Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC₅₀ over Mitomycin C

Abstract

A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesisdriven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.Mitomycin C (MMC, Figure 1), a chemotherapeutic agent isolated from extracts of genus Streptomyces, [1] crosslinks DNA and possesses potent antitumor and antibiotic activities. [2] It has been studied since the 1960s for the treatment of many types of soft and solid tumors, [3] but its use has been restricted because of dose-limiting toxicity and delayed myelosuppression, among other side effects. [2c] Although MMC is readily available by fermentation, [1,4] efforts to improve its therapeutic index through direct modification have been largely limited to the C7, [5] C6, [6] C10, and N1a [7] positions and minor structural perturbations resulting from the delicate and generally sensitive structure, especially under acidic conditions. To date, there have been only a few derivatives with improved efficacy and/or decreased toxicity, [5a,b, 6] but none has reached the market. In contrast, the chemical synthesis of MMC, [8] which has a challenging array of densely organized functional groups including the strained aziridine ring, is a daunting challenge. While several elegant total syntheses [9] have been achieved, access to new structural space pertaining to the MMC core and in particular structural analogues, made available by these synthetic routes, has been hampered by long synthetic sequences and/or low overall yields. In addition, analogous quinone-containing agents with dramatically simplified structures, but still maintaining reductive alkylating capacities, have also failed because of high toxicities or lost anticancer activity in vivo. [10] Herein, we report a succinct and efficient preparation of simplified structural analogues of MMC, in the forms of mitosenes, based on a novel mechanism-driven design. Importantly, one of these compounds is twice as potent as MMC against PPC prostate cancer cell lines, yet shows similar toxicity against RWPE-1 normal cell lines.The established mechanism of action for MMC (Scheme 1 A) is initiated by a cellular reduction of the quinone moiety, followed by the formation of 7-aminoleucoaziridinomitosene upon elimination of MeOH, and culminates with mono-or bisalkylation of DNA, where bisalkylation often results in crosslinking of complementary DNA strands and is the irreversible lethal lesion. [2b] To deviate from the details and yet stay true to the essence of this mechanism, we contrived an approach based on...

Mitomycin C from Birth to Adulthood

“…The research for chemical synthesis of MMC analogues is ongoing. MTSB-6, which is twice as potent as MMC, is under investigation (47).…”