PMID: 11931625Apr 5, 2002Paper

Potent, orally active heterocycle-based combretastatin A-4 analogues: synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation

Journal of Medicinal Chemistry
Le WangHing L Sham

Abstract

The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.

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Citations

Jul 21, 2012·Pharmaceutical Research·Yan LuDuane D Miller
Dec 7, 2002·Bioorganic & Medicinal Chemistry Letters·Hsing-Pang HsiehChiung-Chiu Wang
Mar 7, 2012·Chemical Reviews·Morteza Shiri
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Jan 1, 2010·Acta Crystallographica. Section E, Structure Reports Online·Meng ZhangXiao-Hui Yang
Nov 8, 2011·Acta Crystallographica. Section E, Structure Reports Online·Safa'a Faris KayedIbrahim Baba
Jan 4, 2013·Acta Crystallographica. Section E, Structure Reports Online·Mehmet AkkurtAtash V Gurbanov
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Jul 3, 2013·Cellular & Molecular Biology Letters·Renata MikstackaJakub Różański
Jun 27, 2015·Journal of Fluorescence·Jayaraman JayabharathiVenugopal Thanikachalam
May 26, 2011·Chemistry & Biology·Sergey TcherniukAriane Abrieu
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Jan 17, 2015·Journal of Fluorescence·J JayabharathiP Ramanathan
Feb 9, 2016·Chemical Biology & Drug Design·Syed Mohammed Ali HussainiAhmed Kamal
Jun 28, 2016·Journal of Medicinal Chemistry·María-Jesús Pérez-PérezSandra Liekens
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Oct 25, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Riham I AhmedSamir M El-Moghazy

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