From Natural to Artificial Antitumor Lipidic Alkynylcarbinols: Asymmetric Synthesis, Enzymatic Resolution, and Refined SARs

Abstract

Among acetylenic natural products, chiral lipidic alkynylcarbinol (LAC) metabolites, mostly extracted from marine sponges, have revealed a broad spectrum of biological activities, in particular, remarkable antitumor cytotoxicity. With reference to one of the simplest natural representatives, [(S)-eicos-(4E)-en-1-yn-3-ol], and a given cancer cell line (HCT116), combined extensive efforts in chemical synthesis (relying on the use of a large chemical toolbox) and biological analysis (in vitro tests), have provided systematic structure–activity relationships (SARs) where the initially selected four structural parameters appear as independent principal components: (i) and (ii) the sp/sp2 content and extent of the terminal and internal unsaturations adjacent to the carbinol center, (iii) the absolute configuration of the latter, (iv) the length of the n-aliphatic backbone. Two key criteria have also been established regarding the functional alkynylcarbinol pharmacophore: the alkynylcarbinol unit must be both secondary and terminal (i.e., substituted by a short ethynyl or ethenyl C2 group). This review is intended to provide a further illustration of the value of a simple rational approach for drug design, and to act as a benchmark for future optimization of LACs as antitumor agents.1 Introduction2 2C2-Unsaturated Pharmacophore Candidates2.1 Alkenylalkynylcarbinols (AACs)2.2 Dialkynylcarbinols (DACs or DACys)2.3 Alkynylalkenylcarbinols (iso-AACs) and Dialkenylcarbinols (DACes)2.4 Oxidation-Protected Dialkynylcarbinols and Dialkynylketones2.5 Fluorophore-Labeled Lipidic Dialkynylcarbinols3 C2/C3-Unsaturated Pharmacophore Candidates3.1 Cyclopropylalkynylcarbinols (CACs)3.2 Allenylalkynylcarbinols (AllACs)4 C2/C4- and 3C2-Unsaturated Pharmacophore Candidates4.1 Butadiynylalkynylcarbinols (BACs)4.2 Trialkynylcarbinols (TACs)5 Double-AC-Headed Pharmacophore Candidates6 Screening on the Lipidic Chain Length7 Conclusion

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids

“…Smooth deprotection of the terminal ethynyl group by K 2 CO 3 in MeOH delivered the first PAC target 5.8a . Previous studies of LAC derivatives pointed out a marked influence of the length of the lipidic backbone on cytotoxicity . The same sequence was thus also used for the preparation of homologues 5.6a , 5.9a , 5.10a, and 5.12a embedding a 6 to 12 carbon atoms-long aliphatic chain (Scheme ).…”

“…Our previous work showed the critical importance of the absolute configuration of the carbinol center on the cytotoxicity of LACs. A strong eudismic ratio favoring the enantiomeric series opposite to that most frequently encountered in naturally occurring LACs was notably observed . The preparation of the representative PAC 5.8a under scalemic form was then studied by implementing the Carreira’s method for enantioselective alkynylation of aldehydes modified for ynal substrates (Scheme ).…”

“…The preparation of the representative PAC 5.8a under scalemic form was then studied by implementing the Carreira’s method for enantioselective alkynylation of aldehydes modified for ynal substrates (Scheme ). − , While both disconnections a or b (Scheme ) were potentially compatible with this method, it was previously shown that these two retrosynthetic options were not equivalent in terms of yields and enantiomeric excess . The eutomeric ( S )-enantiomer of 5.8a was first targeted through the disconnection a. Alkyne 3.8a was reacted in DCM with TMS-propynal in the presence of Zn­(OTf) 2 and (−)- N -methyl ephedrine ((−)-NME) as a chiral inductor.…”

“…Structural evolution of synthetic LACs led to an overall 1000-fold increase in toxicity against HCT116 colon cancer cells compared to the natural product of reference (Figure ). An in-depth study of their mechanism of action also provided rationale for these structure–activity trends. It was evidenced that LACs act as prodrugs, the secondary dialkynylcarbinol center being enantiospecifically oxidized by enzymes of the short-chain dehydrogenase/reductase (SDR) family, in particular HSD17B11 (aka SDR16C2, PAN1B, DHRS8, or retSDR2) (Figure ).…”

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

“…Starting from (S)-1, an extensive structure-activity relationship study in human cancer cell lines established that (Supplementary Figure 1): i) the non-natural enantiomer (R)-1 has higher cytotoxic activity, ii) homologues with shorter lipidic tails are more cytotoxic, with an optimum total aliphatic backbone of 17 carbon atoms (e.g. (R)-2), and iii) replacement of the internal C=C bond by a C≡C bond, giving rise to a terminal dialkynylcarbinol (DAC) pharmacophore, further increases cytotoxicity, to reach an IC 50 down to 90 nM for the DAC (S)-3 (8)(9)(10). However, despite this significant level of activity, the mode of action of this family of molecules, including the natural compound (S)-1, remains elusive (7).…”