Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure−Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation

Citations Over TimeTop 10% of 2002 papers

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.

Related Papers

• → Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-Inducing Activity in HL60 and in MDR Cell Lines(2005)147 cited
• → Design, synthesis, biochemical, and biological evaluation of nitrogen-containing trifluoro structural modifications of combretastatin A-4(2008)21 cited
• → Synthesis and SAR studies of a novel class of S1P1 receptor antagonists(2007)14 cited
• → Synthesis and structure–activity relationships of N-substituted spiropiperidines as nociceptin receptor ligands: Part 2(2008)11 cited
• → New nonpeptide angiostensin II receptor antagonists. Synthesis, biological properties and structure-activity relationships of 3-substituted 2,6-dialkyl-4-(biphenyll)methylaminopyridine derivatives.(1994)1 cited