Development of new mitomycin C and porfiromycin analogs

Abstract

New mitomycin C and porfiromycin analogues were prepared by treating mitomycin A and N-methylmitomycin A with a variety of amines, including aziridines, allylamines, propargylamines, chloroalkylamines, hydroxyalkylamines, glycine derivatives, aralkylamines, and heterocyclic amines. All analogues were evaluated against P-388 murine leukemia and selected ones were examined for their leukopenic properties. Certain analogues were found to be superior to mitomycin C in potency, efficacy, and therapeutic ratio in the P-388 assay. The most active substituents at the mitosane 7 position included aziridine, 2-methylaziridine, propargylamine, furfurylamine, methyl glycinate, and 3-aminopyridine. Mitomycin A and the 7-aziridino, 7-(2-methylaziridino), and 3-aminopyridine analogues were less leukopenic than mitomycin C. Certain other analogues, including propargylamino and methyl glycinate, were highly leukopenic. The three compounds tested against B-16 melanoma in mice were significantly more effective than mitomycin C in this assay. Previously established structure--activity relationships were found inadequate to account for all of the new data.

Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin

“…This latter observation is of particular interest, since 4 is a tetrahydropterin analogue rather than an aminopterin analogue. 5 (15), 39.37 g (0.221 mol) of N-bromosuccinimide, 3.0 g of benzoyl peroxide, and 60 mL of benzene was refluxed for 16 h while being irradiated with a 275-W sunlamp. Drugs were administered intraperitoneally daily for 9 days beginning on day 1.…”

Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyidithio) ethyl] mitomycin C (BMY-25067)

“…A number of MMC analogs have been prepared which demonstrated greater antitumor activity than the parent compound in one or more animal tumor systems [1][2][3][4]8,10,17]. At least one compound with equivalent antitumor effects to MMC has been reported which had clearly less hematologic toxicity than MMC including effects on platelets [5].…”

“…Among each of the closely related chemical structures a prototype compound selected for more extensive study has shown superior preclinical antitumor activity [1][2][3][4] or reduced myelosuppression [5]. One of the most promising compounds, BMY-25282, was selected for clinical development but was found to be cardiotoxic to rats with characteristics similar to that associated with anthracyclines in preclinical toxicology studies [6].…”

Synthesis of a mitomycin C–lexitropsin hybrid

“…The key step of linking the chemically fragile mitosane moiety to the N-methyl pyrroles was based on the preceding displacement of the 7-methoxy group of mitomycin A by aromatic primary amines, as described in Scheme 1 [15,16]. The MC-pyrrole hybrids (Figs.…”