Identification of Chiral Alkenyl‐ and Alkynylcarbinols as Pharmacophores for Potent Cytotoxicity

Abstract

Illumination by acetylene: Systematic structural variations in a series of archetypal acetylenic lipids derived from the naturally occurring (S,E)-icos-4-en-1-yn-3-ol allowed the discovery of a series of 3R-like 1,4-di-unsaturated carbinol units with a significant and systematic enantiomeric effect on cytotoxicity.

On terminal alkynylcarbinols and derivatization thereof

“…In view of possible analysis of scalemic samples by chiral HPLC [1], the racemic n- Figure 2). TMS = SiMe 3 .…”

“…dialkynyl-carbinols (DACs), proved to be the most potent pharmacophores, with anti-tumoral cytotoxicity IC 50 values down to 60 nM on HCT116 cell lines [1].…”

Ethynylogation approach in antitumor lipid pharmacochemistry: from dialkynyl-carbinols to trialkynyl-carbinols

“…Beyond efforts aiming at the total synthesis of natural AACs [8], synthesis and biological evaluation of both simplified and modified congeners thereof allowed the identification of non-natural DACs as potent in vitro antitumor cytotoxic agents, in particular against the HCT116 cell-line [9]. Starting from the recently disclosed lead 1 (R = n-C 12 H 25 , IC 50 ≈ 0.10 µM; Figure 1) [5,9a], the C 5 OH DAC unit itself, C≡C-C(OH)-C≡C, has been formally separated from either two components of its surrounding, the terminal acetylenic H and the lipidic chain R, by a distance of ca 2.4 ± 0.1 Å through the insertion of a C 2 ethyndiyl unit.…”

Chemoenzymatic construction of chiral alkenyl acetylenic alcohol, a key building block to access diastereoisomers of polyacetylenes

“…These syntheses focused on the construction of acetylenic alcohols in a highly enantioselective manner through hydroboration, catalytic asymmetric hydrogenation, as well as enzymatic resolution. The direct acetylene addition of enal with chiral alkynylzinc complex was documented to be highly substrate dependent [8,12,13]. The enzymatic kinetic resolution in literature precedents revealed the power of achieving high enantioselectivity of the recovered acetylenic alcohols as well as the esterication product [7][8][9][10][11]14].…”

“…However, target-oriented synthesis (TOS) is limited to a specific target instead of developing a general approach to diversify structural features of polyacetylenes. Only two recent reports undertook this task and disclosed interesting biological profiles [13,14]. However, the chain length and levels of desaturation (numbers and geometry) as well as the chirality for adjusting biological activity remain elusive.…”