Synthesis and Biological Evaluation of 2-Indolyloxazolines as a New Class of Tubulin Polymerization Inhibitors. Discovery of A-289099 as an Orally Active Antitumor Agent

Li, Qun; Woods, Keith W.; Claiborne, Akiyo; Gwaltney, Stephen L.; Barr, Kenneth J.; Li, Gang; Gehrke, Laura; Credo, R.B.; Yu, Hui; Lee, Jang; Warner, Robert B.; Kovar, Peter; Nukkala, Michael A.; Zielinski, Nicolette A.; Tahir, Stephen K.; Fitzgerald, Michael; Kim, Ki H.; Marsh, Kennan C.; Frost, David J.; Ng, Shi Chung; Rosenberg, Saul H.; Sham, Hing L.

doi:10.1016/s0960-894x(01)00759-4

Cited by 111 publications

(31 citation statements)

References 15 publications

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“…As discussed previously, (S, S)-dioxolane 57 was much more potent than (R, R)-dioxolane 58 in both cytotoxic and antitubulin activity. Expecting similar differential in activity, Li et al [101] (91) A-289099 (95) A-204197 (92) A-259745 (94) 93 A-289101 (96) mg/kg/day) and 206% (p.o., qd×28, 100 mg/kg/day) [101,102]. Overall, A-289099 (95) was another successful example of heterocycle-based CA-4 analogues with a promising oral anticancer profile that warrants further evaluation.…”

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

confidence: 84%

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

confidence: 84%

Pharmaceutical Design of Antimitotic Agents Based on Combretastatins

Hsieh

Liou²,

Mahindroo

2005

CPD

149

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“…13) is an indolyloxazoline derivative with antimitotic activity developed also by Abbott Laboratories. It was discovered as a result of structural optimizations of the lead compound A-105972 (146). A-289099 exerts its anticancer activity by inhibition of tubulin polymerization and by binding at the colchicine binding site.…”

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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“…Some representative structures (111)(112)(113)(114)(115) are shown and relevant references concerning the synthesis of these products can be seen for 111 [59]. Other important compounds include A-289 099 (116), an orally active antimitotic agent against various cancer cell lines that acts through inhibition of tubulin polymerization by binding at the colchicine site [60]. A series of indolizidinones of general structure 117 has been designed and synthesized to evaluate their inhibitory effect on Factor VIIA (FVIIa) in comparison to thrombin [61].…”

Section: Relevant Natural And/or Useful Compoundsmentioning

confidence: 99%