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 Introduction

2 2C₂-Unsaturated Pharmacophore Candidates

2.1 Alkenylalkynylcarbinols (AACs)

2.2 Dialkynylcarbinols (DACs or DACys)

2.3 Alkynylalkenylcarbinols (iso-AACs) and Dialkenylcarbinols (DACes)

2.4 Oxidation-Protected Dialkynylcarbinols and Dialkynylketones

2.5 Fluorophore-Labeled Lipidic Dialkynylcarbinols

3 C₂/C₃-Unsaturated Pharmacophore Candidates

3.1 Cyclopropylalkynylcarbinols (CACs)

3.2 Allenylalkynylcarbinols (AllACs)

4 C₂/C₄- and 3C₂-Unsaturated Pharmacophore Candidates

4.1 Butadiynylalkynylcarbinols (BACs)

4.2 Trialkynylcarbinols (TACs)

5 Double-AC-Headed Pharmacophore Candidates

6 Screening on the Lipidic Chain Length

7 Conclusion

Key words

alkynes - asymmetric synthesis - antitumor cytotoxicity - chiral propargylic alcohols - lipidic alkynylcarbinols - marine drugs - stereoselectivity - structure–activity relationships

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