Open Accessn→π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines
Author(s) -
Henry R. Kilgore,
Chase Robert. Olsson,
Kyan A. D’Angelo,
Mohammad Movassaghi,
Ronald T. Raines
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c06477
Subject(s) - chemistry , disulfide bond , ring (chemistry) , stereochemistry , combinatorial chemistry , computational chemistry , organic chemistry , biochemistry
Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n →π* interactions, each with large energies (3-5 kcal/mol). The n →π* interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n →π* interaction in molecular design.