387850-89-7Relevant articles and documents
Potent, orally active heterocycle-based combretastatin A-4 analogues: Synthesis, structure - Activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation
Wang, Le,Woods, Keith W.,Li, Qun,Barr, Kenneth J.,McCroskey, Richard W.,Hannick, Steven M.,Gherke, Laura,Credo, R. Bruce,Hui, Yu-Hua,Marsh, Kennan,Warner, Robert,Lee, Jang Y.,Zielinski-Mozng, Nicolette,Frost, David,Rosenberg, Saul H.,Sham, Hing L.
, p. 1697 - 1711 (2002)
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.
