New analogue of arenastatin A, a potent cytotoxic spongean depsipeptide, with anti-tumor activity.
Two analogues possessing steric hindered substituents on C-15 of arenastatin A (1), a potent cytotoxic spongean depsipeptide, were synthesized and shown to enhance stability in mouse serum. Notably, 15-tert-butylanalogue (6) with higher cytotoxicity exhibited in vivo anti-tumor activity through iv administration different from 1. Additionally, conformation analysis among the two analogues and arenastatin A (1) indicated that the torsion angle from C-14 to C-20 is a conclusive factor for the potent cytotoxicity of 1.
Murakami
Nobutoshi
N
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
Tamura
Satoru
S
Koyama
Kouhei
K
Sugimoto
Masanori
M
Maekawa
Ryuji
R
Kobayashi
Motomasa
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D003603:Cytotoxins; D047630:Depsipeptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D051379:Mice; D008968:Molecular Conformation; D011161:Porifera / Q000737:chemistry; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003603:Cytotoxins; D047630:Depsipeptides; C096566:arenastatin A