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

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-(4 E )-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/sp (2) 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 C (2) 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 2C (2) -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 C (2) /C (3) -Unsaturated Pharmacophore Candidates 3.1 Cyclopropylalkynylcarbinols (CACs) 3.2 Allenylalkynylcarbinols (AllACs) 4 C (2) /C (4) - and 3C (2) -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