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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 [ABSTRACT FROM AUTHOR]

The organocatalyzed Mannich coupling of cyclic carboxaldehydes allowed the concise and simple preparation of spirocyclic aminolactones. Their conversion into pharmaceutically relevant spiro[4.5]cyclic and spiro[4.6]cyclic 3-aminopyrrolidines is also described. [ABSTRACT FROM AUTHOR]

Bidirectional syntheses of C2-symmetrical lipids embedding two terminal alkynylcarbinol pharmacophores are reported. Naturally occurring chiral alkenylalkynylcarbinol units were generated using Pu's procedure for enantioselective addition of terminal alkynes to aldehydes, allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol pharmacophore were secured using Carreira's procedure adapted to ynal substrates. The dramatic effect of the carbinol configuration on cytotoxicity was confirmed with submicromolar IC50 values against HCT116 cells. [ABSTRACT FROM AUTHOR]

carbo-Benzene is an aromatic molecule devised by inserting C 2 units within each C-C bond of the benzene molecule. By integrating the corresponding carbo-quinoid core as bridging unit in a π-extended tetrathiafulvalene (exTTF), it is shown that a carbo-benzene ring can be reversibly formed by electrochemical reduction or oxidation. The so-called carbo-exTTF molecule was thus experimentally prepared and studied by UV-visible absorption spectroscopy and cyclic voltammetry, as well as by X-ray crystallography and by scanning tunneling microscopy (STM) on a surface of highly oriented pyrolytic graphite (HOPG). The molecule and its oxidized and reduced forms were subjected to a computational study at the density functional theory (DFT) level, supporting carbo-aromaticity as a driving force for the formation of the dication, radical cation, and radical anion. By allowing co-planarity of the dithiolylidene rings and carbo-quinoidal core, carbo-exTTFs present a promising new class of redox-active systems., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hexa-tert-butyl-carbo-benzene (C 18 tBu 6 ) and three phenylated counterparts (C 18 tBu m Ph 6-m ; m=4, 2) have been synthesized. The peralkylated version (m=6) provides experimental access to intrinsic features of the insulated C 18 core independently from the influence of π-conjugated substituent. Over the series, structural, spectroscopic, and electrochemical properties are compared with those of the hexaphenylated reference (m=0). Anchoring tBu substituents at the C 18 macrocycle is shown to enhance stability and solubility, and to dramatically modify UV/Vis absorption and redox properties. Whereas all carbo-benzenes reported previously were obtained as dark-reddish/greenish solids, crystals and solutions of C 18 tBu 6 happen to be yellow (λ max =379 vs. 472 nm for C 18 Ph 6 ). In comparison to C 18 Ph 6 , the reduction of C 18 tBu 6 remains reversible, but occurs at twice as high an absolute potential (E 1/2 =-1.36 vs. -0.72 V). Systematic XRD analyses and DFT calculations show that the C 18 ring symmetry is the nearest to D 6h for m=6, which indicates a maximum geometric aromaticity. According to calculated nucleus-independent chemical shifts (NICS), the macrocyclic magnetic aromaticity is also maximum for C 18 tBu 6 : NICS(0)=-17.2 ppm versus (-18.0±0.1) ppm for the theoretical references C 18 H 6 and C 18 F 6 , and -13.5 ppm for C 18 Ph 6 . Accurate correlations of NICS(0) with experimentally recorded or calculated maximum UV/Vis absorption wavelengths, λ max , and chemical hardness, η=E LUMO -E HOMO , are evidenced., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)