title: 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.
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 significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-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.
authors.affiliation: Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA. rubenstein@tularik.com
authors.forename: S M
authors.initials: SM
authors.lastname: Rubenstein
authors.forename: V
authors.initials: V
authors.lastname: Baichwal
authors.forename: H
authors.initials: H
authors.lastname: Beckmann
authors.forename: D L
authors.initials: DL
authors.lastname: Clark
authors.forename: W
authors.initials: W
authors.lastname: Frankmoelle
authors.forename: D
authors.initials: D
authors.lastname: Roche
authors.forename: E
authors.initials: E
authors.lastname: Santha
authors.forename: S
authors.initials: S
authors.lastname: Schwender
authors.forename: M
authors.initials: M
authors.lastname: Thoolen
authors.forename: Q
authors.initials: Q
authors.lastname: Ye
authors.forename: J C
authors.initials: JC
authors.lastname: Jaen
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011108:Polymers; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured; D005464:Fluorobenzenes; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011108:Polymers; D013449:Sulfonamides; D014404:Tubulin; C119368:batabulin; D005464:Fluorobenzenes; D005466:Fluorocarbons; D000096926:Benzenesulfonamides