| Abstract
| - The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization.Amides 3−6 were synthesized using standard methodologies and determined to be significantlyless lipophilic than T138067 based on logP calculations. Tubulin polymerization and [3H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2.Amides 3−5 showed no detectable signs of crossing the blood brain barrier, while amide 6 wasfound in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed invivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6approached that of T138067 and was better tolerated when administered to athymic nude micebearing MX-1 human mammary tumor xenografts.
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