title: Nucleophilic activation of a tetra-substituted mitomycin cyclic bis-disulfide.
abstract: The multimerization of functional DNA alkylating agents has drawn significant, recent interest because these compounds are expected to generate enhanced levels of DNA cross-linked adducts, compared with their monomeric agents. Here we report the evaluation of 7-N,7'-N'-(1'',2'',9'',10''-tetrathia-cyclohexadecanyl-3'',8'',11'',16''-tetramethylenyl)tetrakismitomycin C (8), in which four mitomycin units are attached to the novel bis-disulfide linker, 3,8,11,16-tetrakis(aminomethyl)-1,2,9,10-tetrathia-cyclohexadecane. Compound 8 was designed to undergo preferential C(1) mitomycin activation under nucleophilic as well as under acidic and reductive conditions. We anticipated that treating 8 with nucleophiles would lead to bis-disulfide cleavage thus producing two mitomycin dimers (9) capable of generating DNA interstrand cross-links (ISC). The mitomycin units in 9 are tethered by a stable carbon backbone linkage. According to the procedure reported by Lee and coworkers (Tetrahedron, 61, 1749-1754 (2005)), we synthesized 8 and the reference mitomycin dimer, 7-N,7'-N'-(2'',7''-dihydroxy-1'',8''-octanediyl)bismitomycin C (15). Compound 8 was activated under acidic conditions thereby generating mitosene product 16, in which all four mitomycin units within the 16-membered ring were activated. Using the nucleophile Et(3)P, we found that 8 underwent significantly enhanced mitosene production compared with its reference compound 15. We further demonstrated that under nucleophilic activation conditions 8 generated higher levels of DNA ISC than either 1 or 15. The cytotoxicities of 8 and 15 in a select tumor cell line were evaluated and compared with mitomycin C (1).
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea. sanghyup@duksung.ec.kr
authors.forename: Sang Hyup
authors.initials: SH
authors.lastname: Lee
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D015195:Drug Design; D004587:Electrophoresis, Agar Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol / Q000737:chemistry; D016685:Mitomycin / Q000737:chemistry* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013440:Sulfides
chemical_list: D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D013440:Sulfides; D016685:Mitomycin; D004247:DNA; D000432:Methanol