Chiral alkynylcarbinols from marine sponges: asymmetric synthesis and biological relevance

Abstract

Covering: up to March 2014. Previous review on the topic: B. W. Gung, C. R. Chim., 2009, 12, 489-505. Chiral α-functional lipidic propargylic alcohols extracted from marine sponges, in particular of the pacific genus Petrosia, constitute a class of acetylenic natural products exhibiting remarkable in vitro biological activities, especially anti-tumoral cytotoxicity. These properties, associated to functionalities that are uncommon among natural products, have prompted recent projects on asymmetric total synthesis. On the basis of a three-sector structural typology, three main sub-types of secondary alkynylcarbinols (with either alkyl, alkenyl, or alkynyl as the second substituent) can be identified as the minimal pharmacophoric units. Selected natural products containing these functionalities have been targeted using previously known or on purpose-designed procedures, where the stereo-determining step can be: (i) a C-C bond forming reaction (e.g. the Zn-mediated addition of alkynyl nucleophiles to aldehydes in the presence of chiral aminoalcohols), (ii) a functional layout (e.g. the asymmetric organo- or metallo-catalytic reduction of ynones), or (iii) an enantiomeric resolution (e.g. a lipase-mediated kinetic resolution via acetylation). The promising medicinal importance of these targets is finally surveyed, and future investigation prospects are proposed, such as: (i) further total synthesis of known or future extraction products; (ii) the synthesis of non-natural analogues, with simpler lipophilic environments of the alkynylcarbinol-based pharmacophoric units; (iii) the variation and optimization of both the pharmacophoric units and their lipophilic environment; and (iv) investigations into the biological mode of action of these unique structures.

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

“…12 These different procedures have been applied in several total syntheses of marine LACs. 2 The emergence of efficient wide-scope methodologies for the asymmetric synthesis of chiral propargylic alcohols prompted the launch of a systematic structure-activity relationship (SAR) study of the cytotoxicity of LACs against cancer cells. Starting from (S)-eicos-(4E)-en-1-yn-3-ol [(S)-1] as an archetypal natural LAC benchmark, a chemistrydriven four-parameter study was undertaken, addressing the variation of: (i) the nature of the terminal unsaturation, (ii) the nature of the internal unsaturation, (iii) the absolute configuration of the carbinol center, and (iv) the length of the saturated n-alkyl chain (Figure 2).…”

“…23a Desilylation of (S)-14 delivered enantiopure (S)-12 with the same configuration as most natural LACs. 2,20 The preparation of 15, the internal regioisomer of 12, was performed in the racemic series by simple addition of ethylmagnesium bromide to pentadec-2-ynal (Scheme 3). 20 The two mono-C 2 -unsaturated LACs (S)-12 and rac-15 did not show any detectable cytotoxicity against HCT116 cells, thus evidencing the requirement of two unsaturated…”

“…Many of them were reported to exhibit significant biological activities and more particularly, remarkable in vitro antitumoral cytotoxicity. 2 These natural ACs typically possess an unbranched aliphatic backbone containing one or more unsaturations and a lipidic (paraffinic) tail. One of the simplest structures is found in eicos-(4E)-en-1-yn-3-ol (1), a reference representative extracted from the sponge Cribrochalina vasculum and exhibiting cytotoxicity against murine P388 leukemia tumor cells (IC 50 = 1 μg/mL = 3.4 μM).…”

“…14 Several methods have thus been developed to access chiral secondary propargylic alcohols from aldehydes using in situ generated alkynylzinc reactants (Scheme 1). 2 A userfriendly procedure, developed by Carreira et al, 15 involves Zn(OTf) 2 and (+)-or (-)-N-methylephedrine (NME) as the chiral inducer. However, the procedure was reported to be inefficient for aliphatic and α,β-unsaturated aldehydes.…”

Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells

“…Both molecules are acetylene alcohols (3 R )-icos-(4 E )-en-1-yn-3-ol (compound 1 ) and (3 R )-14-methyldocos-(4 E )-en-1-yn-3-ol (compound 2 ) and were also previously reported to have anti-tumor activity [34–38]. …”