C(10) halogen 10-des(carbamoyloxy)porfiromycins: Synthesis, chemistry, and biological activity

Article abstract of DOI:10.1021/jo00116a024

An efficient four-step procedure for the preparation of C(10) halogen 10-des(carbamoyloxy)porfiromycins 3-5 beginning with mitomycin C(1) is described. Solvolytic removal (NaOMe, MeOH/benzene) of the C(10) carbamoyl group in 1 followed by N-methylation (dimethyl sulfate (15 equiv), 1,8-bis(dimethylamino)naphthalene (15 equiv) in THF) provided 10-decarbamoylporfiromycin (7) in 65% yield. Treatment of 7 with methanesulfonyl chloride in pyridine gave 10-decarbamoyl-10-methanesulfonylporfiromycin (8) in 83% yield, which upon heating with metal halides (i.e., LiCl, LiBr, NaI) in either DMF or ethylene glycol dimethyl ether furnished the C(10) halogen 10-des(carbamoyloxy)porfiromycins 3-5 in 68-81% yields. The C(10) halogen 10-des(carbamoyloxy)porfiromycins served as useful starting materials for C(10)-modified derivatives. Treatment of the C(10) bromo derivative 4 with 1,8-diazabicyclo[5.4.0]undec-7-ene provided the elimination product, 10-des(carbamoyloxy)-9-dehydroporfiromycin (12), while addition of AgSCN to the C(10) iodo porfiromycin 5 led to the substituted adducts 10-des(carbamoyloxy)-10-thiocyanatoporfiromycin (10) and 10-des(carbamoyloxy)-10-thiocyanato-9-epi-mitomycin D (11). The C(10) halogen 10-des(carbamoyloxy)porfiromycins also underwent novel radical and thermal skeletal rearrangements. Treatment of the C(10) iodo derivative 5 with tributyltin hydride and A1BN led to the production of the ring-expanded quinone 14. Thermolysis of the C(10) bromo (4) and the C(10) iodo (5) adducts gave the tetracycles 18 and 19, respectively, in which the C(2) nitrogen bond in the starting porfiromycin had been preferentially cleaved in favor of the C(1) bond. Potential pathways for these rearrangements are briefly outlined. The in vitro cytotoxicities of 3-5 in human colon carcinoma cell lines were evaluated. All three C(10) halogen 10-des(carbamoyloxy)porfiromycins were noticeably less potent than mitomycin C.