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

Abstract

Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders. Inhibition of ALDH2 impairs detoxification of reactive aldehydes and limits oxidative stress response, two crucial pathways for cellular viability.

Highly Enantioselective Synthesis and Anticancer Activities of Chiral Conjugated Diynols

“…Thus, with synthetically optically active diynols in hand, we evaluated their antiproliferative effects on the HepG2 and HeLa cancer cells. As natural falcarinol exhibited no cytotoxicity toward HepG2 cancer cells with an undetectable half maximal inhibitory concentration (IC 50 ) value, we selected 5‐fluorouracil (5‐FU) as a positive control (Tables S4 and S5), which is currently widely used in clinical therapeutics as an anticancer drug.…”

“…Recently, Sieber et al. reported that a falcarinol‐based probe molecule could be used as a selective tool to target a specific protein in cancer cells, in which a conserved preference of a chiral propargyl alcohol by irreversibly binding to Cys of the active site was observed with sterically selective catalytic inhibition . To investigate whether there was stereoselective cytotoxic activity against HepG2 and HeLa cancer cells, we studied the anticancer activity of enantiomers ( R )‐ 1 , ( R )‐ 2 , ( R )‐ 3 , and ( S )‐ 14 against HepG2 and HeLa cells (Table , entries 1–4 and Table S5).…”

“…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.…”

Furospinosulin‐1, Marine Spongean Furanosesterterpene, Suppresses the Growth of Hypoxia‐Adapted Cancer Cells by Binding to Transcriptional Regulators p54nrb and LEDGF/p75

“…Recently, we showed that agelasine D (a marine spongean diterpene alkaloid) binds to the mycobacterial protein BCG3185c (a putative dioxygenase), and we suggested that this protein is a novel drug target against tuberculosis . In addition, some lipid‐like natural products are also known to have unique targets in cancer cells …”

“…[8] In addition, some lipid-like natural products are also known to have unique targets in cancer cells. [9,10] The furanosesterterpenef urospinosulin-1 (1)w as originally isolated from the marine sponge Ircinia spinosula. [11] Ta sdemir et al [12] reported that 1 showedw eak anti-proliferative activity against isogenic human colon cancerH CT-116 cells under normoxic conditions, and Erdogan-Orhan et al [13] reported that 1 inhibited CDC25A (cell division cycle 25 homologue Ap hos-Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer.C ancer research has therefore focused on the identification of molecules responsible for hypoxiaa daptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells.…”