Ethynylogation approach in pharmacophore design: from alkynyl-to butadiynyl-carbinols vs antitumoral cytotoxicity

Ethynylogation of a chiral lipidic dialkynylcarbinol (DAC), identified as a lead for cytotoxicity against HCT116 cancer cells, is shown to typify the butadiynyl-alkynylcarbinol (BAC) unit as a new pharmacophore. The enantiomers of the internal BAC have been synthesized with 72–75% yield and 85% ee through the use of a modified Carreira reaction shown here for the first time to be compatible with butadiyne and ynal substrates. One enantiomer of the internal BAC could be characterized by X-ray crystallography. In this particular case, the ‘DAC to BAC’ ethynylogation results in a slight enhancement of the eutomer potency with a preserved vanishing eudismic ratio (IC50 values from 102±14 nM to 42±12 nM for the (+) enantiomers).

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