Forward Chemical Genetic Screen for Oxygen-Dependent Cytotoxins Uncovers New Covalent Fragments that Target GPX4.

The identification of growth inhibitory compounds with the ability to selectively target the cellular oxygenation state may be of therapeutic interest. Here, a phenotypic screen of a covalent fragment library revealed diverse compounds containing propiolamide warheads with selective toxicity for liver cancer cells in normoxic conditions. Target identification and validation through CETSA and direct pulldown experiments demonstrated that several compounds target glutathione peroxidase 4 (GPX4) and induce ferroptotic cell death. Although being an oxidative cell death mechanism, ferroptosis can be induced also under hypoxic conditions. Prompted by the selective toxicity discovered in the screen, we mapped the oxygen-dependence of several ferroptosis-inducing compounds across three different cell lines. These studies revealed combinations with notable reductions in sensitivity under hypoxic conditions. These observations are mechanistically interesting and may be relevant for the use of ferroptosis-inducers as anti-cancer agents.

Dehydration reactions in polyfunctional natural products.

Covering: up to 2020In this review, we present state of the art methods for performing dehydration reactions in alcohol substrates to deliver alkene products. The dehydration of alcohols typically proceeds through activation of the alcoholic moiety to a nucleofugal species followed by a subsequent elimination step. While the alcohol is a quintessential functional group, selective dehydration of alcohols in complex molecular scaffolds has not been harnessed to allow molecular diversification strategies. We present the perspective of utilizing complex molecular compounds containing alcoholic functionalities to generate novel molecular constructs that impose on chemical space of characterized bioactivity. Nature inspires the direct and selective dehydration of alcohols in complex molecules and demonstrates a potential that has not yet been realized by chemical methodology. We present challenging substrates for direct and selective dehydration reactions and argue that chemical methodology solving the challenges presented will be valued by synthetic and natural product chemists alike.

A Catalytic Oxidative Quinone Heterofunctionalization Method: Synthesis of Strongylophorine-26.

The preparation of heteroatom-substituted p-quinones is ideally performed by direct addition of a nucleophile followed by in situ reoxidation. Albeit an appealing strategy, the reactivity of the p-quinone moiety is not easily tamed and no broadly applicable method for heteroatom functionalization exists. Shown herein is that Co(OAc)2 and Mn(OAc)3 ⋅2 H2 O act as powerful catalysts for oxidative p-quinone functionalization with a collection of O, N, and S nucleophiles, using oxygen as the terminal oxidant. Preliminary mechanistic observations and the first synthesis of the cytotoxic natural product strongylophorine-26 is presented.

A Concise Route to the Strongylophorines.

An efficient eight-step semisynthesis of strongylophorine-2 from the abundant building block isocupressic acid is reported. The route represents the first synthetic entry into this class of natural products and provides access to six additional family members. A novel iron(III)-mediated rearrangement-cyclization cascade and a directed photochemical sp(3) C-H δ-lactonization are the key transformations that enable concise assembly of these bioactive polycyclic meroterpenoids.