Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids.

A series of 25 chiral anti-cancer lipidic alkynylcarbinols (LACs) were devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting phenyl-dialkynylcarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC down to 40 nM for resolved eutomers. A clickable probe was used to confirm the PAC prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 short-chain dehydrogenase/reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin-proteasome system inhibition, and apoptosis.

Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols.

In line with a recent study of the pharmacological potential of bioinspired synthetic acetylenic lipids, after identification of the terminal dialkynylcarbinol (DAC) and butadiynyl alkynylcarbinol (BAC) moieties as functional antitumor pharmacophoric units, this work specifically addresses the issue of carbon backbone length. A systematic variation of the aliphatic chain length was thus carried out in both the DAC and BAC series. The critical impact of the length of the lipidic skeleton was first confirmed in the racemic series, with the highest cytotoxic activity observed for C to C backbones.

Asymmetric synthesis and biological evaluation of natural or bioinspired cytotoxic C2-symmetrical lipids with two terminal chiral alkynylcarbinol pharmacophores.

Bidirectional syntheses of C2-symmetrical lipids embedding two terminal alkynylcarbinol pharmacophores are reported. Naturally occurring chiral alkenylalkynylcarbinol units were generated using Pu's procedure for enantioselective addition of terminal alkynes to aldehydes, allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol pharmacophore were secured using Carreira's procedure adapted to ynal substrates.