jo9b03371_si_001.pdf (5.98 MB)
Synthesis of Potent Cytotoxic Epidithiodiketopiperazines Designed for Derivatization
journal contribution
posted on 2020-03-19, 15:36 authored by Chase
R. Olsson, Joshua N. Payette, Jaime H. Cheah, Mohammad MovassaghiWe
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.