Chemoproteomic Evaluation of the Polyacetylene Callyspongynic Acid

Abstract

Polyacetylenes are a class of alkyne-containing natural products. Although potent bioactivities and thus possible applications as chemical probes have already been reported for some polyacetylenes, insights into the biological activities or molecular mode of action are still rather limited in most cases. To overcome this limitation, we describe the application of the polyacetylene callyspongynic acid in the development of an experimental roadmap for characterizing potential protein targets of alkyne-containing natural products. To this end, we undertook the first chemical synthesis of callyspongynic acid. We then used in situ chemical proteomics methods to demonstrate extensive callyspongynic acid-mediated chemical tagging of endoplasmic reticulum-associated lipid-metabolizing and modifying enzymes. We anticipate that an elucidation of protein targets of natural products may serve as an effective guide to the development of subsequent biological assays that aim to identify chemical phenotypes and bioactivities.

Marine natural products

“…[708][709][710] Chemical examination of adult and bud larvae of the chemically-defended sponge Tethya maza indicated that the sterol composition of both were largely similar, suggesting that the larvae are also defended during reproduction. 711 First total syntheses were reported for many compounds including the lipids motualevic acid F, (E)-and (Z)-antazirine, [712][713][714] mycalol (revised to 1105) [715][716][717] and myrmekioside A, 718,719 and polyacetylenes callyspongynic acid, 720,721 phosphoiodyn A and placotylene A. [722][723][724][725] The structure of plakinidone has been corrected to 1106; the compound is highly sensitive to air oxidation.…”

Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site

“…A suite of metabolic enzymes was identified that are involved in the metabolism and degradation of lipids and fatty acids. 9 Here, we prepare the first falcarinol probes capable of bioorthogonal ligation to affinity tags for proteome-wide target identification via quantitative mass spectrometry. [10][11][12] Our studies confirm ALDH2 as a specific target that irreversibly binds to the electrophilic core scaffold of falcarinol via a nucleophilic cysteine.…”

Highly Enantioselective Synthesis and Anticancer Activities of Chiral Conjugated Diynols

“…Using conventional synthetic methods to prepare the enantiomers of chiral conjugated diynols has proven challenging . Usually, these diynols are prepared by asymmetric reduction of ynones to form chiral propargyl alcohols, and this is followed by copper‐catalyzed Cadiot–Chodkiewicz cross‐coupling to introduce the second acetylene unit . A shorter pathway requires enantioselective addition of 1,3‐diynes to aldehydes to generate chiral diynols in a single chemical procedure.…”