Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier

Citation
Sm. Rubenstein et al., Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier, J MED CHEM, 44(22), 2001, pp. 3599-3605
Citations number
13
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
0022-2623 → ACNP
Volume
44
Issue
22
Year of publication
2001
Pages
3599 - 3605
Database
ISI
SICI code
0022-2623(20011025)44:22<3599:HPAOTA>2.0.ZU;2-0
Abstract
The novel anticancer compound T138067 is an irreversible inhibitor of tubul in polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on l ogP calculations. Tubulin polymerization and [H-3]-T138067 competition assa ys 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 ami de 6 was found in extremely small amounts (12 ng/g of brain tissue). Anilin e 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 tha t of T138067 and was better tolerated when administered to athymic. nude mi ce bearing MX-1 human mammary tumor xenografts.