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n→π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines.

ABSTRACT: 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.

SUBMITTER: Kilgore HR

PROVIDER: S-EPMC7484275 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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<i>n</i>→π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines.

Kilgore Henry R HR Olsson Chase R CR D'Angelo Kyan A KA Movassaghi Mohammad M Raines Ronald T RT

Journal of the American Chemical Society 20200821 35

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 <i>n</i>→π* interactions, each with large energies (3 ...[more]

PMID: 32701272

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