Synthesis of complex epipolythiodiketopiperazine alkaloids for mechanistic studies
Author(s)Olsson, Chase Robert.
Massachusetts Institute of Technology. Department of Chemistry.
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I. Synthesis of Potent Cytotoxic Epidithiodiketopiperazines Designed for Derivatization. We describe our design, synthesis, and chemical study of a set of functional epidithiodiketopiperazines (ETPs) and evaluation of their activity against five human cancer cell lines. Our structure-activity relationship-guided substitution of ETP alkaloids offers versatile derivatization while maintaining potent anticancer activity, offering exciting opportunity for their use as there are no examples of complex and potently anticancer (nM) ETPs being directly used as conjugatable probes or warheads. Our synthetic solutions to strategically designed ETPs with functional linkers required advances in stereoselective late-stage oxidation and thiolation chemistry in complex settings, including the application of novel reagents for dihydroxylation and cis-sulfidation of diketopiperazines.We demonstrate that complex ETPs equipped with a strategically substituted azide functional group are readily derivatized to the corresponding ETP-triazoles without compromising anticancer activity. Our chemical stability studies of ETPs along with cytotoxic evaluation of our designed ETPs against A549, DU 145, HeLa, HCT 116, and MCF7 human cancer cell lines provide insights into the impact of structural features on potency and chemical stability, informing future utility of ETPs in chemical and biological studies. II. Redox by Stereoelectronic Design: The Malleable n-->[pi]* Interactions Behind Epidithiodiketopiperazine Thiol-Disulfide Exchange Equilibria We describe our efforts seeking to elucidate the mechanisms impacting the physicochemical properties of epidithiodiketopiperazine (ETP) alkaloids.Prompted by observations that subtle substitutions of the polysulfide-bridged diketopiperazine pharmacophore could significantly impact the anticancer activity of ETPs, we developed an array of C4-substituted bisprolyl-ETPs designed to further deconvolute their structure-activity relationship. The complete structural analysis of our training set of synthetic ETPs was enriched by collaborative computational and reduction studies seeking to assess the stereoelectronic forces behind their reactivity. We found a complement of structural parameters correlated to the strongest example of the n-->[pi]* interaction ever observed, compensating for the energetic barrier associated with the eclipsed conformation of ETPs. In addition to providing insight into the stereoelectronic effects governing the physicochemical properties of ETPs, our observations reveal a molecular design strategy that uses the n-->[pi]* interaction to modulate the reduction potential of ETPs.
Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, May, 2020Cataloged from the official PDF of thesis. Vita.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology