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 Et₃P, 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).