Additional Nucleotide Derivatives of Mitosenes. Synthesis and Activity against Parental and Multidrug Resistant L1210 Leukemia

Article abstract of DOI:10.1021/jm00111a004

Cytidine 5'-monophosphate and 5'-ara-CMP conjugates of 2,7-diaminomitosene, with the phosphate groups linked to C-1, were prepared by treating mitomycin C with the appropriate nucleotides. 5'-UMP conjugates were prepared from mitomycin A, 7 (M-83) and 8 (BMY-25282) by similar procedures.A conjugate could not be prepared from mitomycin C and 6-MPRP, but a sulfur-linked derivative was made with 6-MP ribonucleoside.The corresponding 1-hydroxy-2-aminomitosenes were prepared from the parent mitomycin analogues for structure-activity comparisons.All compounds were tested ag ainst L1210 murine leukemia in the MTT tetrazolium dye assay.In general, the conjugates were less potent than the parent mitomycins; however 5'-ara-CMP conjugate 14 derived from mitomycin C was more potent than the parent compound or any mitomycin tested except mitomycin A.It also was more potent than ara-C.This result establishes the value of this approach to prodrugs, at least in cell culture.Against a multidrug-resistant L1210 cell line, all of the conjugates derived from mitomycin C were more potent than the parent compound. 6-Mercaptopurine ribonucleoside conjugate 15 was more active against the resistant cells than it was against the parental cell line.