New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models

Szczepankiewicz, Bruce G.; Liu, Gang; Jae, Hwan-Soo; Tasker, Andrew S.; Gunawardana, Indrani; Geldern, Thomas W von; Gwaltney, Stephen L.; Wu-Wong, Jinshyun R.; Gehrke, Laura; Chiou, William J.; Credo, R.B.; Alder, Jeffrey; Nukkala, Michael A.; Zielinski, Nicolette A.; Jarvis, Ken; Mollison, Karl W.; Frost, David J.; Bauch, Joy; Yu, Hui; Claiborne, Akiyo; Li, and Qun; Rosenberg, Saul H.

doi:10.1021/jm010231w

Cited by 58 publications

(15 citation statements)

References 13 publications

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“…The two drugs have the exact same scaffold and the only difference is a functional group in the aromatic ring. They are potential anticancer agents and were undergoing preclinical development by Abbott Laboratories (144). A-105972 inhibited the growth of several tumor cell lines, including breast, central nervous system, colon, liver, lung, and prostate cancer cell lines, as well as multidrug-resistant cells with IC 50 in between 20 and 200 nM depending on specific cell types, but its utility in vivo was limited by a short half-life.…”

Section: Reported Cbsi In Preclinical Studiesmentioning

confidence: 99%

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

et al. 2012

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Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

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Section: Reported Cbsi In Preclinical Studiesmentioning

confidence: 99%

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

et al. 2012

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“…In search of a compound with better chemical stability, a series of heterocyclic analogues with pyrazole, oxadiazole, thiadiazole, thiadiazoline, oxazoline, and dioxolane were synthesized based on lead compounds A-105972 (91) and A-204197 (92) [100]. This led to the discovery of oxazoline 93, bearing a 4-dimethylaminophenyl ring, with good in vitro cytotoxicity (120 nM for HCT-15 and 350 nM for NCI-H460), thus proving 1, 3-oxazoline as an excellent surrogate for the oxadiazoline.…”

Section: (A) 1 3-oriented Heterocyclic Bridgehead Analoguesmentioning

confidence: 99%

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Hsieh

Liou²,

Mahindroo

2005

CPD

149

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The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

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“…According to SAR (the structure–activity relationship), C‐4 position is capable of resisting large groups, so it has great potential in functionalization . It is widely recognized that 1,3,4‐oxadiazole is a large group of heterocyclic compounds which has been discovered to reveal antitumor activities . Moreover, 1,3,4‐oxadiazole heterocycles can remarkably improve the drug activity by utilizing the chemical force to combine the receptor from the view of SAR .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, biological evaluation, and 3D‐QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents

et al. 2017

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The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC = 2.54 ± 0.82 μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.

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New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models

Cited by 58 publications

References 13 publications

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Design, synthesis, biological evaluation, and 3D‐QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents

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