| Autor: |
Rubenstein, S. M., Baichwal, V., Beckmann, H., Clark, D. L., Frankmoelle, W., Roche, D., Santha, E., Schwender, S., Thoolen, M., Ye, Q., Jaen, J. C. |
| Zdroj: |
Journal of Medicinal Chemistry; October 2001, Vol. 44 Issue: 22 p3599-3605, 7p |
| Abstrakt: |
The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3−6 were synthesized using standard methodologies and determined to be significantly less 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 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts. |
| Databáze: |
Supplemental Index |
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