ACTINOMYCIN FAMILIAL DIVERSITY DRIVEN BY PHENOXAZINONE-CORE REACTIVITY

• Main Author: McErlean, Matthew Richard
• Format: Others
• Published: UKnowledge 2019
• Subjects: Actinomycin; Streptomyces; Reactivity; Discover; Antibiotics; Natural Products Chemistry and Pharmacognosy
• Online Access: https://uknowledge.uky.edu/pharmacy_etds/97; https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1100&context=pharmacy_etds

Actinomycins are a class of compounds consisting of phenoxazinone-like core attached to two peptidolactone rings, denoted as α and β. A unique component of a few families—actinomycins G, Y, and Z—is a chlorinated β-ring threonine residue. Families G and Y also contained an actinomycin that possess a β-ring heterocycle (actinomycins G5 and Y5, respectively); prior to this work, no β-ring heterocycle-containing actinomycins were reported for the Z family. Unlike other actinomycin derivatives, Y5’s cytotoxicity was abolished while still maintaining some antibacterial potency. We constructed a model compound to probe the physical properties of the actinomycin core to test conditions under which heterocycle formation would occur. We also analyzed the gene clusters of these actinomycin producers for gene candidates to from this structural motif. We found the the actinomycin core aniline to have pKa values of 2.976 and 8.429 and a significant shift in UV absorption between 300-310nm when the group becomes charged. We also found cyclization conditions and no obvious gene candidates to form the β-ring heterocycle based on our gene cluster analysis. We hypothesize that the familial diversity of the actinomycin G, Y and Z familes is due to the reactivity of the phenoxazinone-like core.