Investigations into the Complete Synthesis of Aziridinomitosene Chemotherapeutics
Faculty Mentor Information
Don Warner
Presentation Date
7-2015
Abstract
Mitomycin C (MC) is a naturally occurring anti-tumor chemotherapeutic that has historically seen extensive use as a treatment for a wide variety of cancers. Recently, MC has seen reduced use in the treatment of cancer due to its severe side effects including myelosuppression. We have prepared structurally similar compounds, called aziridinomitosenes (AZMs), that have similar anticancer activity but may be operating by a mechanism different than that of MC. The AZMs contain electrophilic centers at the C6 and C7 positions which are thought to play a role in cytotoxicity and increased potency over MC in cancer cell lines. This present study aims to investigate the importance of these electrophilic centers by preparing analogs with varying alkyl groups at these positions. The key steps of the synthesis include starting with the enolate alkylation of γ-butyrolactone, leading to the closing of an aziridine ring. After this, a lithiated propargyl alcohol is used to install a tethered dipolarophile, which is subjected to the oxazolium salt/azomethine ylide cycloaddition sequence that leads to the final tetracyclic core followed by addition of a carbamate. Results are presented herein.
Investigations into the Complete Synthesis of Aziridinomitosene Chemotherapeutics
Mitomycin C (MC) is a naturally occurring anti-tumor chemotherapeutic that has historically seen extensive use as a treatment for a wide variety of cancers. Recently, MC has seen reduced use in the treatment of cancer due to its severe side effects including myelosuppression. We have prepared structurally similar compounds, called aziridinomitosenes (AZMs), that have similar anticancer activity but may be operating by a mechanism different than that of MC. The AZMs contain electrophilic centers at the C6 and C7 positions which are thought to play a role in cytotoxicity and increased potency over MC in cancer cell lines. This present study aims to investigate the importance of these electrophilic centers by preparing analogs with varying alkyl groups at these positions. The key steps of the synthesis include starting with the enolate alkylation of γ-butyrolactone, leading to the closing of an aziridine ring. After this, a lithiated propargyl alcohol is used to install a tethered dipolarophile, which is subjected to the oxazolium salt/azomethine ylide cycloaddition sequence that leads to the final tetracyclic core followed by addition of a carbamate. Results are presented herein.