title: Interconversion and stability of duocarmycins, a new family of antitumor antibiotics: correlation to their cytotoxic and antimicrobial activities in vitro.
abstract: Stability and interconversion of duocarmycins were studied in relation to their cytotoxicities and antimicrobial activities. The compounds studied included duocarmycin A and SA, which have a spirocyclopropylhexadienone moiety, and four halogenated seco-compounds of duocarmycin A: duocarmycin B1, B2, C1 and C2, from which the cyclopropane ring structure is absent. Duocarmycins were potent cytotoxic compounds to cells. The cytotoxic activity seen on Balb 3T3/H-ras cells after 72 h drug exposure was in the following order (IC50 (nM): concentration for 50% growth inhibition); SA (0.05) > A (0.3) > B2 (1.5) > B1 (3.0) > C2 (20) > C1 (40). Average minimum inhibitory concentrations (MICs) of duocarmycins against microorganisms showed essentially the same ranking order as that of cytotoxicity. There was a large difference between SA and A in their stability in aqueous solvents. For halogenated seco-compounds, a good correlation was found between their cytotoxicities in vitro and their conversion rate to duocarmycin A, suggesting that halogenated seco-compounds undergo closure to the spirocyclopropylhexadienone structure, the pertinent active form, in cells.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Co., Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Mihara
authors.forename: I
authors.initials: I
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Nakano
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D004355:Drug Stability; D000080890:Duocarmycins; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007211:Indoles; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D013696:Temperature
chemical_list: D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; C057901:pyrindamycin B; C057900:pyrindamycin A; C060648:duocarmycin B1; C060649:duocarmycin B2; C066098:duocarmycin SA; C058289:duocarmycin A