Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 7; p. 127003
• Main Authors: Gapil Tiamas, Shelly, Daressy, Florian, Abou Samra, Alma, Bignon, Jérome, Steinmetz, Vincent, Litaudon, Marc, Fourneau, Christophe, Hoong Leong, Kok, Ariffin, Azhar, Awang, Khalijah, Desrat, Sandy, Roussi, Fanny
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2020; Elsevier
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bcl-X Protein - antagonists & inhibitors; Carboxamide; Cell Line, Tumor; Chemical Sciences; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cyclohexanecarboxylic Acids - chemical synthesis; Cyclohexanecarboxylic Acids - pharmacology; Diels-Alder; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Mcl-1; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Natural product; Organic chemistry; Pharmacology & Pharmacy; Physical Sciences; Pro-apoptotic; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - pharmacology; Stereoisomerism; Natural product; Pro-apoptotic; Mcl-1; Carboxamide; Diels-Alder; PENTACYCLIC POLYKETIDES; DISCOVERY; FAMILY; POTENT; XL; ENDIANDRA-KINGIANA; DUAL INHIBITORS; PROTEINS; XL/BAK
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127003

[Display omitted] A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities.