastava, Neetika,Ashraf, Raghib,Sharma, Abhisheak,Mahar, Rohit,Shukla, Sanjeev K.,Sarkar, Jayanta,Ramachandran, Ravishankar,Lal, Jawahar,Konwar, Rituraj,Tripathi, Rama Pati
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p. 1338 - 1358
(2016/02/03)
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- Copper-Catalyzed Divergent Trifluoromethylation/Cyclization of Unactivated Alkenes
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Most of the precedent copper-catalyzed trifluoromethylation reactions of unactivated alkenes concern terminal alkenes, and these processes are terminated in elimination, or nucleophilic addition, or semipinacol rearrangement, or C-H bond functionalization steps. In this study, we develop a trifluoromethylation method for both unactivated terminal and internal alkenes to enable divergent late-stage radical cyclization and achieve high molecular complexity. These cyclizations are well consistent with Baldwin's rule. Furthermore, a kinetic isotope effect (KIE) study and control reactions were conducted, and a plausible mechanism is proposed.
- Zheng, Jing,Deng, Ziyang,Zhang, Yan,Cui, Sunliang
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supporting information
p. 746 - 751
(2016/03/09)
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- Modulating lipophilicity of rohitukine via prodrug approach: Preparation, characterization, and in vitro enzymatic hydrolysis in biorelevant media
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Rohitukine is a medicinally important natural product which has inspired the discovery of two anticancer clinical candidates. Rohitukine is highly hydrophilic in nature which hampers its oral bioavailability. Thus, herein our objective was to improve the drug-like properties of rohitukine via prodrug-strategy. Various ester prodrugs were synthesized and studied for solubility, lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. All prodrugs displayed lower aqueous solubility and improved lipophilicity compared with rohitukine, which was in accordance with the criteria of compounds in drug-discovery. The stability of synthesized prodrugs was evaluated in buffers at different pH, SGF, SIF, rat plasma and in esterase enzyme. The rate of hydrolysis in all incubation media was dependent primarily on the acyl promoieties. Hexanoyl ester prodrug of rohitukine, 3d, was stable under chemical conditions; however it was completely hydrolyzed to rohitukine, in plasma and in esterase in 4?h. Hexanoate ester 3d appeared to be the most promising prodrug as it remained intact at gastric/intestinal pH and was completely transformed to the parent compound in plasma as desired for an ideal prodrug. The data presented herein, will help in designing prodrugs with desired physicochemical properties in future in structurally similar chemotypes.
- Kumar, Vikas,Bharate, Sonali S.,Vishwakarma, Ram A.
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p. 203 - 211
(2016/07/25)
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- Synthesis and biological evaluation of 1-(2-aminophenyl)-3-arylurea derivatives as potential EphA2 and HDAC dual inhibitors
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A series of 1-(2-aminophenyl)-3-arylurea novel derivatives were synthesized and evaluated against Ephrin type-A receptor 2 (EphA2) and histone deacetylases (HDACs) kinase. Most of the compounds exhibited inhibitory activity against EphA2 and HDAC. The antiproliferative activities were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (thiazolyl blue, tetrazolium blue) against the human cancer cell lines HCT116, K562 and MCF7. Compounds 5a and b showed the most potent inhibitory activity against EphA2 and HDAC. However, compound 5b exhibited higher potency against HCT116 (IC50=5.29 μM) and MCF7 (IC50=7.42 μM). 1-(2-Aminophenyl)-3-arylurea analogues may serve as new EphA2-HDAC dual inhibitors.
- Zhu, Yong,Ran, Ting,Chen, Xin,Niu, Jiaqi,Zhao, Shuang,Lu, Tao,Tang, Weifang
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p. 1136 - 1141
(2016/08/11)
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- An alternate method for the synthesis of 2-aryl/alkyl-5-bromo-7-methoxy benzofurans; application to the synthesis of Egonol, Homoegonol, and analogs via Heck reaction
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We herein report the general, versatile, and convenient method for the synthesis of 2-arly/alkyl-5-bromo-7-methoxy benzofurans from easily available o-Vanillin in five steps. These benzofurans was successfully converted into biological active natural products Egonol, Homoegonol, and analogous on applying Heck reaction using ethyl/methyl acrylate in the presence of palladium catalyst.
- More, Kishor R.,Mali
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p. 7496 - 7504
(2016/11/11)
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- Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness
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In a recent investigation carried out on a panel of trimethoxybenzanilides, we showed that the formation of an intramolecular hydrogen bond is a key element for tuning P-gp inhibitory activity. In this study, we designed new structurally simplified trimet
- Stefanachi, Angela,Mangiatordi, Giuseppe Felice,Tardia, Piero,Alberga, Domenico,Leonetti, Francesco,Niso, Mauro,Colabufo, Nicola Antonio,Adamo, Carlo,Nicolotti, Orazio,Cellamare, Saverio
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p. 820 - 831
(2016/11/11)
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- Benzimidazole compound and use thereof
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The invention provides a benzimidazole compound and an application thereof. The compound has a structure shown in a formula (I). The compound is obtained by compound modification (namely respectively introducing R1 and R2) in site 1 and/or site 2 of 2-(3, 4, 5-trihydroxyl phenyl)-1H-benzimidazole. The benzimidazole compound provided by the invention can simulate Bim and competitively bind and antagonize Bcl-2/Mcl-1 protein in vitro and in cells so as to induce cell apoptosis, so that the benzimidazole compound is an apoptosis inducer and an anti-tumor compound with high activity.
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Paragraph 0069-0070
(2017/04/19)
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- Stereoselective synthesis of cis-2,6-disubstituted morpholines and 1,4-oxathianes by intramolecular reductive etherification of 1,5-diketones
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A simple and efficient, Lewis acid catalysed reductive etherification strategy for the stereoselective synthesis of cis-2,6- disubstituted morpholines and 1,4-oxathianes starting from readily available 1,5-diketones has been developed. The strategy is used in the total synthesis of morpholine-based natural products (±)-chelonin A and formal total synthesis of (±)-chelonin C.
- Gharpure, Santosh J.,Anuradha, Dandela,Prasad, Jonnalagadda V. K.,Rao, Pidugu Srinivasa
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supporting information
p. 86 - 90
(2015/01/16)
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- Design and synthesis of N-methylpyrimidone derivatives as HIV-1 integrase inhibitors
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A series of novel β-diketo derivatives which combined the virtues of dihydroxypyrimidine carboxamide derived from the evolution of DKA and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and
- Wang, Yujie,Rong, Jie,Zhang, Bin,Hu, Liming,Wang, Xiaoli,Zeng, Chengchu
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p. 735 - 741
(2015/02/19)
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- Novel Mcl-1/Bcl-2 dual inhibitors created by the structure-based hybridization of drug-divided building blocks and a fragment deconstructed from a known two-face BH3 mimetic
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We have previously reported a small-molecule two-face Bim BH3 mimetic, 2,3-dihydroxy-6-(4-isopropylphenylthio)anthracene-9,10-dione (1). Herein, we linked a polyphenol fragment, which was deconstructed from compound 1, with a drug-derived building block g
- Zhang, Zhichao,Su, Pengchen,Li, Xiangqian,Song, Ting,Chai, Gaobo,Yu, Xiaoyan,Zhang, Keren
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- Design, synthesis and cytotoxic evaluation of novel imatinib amide derivatives that target Abl kinase
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Novel imatinib amide derivatives (a1-28, b1-9) were synthesized and evaluated for their biological activities. All compounds were characterized by 1H NMR, MS and elemental analysis. Among all the derivatives, compounds a4, a10, a21, b1 and b2 displayed the most significant ability of inhibiting K562 cell proliferation with the IC50 values of 0.67, 0.66, 0.65, 0.59 and 0.62 μM, respectively, indicating that these compounds were potent inhibitors of Bcr-Abl in leukemic K562 cells, comparable to the reference compound imatinib. Molecular docking study was performed to position compounds a21 and b1 into the active site of Abl to determine the probable binding modes
- Yao, Ri-Sheng,Guan, Qiu-Xiang,Lu, Xiao-Qin,Ruan, Ban-Feng
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- Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity
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A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 μM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.
- Shi, Jing Bo,Tang, Wen Jian,Qi, Xing Bao,Li, Rong,Liu, Xin Hua
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p. 889 - 896
(2015/06/02)
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- Synthesis, biological evaluation, and molecular docking studies of novel 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as potential tubulin polymerization inhibitors
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A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity.
- Wang, Yan-Ting,Qin, Ya-Juan,Yang, Na,Zhang, Ya-Liang,Liu, Chang-Hong,Zhu, Hai-Liang
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p. 125 - 137
(2015/06/22)
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- Biological evaluation of halogenated thioureas as cholinesterases inhibitors against alzheimer's disease & molecular modeling studies
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Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition is thought to be an encouraging approach towards the therapy of Alzheimer's disease (AD). The current paper targets to give a concise information of mono and dihalo- substituted thioureas similarity with anti-AD potential. The present results represent evaluation of cholinesterase inhibitory potential for halogenated thioureas derivatives. Compound 1t was constituted to be highly potent inhibitor with Ki value 0.12 ± 0.05 μM against AChE, while 1b was most the active inhibitor for BChE with Ki value of 0.03 ± 0.001 μM. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the plausible binding modes of synthesized compounds.
- Iqbal, Jamshed,Zaib, Sumera,Saeed, Aamer,Muddassar, Muhammad
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p. 488 - 494
(2015/06/22)
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- Sulfonamide and urea-based anions chemosensors
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The detection of anions has attracted considerable interest because of their importance in various physiological processes. In this study, two sulfonamide and urea-based compounds (1a and 1b) were successfully developed and their spectroscopic and anion recognition properties were fully investigated. These results showed that: (1) compounds showed high selectivity towards cyanide and fluoride ions in CH3CN; (2) compounds only exhibited a large change in fluorescence in the presence of cyanide ions in CH3CN-H2O (95:5, v/v); and (3) compound 1b could act as a gel in dimethyl sulfoxide that transforms into a homogeneous solution upon exposure to cyanide ions. This research suggests that sulfonamide and urea can act as hydrogen-bond donors and provides an alternative approach to the design of novel anion chemosensors.
- Hu, Fang,Cao, Meijiao,Huang, Juanyun,Chen, Zhao,Wu, Di,Xu, Zhiqiang,Liu, Sheng Hua,Yin, Jun
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p. 108 - 115
(2015/04/27)
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- Synthesis and antibacterial activity of 4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-yl-methanone derivatives and its intermediates
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Encouraged by the interesting biological activities associated with benzo[b]furan derivatives, we report here the synthesis, spectroscopic identification and antibacterial activity of benzo[b]furan derivatives (6a-6g) prepared from commercially available,
- Krishna Reddy,Venkateswara Rao,Bhaskar Reddy,Ram,Balram
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p. 2245 - 2248
(2015/12/01)
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- Synthesis, evaluation, and molecular docking studies of cycloalkyl/aryl-3,4,5-trimethylgallates as potent non-ulcerogenic and gastroprotective anti-inflammatory agents
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In our effort to identify the effective gastric sparing and protective anti-inflammatory agents, a series of cycloalkyl/aryl-3,4,5-trimethylgallates were synthesized and characterized. The physicochemical properties were studied to assess the lipophilicity and chemical stability. Subsequently, the compounds were evaluated for their anti-inflammatory activity and effect on gastric mucosa by most active compounds. All the compounds exhibited promising anti-inflammatory activity. In particular, 4a, 4b, 4g, and 4h emerged as the most active compounds in the series. The results of gastric mucosal studies and biochemical estimations suggested that these compounds are non-ulcerogenic and gastroprotective. The molecular docking analysis was performed to understand the binding interactions of these compounds to cyclooxygenase isoenzyme (COX-1 and COX-2). The results from this investigation suggests cycloalkyl/aryl-3,4,5- trimethylgallates as potent safer gastrosparing and protective anti-inflammatory agents.
- Dhingra, Mamta Sachdeva,Deb, Pran Kishore,Chadha, Renu,Singh, Tejvir,Karan, Maninder
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- Design, synthesis and preliminary bioactivity studies of 1,2-dihydrobenzo[d]isothiazol-3-one-1,1-dioxide hydroxamic acid derivatives as novel histone deacetylase inhibitors
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Histone deacetylase (HDAC) is a clinically validated target for antitumor therapy. In order to increase HDAC inhibition and efficiency, we developed a novel series of saccharin hydroxamic acids as potent HDAC inhibitors. Among them, compounds 11e, 11m, 11
- Han, Leiqiang,Wang, Lei,Hou, Xuben,Fu, Huansheng,Song, Weiguo,Tang, Weiping,Fang, Hao
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p. 1529 - 1538
(2014/03/21)
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- Effect of alkoxy terminal chain length on mesomorphism of 1,6-disubstituted pyrene-based hexacatenar liquid crystals: Columnar phase control
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Synthesis and mesophase-transition behaviors of six 1,6-disubstituted pyrene-based hexacatenar liquid crystals 1n (n=8-18) are reported here. They were synthesized by the Sonogashira coupling between 1,6-diethynylpyrene and 2-bromothiophene bearing a trialkoxybenzoyl group. The phase-transition behavior was studied by differential scanning calorimetry and polarized optical microscopy; a few mesophase progressions, I-Col/I-X-Col and Col-Sm, were observed, where X was an optically isotropic but unidentified phase. The structures of Colr, Colh, and Sm phases were analyzed by the X-ray crystallography, and the effect of the terminal alkoxy chain length on the mesomorphism was evaluated.
- Hirose, Takuji,Takai, Hiroaki,Watabe, Mizuki,Minamikawa, Hiroyuki,Tachikawa, Tatsuya,Kodama, Koichi,Yasutake, Mikio
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p. 5100 - 5108
(2014/07/08)
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- Effect of alkoxy terminal chain length on mesomorphism of 1,6-disubstituted pyrene-based hexacatenar liquid crystals: Columnar phase control
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Synthesis and mesophase-transition behaviors of six 1,6-disubstituted pyrene-based hexacatenar liquid crystals 1n(n=8-18) are reported here. They were synthesized by the Sonogashira coupling between 1,6-diethynylpyrene and 2-bromothiophene bearing a trialkoxybenzoyl group. The phase-transition behavior was studied by differential scanning calorimetry and polarized optical microscopy; a few mesophase progressions, I-Col/I-X-Col and Col-Sm, were observed, where X was an optically isotropic but unidentified phase. The structures of Colr, Colh, and Sm phases were analyzed by the X-ray crystallography, and the effect of the terminal alkoxy chain length on the mesomorphism was evaluated.
- Hirose, Takuji,Takai, Hiroaki,Watabe, Mizuki,Minamikawa, Hiroyuki,Tachikawa, Tatsuya,Kodama, Koichi,Yasutake, Mikio
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p. 5100 - 5108
(2014/12/10)
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- Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N, N -bis(alkanol)amine aryl esters
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As a continuation of our research on potent and efficacious P-gp-dependent multidrug resistance (MDR) reversers, several new N,N-bis(alkanol)amine aryl esters were designed and synthesized, varying the aromatic moieties or the length of the methylenic chain. The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay, where most of the new compounds were shown to be active. In particular the asymmetrical compounds, characterized by two linkers of different length, generally showed fairly high activities as MDR reversers. Some selected compounds (isomers 15-17) were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) on the K562/DOX cell line. The results of both pharmacological assays indicate that compounds 16 (GDE6) and 17 (GDE19) could be interesting leads for the development of new P-gp dependent MDR modulators.
- Dei, Silvia,Coronnello, Marcella,Floriddia, Elisa,Bartolucci, Gianluca,Bellucci, Cristina,Guandalini, Luca,Manetti, Dina,Romanelli, Maria Novella,Salerno, Milena,Bello, Ivan,Mini, Enrico,Teodori, Elisabetta
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p. 398 - 412
(2015/01/08)
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- Dynamic mirror-symmetry breaking in bicontinuous cubic phases
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Chiral segregation of enantiomers or chiral conformers of achiral molecules during self-assembly in well-ordered crystalline superstructures has fascinated chemists since Pasteur. Here we report spontaneous mirror-symmetry breaking in cubic phases formed
- Dressel, Christian,Liu, Feng,Prehm, Marko,Zeng, Xiangbing,Ungar, Goran,Tschierske, Carsten
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supporting information
p. 13115 - 13120
(2015/01/16)
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- N,N+hu 1 +l SUBSTITUTED PIPERAZINES HAVING COMBINED ANTIAGGREGANT, ANTICOAGULANT AND VASODILATORY ACTIVITY, AND METHOD FOR PRODUCING SAME
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The invention relates to derivatives of N,N′-substituted piperazines of the general formula (I): where R1 and R2 denote linear or branched (C1-C4)alkyl, linear or branched (C1-C4)alkoxy, CH
- -
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Paragraph 0061; 0062; 0063
(2013/10/22)
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- Factors influencing the antifolate activity of synthetic tea-derived catechins
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Novel tea catechin derivatives have been synthesized, and a structure-activity study, related to the capacity of these and other polyphenols to bind dihydrofolate reductase (DHFR), has been performed. The data showed an effective binding between all molecules and the free enzyme, and the dissociation constants of the synthetic compounds and of the natural analogues were on the same order. Polyphenols with a catechin configuration were better DHFR inhibitors than those with an epicatechin configuration. Antiproliferative activity was also studied in cultured tumour cells, and the data showed that the activity of the novel derivatives was higher in catechin isomers. Derivatives with a hydroxyl group para on the ester-bonded gallate moiety presented a high in vitro binding to DHFR, but exhibited transport problems in cell culture due to ionization at physiologic pHs. The impact of the binding of catechins to serum albumin on their biological activity was also evaluated. The information provided in this study could be important for the design of novel medicinal active compounds derived from tea catechins. The data suggest that changes in their structure to avoid serum albumin interactions and to facilitate plasmatic membrane transport are essential for the intracellular functions of catechins.
- Saez-Ayala, Magali,Fernandez-Perez, Maria Piedad,Chazarra, Soledad,McHedlishvili, Nani,Tarraga-Tomas, Alberto,Rodriguez-Lopez, Jose Neptuno
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p. 8319 - 8341
(2013/08/23)
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- Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents
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A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
- Li, Yang-Biao,Zhao, Wu-Li,Wang, Yan-Xiang,Zhang, Cai-Xia,Jiang, Jian-Dong,Bi, Chong-Wen,Tang, Sheng,Chen, Ru-Xian,Shao, Rong-Guang,Song, Dan-Qing
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p. 463 - 472
(2013/10/01)
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- Metal-free aryltrifluoromethylation of activated alkenes
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Metal-free: The first metal-free aryltrifluoromethylation of activated alkenes has been developed. With this method, trifluoromethylated isoquinolinediones, spirobicycles, oxindoles, and α-aryl-β- trifluoromethylamides were obtained with high control of the regioselectivity. Copyright
- Kong, Wangqing,Casimiro, Maria,Fuentes, Noelia,Merino, Estibaliz,Nevado, Cristina
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supporting information
p. 13086 - 13090
(2014/01/06)
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- Facile synthesis and herbicidal evaluation of 2-Aryl-4H-3, 1-benzoxazin-4-ones
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The present work deals with the synthesis of 4H-3,1-benzoxazin-4-ones carrying an aryl functional group at position-2. Synthesized compounds tested for herbicidal activity at three different doses (500 μg/mL, 50 μg/mL and 5μg/mL). Most of the compounds exhibited significant herbicidal activity against Lemna aequinocitalis welv. at higher dose (500 μg/mL). Among the tested compounds 2-phenyl-4H-3,1-benzoxazin-4-one (3a) and 2-(3-chlorophenyl)- 4H-3,1-benzoxazin-4- one (3l) completely inhibited the plant growth at 500 and 50 μg/mL concentrations. All the synthetic compounds were characterized by FT-IR, 1H NMR, EI-MS and elemental analysis.
- Hussain, Zaib,Khan, Zulfiqar Ali,Naqvi, Syed Ali Raza,Shahzad, Sohail Anjum,Yar, Muhammad,Hussain, Abdullah Ijaz,Chatha, Shahzad Ali Shahid,Mahmood, Nasir,Khan, Khalid Mohammed
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p. 449 - 455
(2013/07/27)
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- Synthesis and solid-state polymerization of butadiyne derivatives with Trialkoxyphenylurethane groups
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3,4,5-Trialkoxyphenyl isocyanate derivatives, in which alkoxy was dodecyloxy or methoxy, reacted with 4,6- decadiyn-1,10-diol and 5,7-dodecadiyn-1,12-diol, and four butadiyne derivatives with (N-trialkoxyphenyl)urethane groups were successfully synthesized. Their solid-state polymerization stimulated by UV or ￡-ray irradiation was investigated. All monomers in crystals were found to be polymerizable. However, conversion was different depending on the compounds. The derivatives from 5,7-dodecadiyn-1,12-diol showed better conversion, suggesting that they have more favorable monomer arrangement for the solid-state polymerization. Polymers of dodecyloxy derivatives could be partially dissolved in chloroform and they showed solvatochromism when hexane was added to the solution. As was expected from the structure of tridodecyloxyphenyl groups introduced, dodecyloxy derivatives gave organogels in various organic solvents in the concentration less than 2wt%. However, these gels could not be polymerized by UV irradiation, and the monomer alignment was found to be different between crystalline and gel states.
- Takahashi, Rintaro,Nunokawa, Tatsuya,Shibuya, Tadahiro,Tomita, Ryohei,Tatewaki, Yoko,Okada, Shuji,Kimura, Tatsumi,Shimada, Satoru,Matsuda, Hiro
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experimental part
p. 236 - 244
(2012/04/23)
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- Acylthiourea, acylurea, and acylguanidine derivatives with potent Hedgehog inhibiting activity
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The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC50 values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.
- Solinas, Antonio,Faure, Hélène,Roudaut, Hermine,Traiffort, Elisabeth,Schoenfelder, Angèle,Mann, André,Manetti, Fabrizio,Taddei, Maurizio,Ruat, Martial
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body text
p. 1559 - 1571
(2012/04/17)
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- Gallic acid based steroidal phenstatin analogues for selective targeting of breast cancer cells through inhibiting tubulin polymerization
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Phenstatin analogues were synthesized on steroidal framework, for selective targeting of breast cancer cells. These analogues were evaluated for anticancer efficacy against breast cancer cell lines. Analogues 12 and 19 exhibited significant anticancer activity against MCF-7, hormone dependent breast cancer cell line. While analogues 10-14 exhibited significant anticancer activity against MDA-MB-231, hormone independent breast cancer cell line. Compound 10 showed significant oestrogen antagonistic activities with low agonistic activity in in vivo rat model. These analogues also retain tubulin polymerization inhibition activity. The most active analogue 10 was found to be non-toxic in Swiss albino mice up to 300 mg/kg dose. Gallic acid based phenstatin analogues may further be optimized as selective anti-breast cancer agents.
- Parihar, Swati,Gupta, Atul,Chaturvedi, Amit K.,Agarwal, Jyoti,Luqman, Suaib,Changkija, Bendangla,Manohar, Murli,Chanda, Debabrata,Chanotiya,Shanker, Karuna,Dwivedi, Anila,Konwar, Rituraj,Negi, Arvind S.
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experimental part
p. 878 - 886
(2012/07/14)
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- Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists
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The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pKi values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.
- Wijtmans, Maikel,Maussang, David,Sirci, Francesco,Scholten, Danny J.,Canals, Meritxell,Muji?-Deli?, Azra,Chong, Milagros,Chatalic, Kristell L.S.,Custers, Hans,Janssen, Elwin,De Graaf, Chris,Smit, Martine J.,De Esch, Iwan J.P.,Leurs, Rob
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supporting information; experimental part
p. 184 - 192
(2012/07/14)
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- Synthesis of novel 3,4-diaryl-5-aminopyrazoles as potential kinase inhibitors
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Synthesis of a diverse series of novel 3,4-diaryl-5-aminopyrazoles as candidates in the development of new protein kinase inhibitors is reported for the first time. In the course of a wider study into bisindolylmaleimide (BIM) derivatives, we examined a novel 5-aminopyrazole heterocyclic moiety as a structural analogue of the highly potent VEGF-R2/3 inhibitor pyrrole-2-one (8). The versatile nature of this pharmacophore allows considerable scope for derivatisation and hence exploration of structure activity relationships. Consequently, a variety of structural modifications were used in order to diversify the aminopyrazole ring substituents. Bicyclic derivatives of the parent aminopyrazoles (11, 12) were also synthesised as a means of probing the kinase active site, leading to formation of complex planar pyrimidine moieties. This work provides the framework for new explorations into kinase inhibition and critical investigations into selectivity of inhibitory activity.
- Pierce, Larry T.,Cahill, Michael M.,McCarthy, Florence O.
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experimental part
p. 4601 - 4611
(2011/07/08)
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- Synthesis and biological evaluation of phenstatin metabolites
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Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed the formation of nine main metabolites. The structures of eight of these metabolites have been now confirmed by synthesis and their biological properties have been reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, a simple multigram scale preparation of phenstatin. Synthesized metabolites and related compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell line panel, and for their effect on microtubule assembly. Metabolite 23 (2′-methoxyphenstatin) exhibited the most potent in vitro cytotoxic activity: inhibition of the growth of K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, and HS 578T cell lines with GI50 values 50 = 3.2 μM vs 15.0 μM) and induced G2/M arrest in murine leukemia DA1-3b cells. The identification of this active metabolite led to the design and synthesis of analogs with potent in vitro cytotoxicity and inhibition of microtubule assembly.
- Ghinet, Alina,Rigo, Beno?t,Hénichart, Jean-Pierre,Le Broc-Ryckewaert, Delphine,Pommery, Jean,Pommery, Nicole,Thuru, Xavier,Quesnel, Bruno,Gautret, Philippe
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supporting information; experimental part
p. 6042 - 6054
(2011/11/29)
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- Imidazolone-amide bridges and their effects on tubulin polymerization in cis-locked vinylogous combretastatin-A4 analogues: Synthesis and biological evaluation
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A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone-amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3′-NH2-4′-OCH 3, 4′-CH3 and 3′-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds' structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.
- Li, Yao-Wu,Liu, Jia,Liu, Na,Shi, Duo,Zhou, Xiao-Tian,Lv, Jia-Guo,Zhu, Ju,Zheng, Can-Hui,Zhou, You-Jun
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scheme or table
p. 3579 - 3584
(2011/07/09)
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