Methinylogation Approach in Chiral Pharmacophore Design: from Alkynyl‐ to Allenyl‐carbinol Warheads against Tumor Cells

• Published in: ChemMedChem
• Main Authors: Listunov, Dymytrii, Joly, Etienne, Duhayon, Carine, Saffon‐Merceron, Nathalie, Fabing, Isabelle, Génisson, Yves, Maraval, Valérie, Chauvin, Remi
• Other Authors: CNRS, Toulouse IDEX Transversalité program 2015, The French Embassy in Kiev, Ukraine
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2018
• Subjects: antartic*
• Online Access: http://dx.doi.org/10.1002/cmdc.201800284; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fcmdc.201800284; http://onlinelibrary.wiley.com/wol1/doi/10.1002/cmdc.201800284/fullpdf

Abstract Extension of a structure–activity relationship study of the antitumor cytotoxicity of lipidic dialkynylcarbinols (DACs) is envisaged by formal methinylogation of one of the ethyndiyl moieties of the DAC warhead into the corresponding allenylalkynylcarbinol (AllAC) counterpart. External AllACs were directly obtained by methinylation of the parent DACs with formaldehyde in either the racemic or scalemic series. Isomers containing external progargyl and propynyl motifs were also prepared. Internal AllACs were obtained as racemic statistical mixtures of stereoisomers in two steps from the key C 5 ‐DAC rac ‐TIPS‐C≡C‐CH(OH)‐C≡CH and aldehydes. Kinetic resolution of the ( S )‐C 5 ‐DAC in 97 % ee and ( R )‐C 5 ‐DAC in 99 % ee was achieved by sequential lipase‐mediated acetylation/hydrolysis using the Candida antartica lipase (Novozyme 435). The four internal AllAC stereoisomers were prepared by asymmetric methinylation with ( R )‐ or ( S )‐diphenylprolinol as chiral auxiliary. Cytotoxicity assays on HCT116 cancer cells showed that the most active (eutomeric) external or internal AllAC exhibits an S configuration, a fatty chain length of n =12, and a 50 % inhibitory concentration IC 50 ≈1.0 μ m .