Synthesizing C6 and C7 Methylated Aziridinomitosenes to Elucidate Their Interactions with DNA
Dr. Don L. Warner
Aziridinomitosenes (AZMs) are a family of cytotoxic molecules derived from the mitomycins, a family of tetracyclic molecule isolated from a soil bacterium, and used in cancer treatment, ocular surgery, and more. cells, mitomycin C (MC), the most investigated mitomycin, is enzymatically reduced. Following this, MC can be converted to a leuco-AZM. These AZMs are then able to form DNA interstrand-crosslinks (ICLs) selectively at 5′-CpG-3′ sequences, along with DNA monoadducts. This type of DNA damage, especially the DNA ICLs, cause apoptosis at a very high rate. AZMs, a metabolite of MC and other mitomycins have been the focus of much research since their discovery and have been found to be able to form DNA monoadducts in the absence of extracellular reductant. AZMs had been thought to be unable to form ICLs. However, previous research revealed that both C7-H/C6-methyl and C7-H/C6-H AZMs formed ICLs in the absence of reductant. Along with this research, later studies revealed that these AZMs could additionally form DNA-Protein crosslinks (DPCs), which had not been previously observed. Two separate mechanisms for this action have been proposed, one involving acidic activation, while the other proceeds by nucleophilic attack. In order to determine the mechanism, we are synthesizing four different AZMs with differing patterns of methylation on the C6 and C7 carbons. These compounds will be subjected to a battery of tests, providing evidence for which mechanism is consistent.
Walters, Zach G.; Merlo, Anthony V.; Blair, Michael A.; and Warner, Don L., "Synthesizing C6 and C7 Methylated Aziridinomitosenes to Elucidate Their Interactions with DNA" (2021). 2021 Undergraduate Research Showcase. 118.