Nucleophilic Activation of a Tetra-Substituted Mitomycin Cyclic Bis-Disulfide

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概要

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• 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_3P, 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).

• 公益社団法人日本薬学会の論文
• 2009-02-01

著者

• Lee Sang

  College Of Agriculture And Life Sciences Kyungpook National University

• Kohn Harold

  Division Of Medicinal Chemistry And Natural Products School Of Pharmacy University Of North Carolina

• LEE Sang

  College of Pharmacy, Duksung Women's University

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