title: Synthesis and antitumor activity of duocarmycin derivatives.
abstract: A series of duocarmycin B2 derivatives, modified at the phenolic hydroxyl group to ester, carbonate and carbamate, was synthesized. Antitumor activity of these analogs was preliminarily evaluated by assays of growth inhibition of HeLa S3 cells (in vitro) and antitumor activity against murine sarcoma 180 (in vivo). The stability of the compounds under aqueous conditions was examined, and we found a correlation between antitumor activity in vivo and stability in aqueous solution, that is, the more stable derivatives exhibited higher antitumor activity. Among these derivatives, the N,N-dialkylcarbamoyl analogs exhibited both improved antitumor activity and higher stability compared with duocarmycin B2. These analogs were subjected to further biological evaluation and they expressed broad-spectrum activity toward murine solid tumors M5076, Colon 26 and Colon 38, and human xenografted carcinoma MX-1.
authors.affiliation: Kyowa Hakko Kogyo Co., Ltd., Tokyo Research Laboratories, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nagamura
authors.forename: Y
authors.initials: Y
authors.lastname: Kanda
authors.forename: E
authors.initials: E
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Gomi
authors.forename: H
authors.initials: H
authors.lastname: Saito
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004355:Drug Stability; D000080890:Duocarmycins; D006367:HeLa Cells; D006801:Humans; D007211:Indoles; D051379:Mice; D008807:Mice, Inbred BALB C; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; C060649:duocarmycin B2; D004247:DNA