- Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
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Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
- Greene, Thomas F.,Wang, Shu,Greene, Lisa M.,Nathwani, Seema M.,Pollock, Jade K.,Malebari, Azizah M.,McCabe, Thomas,Twamley, Brendan,OBoyle, Niamh M.,Zisterer, Daniela M.,Meegan, Mary J.
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- Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
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A series of new molecules have been designed based on a hybridization approach by combining the arylcinnamide and combretastatin pharmacophores. These were synthesized and evaluated for their cytotoxic activity, effect on inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant cytotoxic activity against some representative human cancer cell lines and two of the conjugates 6i and 6p displayed potent cytotoxicity with GI50 values of 56 nM and 31 nM respectively against the human breast cancer cell line (MCF-7). SAR studies revealed that 3,4-substitution on the phenyl ring of the cinnamide moiety is beneficial for enhanced cytotoxicity. Moreover, G2/M cell cycle arrest was induced by these conjugates (6i and 6p) apart from tubulin polymerization inhibition (IC50 of 1.97 μM and 1.05 μM respectively). Further, mitochondrial membrane potential, Annexin V-FITC and caspase-9 activation assays suggested that these conjugates induce cell death by apoptosis. Docking studies revealed that these conjugates interact and bind at the colchicine binding site of the tubulin.
- Kamal, Ahmed,Bajee, Shaik,Lakshma Nayak, Vadithe,Venkata Subba Rao, Ayinampudi,Nagaraju, Burri,Ratna Reddy, Challa,Jeevak Sopanrao, Kapure,Alarifi, Abdullah
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supporting information
p. 2957 - 2964
(2016/06/06)
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- COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
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The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0174; 0175
(2015/05/05)
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- COMPOUND OF CAMPTOTHECIN AND PREPARATION AND USE THEREOF
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The present disclosure relates to a compound of formula I, a pharmaceutical composition thereof and the use thereof as an anti-tumor drug.
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Paragraph 0232; 0233
(2015/06/24)
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- Design and Synthesis of Aminostilbene-Arylpropenones as Tubulin Polymerization Inhibitors
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A series of aminostilbene - arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50% growth inhibition (GI50) values in the range from 50 value of 50) values ranging from 0.011 to 8.56μM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79μM. Moreover, dot-blot analysis of cyclinB1 demonstrated that some of the congeners strongly induced cyclinB1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
- Kamal, Ahmed,Kumar, G. Bharath,Polepalli, Sowjanya,Shaik, Anver Basha,Reddy, Vangala Santhosh,Reddy, M. Kashi,Reddy, Ch. Ratna,Mahesh, Rasala,Kapure, Jeevak Sopanrao,Jain, Nishant
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p. 2565 - 2579
(2015/08/24)
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- Synthesis and antitumor activity of feruloyl and caffeoyl derivatives This paper is dedicated to Prof. Wei-xiao Hu for his lifelong commitment to mentoring graduate students
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We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg-1.
- Chen, Hui-Zhen,Chen, You-Bao,Lv, Ya-Ping,Zeng, Fang,Zhang, Juan,Zhou, Yong-Lie,Li, Han-Bing,Chen, Li-Fei,Zhou, Bin-Jie,Gao, Jian-Rong,Xia, Chun-Nian
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supporting information
p. 4367 - 4371
(2015/02/06)
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- Fluorinated cannabinoid CB2 receptor ligands: Synthesis and in vitro binding characteristics of 2-oxoquinoline derivatives
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Cannabinoid receptor 2 (CB2) plays an important role in human physiology and the pathophysiology of different diseases, including neuroinflammation, neurodegeneration, and cancer. Several classes of CB2 receptor ligands, including 2-oxoquinoline derivatives, have been previously reported. We report the synthesis and results of in vitro receptor binding of a focused library of new fluorinated 2-oxoquinoline CB2 ligands. Twelve compounds, 13-16 18, 19, 21-24, 27, and 28 were synthesized in good yields in multiple steps. Human U87 glioma cells expressing either hCB1 (control) or hCB2 were generated via lentiviral transduction. In vitro competitive binding assay was performed using [3H]CP-55,940 in U87hCB1 and U87hCB2 cells. Inhibition constant (Ki) values of compounds 13-16, 18, 19, 21-24, 27, and 28 for CB2 were >10,000, 2.8, 5.0, 2.4, 22, 0.8, 1.4, >10,000, 486, 58, 620, and 2400 nM, respectively, and those for CB1 were >10,000 nM. Preliminary in vitro results suggest that six of these compounds may be useful for therapy of neuropathic pain, neuroinflammatory diseases and immune disorders. In addition, compound 19, with its subnanomolar Ki value, could be radiolabeled with 18F and explored for PET imaging of CB2 expression.
- Turkman, Nashaat,Shavrin, Aleksander,Ivanov, Roman A.,Rabinovich, Brian,Volgin, Andrei,Gelovani, Juri G.,Alauddin, Mian M.
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supporting information; experimental part
p. 5698 - 5707
(2011/10/13)
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- Synthesis and in vitro biological evaluation of carbon-11-labeled quinoline derivatives as new candidate PET radioligands for cannabinoid CB2 receptor imaging
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Cannabinoids have been recently proposed as a new family of potential antitumor agents, and cannabinoid receptor 2 (CB2) is believed to be over-expressed in tumor cells. This study was designed to develop new radioligands for imaging of CB2 receptor in ca
- Gao, Mingzhang,Wang, Min,Miller, Kathy D.,Hutchins, Gary D.,Zheng, Qi-Huang
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experimental part
p. 2099 - 2106
(2010/06/12)
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- Synthesis and evaluation of 3-aroylindoles as anticancer agents: Metabolite approach
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BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterismprinciple.Metabolites of 2, proposed from in vitrohumanmicrosome studies,were synthesized, leading to the identification of metabolite-der
- Wu, Yu-Shan,Coumar, Mohane Selvaraj,Chang, Jang-Yang,Sun, Hsu-Yi,Kuo, Fu-Ming,Kuo, Ching-Chuan,Chen, Ying-Jun,Chang, Chi-Yen,Hsiao, Chia-Ling,Liou, Jing-Ping,Chen, Ching-Ping,Yao, Hsien-Tsung,Chiang, Yi-Kun,Tan, Uan-Kang,Chen, Chiung-Tong,Chu, Chang-Ying,Wu, Su-Ying,Yeh, Teng-Kuang,Lin, Chin-Yu,Hsieh, Hsing-Pang
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scheme or table
p. 4941 - 4945
(2010/03/02)
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- Synthesis and biological evaluation of new disubstituted analogues of 6-methoxy-3-(3′,4′,5′-trimethoxybenzoyl)-1H-indole (BPR0L075), as potential antivascular agents
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6-Methoxy-3-(3′,4′,5′-trimethoxybenzoyl)-1H-indole (BPR0L075) (1) is a potent inhibitor of tubulin polymerization which exhibits both in vitro and in vivo activities against a broad spectrum of solid tumors. This compound was designed as a heterocyclic an
- Ty, Nancy,Dupeyre, Gregory,Chabot, Guy G.,Seguin, Johanne,Tillequin, Francois,Scherman, Daniel,Michel, Sylvie,Cachet, Xavier
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p. 7494 - 7503
(2008/12/23)
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- Synthesis and SAR studies of 2-oxoquinoline derivatives as CB2 receptor inverse agonists
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The highly CB2 selective cannabinoid receptor inverse agonist, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid N-benzo[1,3]dioxol-5-ylmethyl)amide (JTE-907; 9b), served as the lead compound for investigating the structure-activity relat
- Raitio, Katri H.,Savinainen, Juha R.,Veps?l?inen, Jouko,Laitinen, Jarmo T.,Poso, Antti,J?rvinen, Tomi,Nevalainen, Tapio
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p. 2022 - 2027
(2007/10/03)
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- 2-oxoquinoline compounds and medicinal uses thereof
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A 2-oxoquinoline compound or its pharmaceutically acceptable salt of general formula [I]: ? (wherein each symbol in the formula is as determined in the description), and its pharmaceutical use. The compound [I] of the present invention and its pharmaceutically acceptable salts selectively act on cannabinoid receptors, particularly on peripheral type cannabinoid receptors, and have fewer side effects on the central nervous system, having great immunosuppressive action, anti-inflammatory action or antiallergic action. Therefore, these compounds are useful as cannabinoid receptors (particularly peripheral type cannabinoid receptors) modulator, immunosuppressants, anti-inflammatory agents, and antiallergic agents.
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- Compounds and pharmaceutical use thereof
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PCT No. PCT/JP97/00291 Sec. 371 Date Aug. 6, 1998 Sec. 102(e) Date Aug. 6, 1998 PCT Filed Feb. 6, 1997 PCT Pub. No. WO97/29079 PCT Pub. Date Aug. 14, 1997The compounds of the formula (I) wherein each symbol is as defined in the specification, pharmaceutically acceptable salts thereof and pharmaceutical use thereof. The Compound (I) and pharmaceutically acceptable salts thereof of the present invention selectively act on cannabinoid receptors, particularly peripheral receptors, cause less side effects on the central system, and have superior immunoregulating action, antiinflammatory action, antiallergic action and therapeutic effect on nephritis. Therefore, they are useful as cannabinoid receptor, particularly peripheral cannabinoid receptor activators and antagonists, immunoregulators, therapeutic agents for autoimmune diseases, antiinflammatory agents, antiallergic agents and therapeutic agents for nephritis.
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- Regioselectivity of the nitration of phenol by acetyl nitrate adsorbed on silica gel
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The reaction of phenol with acetyl nitrate in chloroform gives nitrophenol with an ortho/para ratio of 1.8. This ratio increase to 13.3 when the reaction was carried out with acetyl nitrate pre-adsorbed on dry silica gel. Silica may be acting as a template to bring phenol close to acetyl nitrate by hydrogen bonds forming a ternary complex, which undergoes a six- center rearrangement to o-nitrophenol. The formation of this ternary complex is evaluated by ab initio molecular orbital calculation.
- Augusto,Rodrigues,De Oliveira Filho, Antonio Pedro,Moran, Paulo J. S.,Custodio, Rogerio
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p. 6733 - 6738
(2007/10/03)
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- Antimicrobial indolequinones from the mid-intestinal gland of the muricid gastropod Drupella fragum
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Three new indolequinones, 6-methoxyindole-4,7-quinone (1), 5- methoxyindole-4,7-quinone (2) and 5-methylindole-4,7-quinone (3) were isolated from the mid-intestinal gland of the muricid gastropod Drupella fragum. The structures of 1 and 2 were established
- Fukuyama, Yoshiyasu,Iwatsuki, Chie,Kodama, Mitsuaki,Ochi, Masamitsu,Kataoka, Kumi,Shibata, Kozo
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p. 10007 - 10016
(2007/10/03)
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