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carbo‐Benzene is an aromatic molecule devised by inserting C2 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. [ABSTRACT FROM AUTHOR]

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]

Abstract: Hexa‐tert‐butyl‐carbo‐benzene (C18tBu6) and three phenylated counterparts (C18tBumPh6−m; m=4, 2) have been synthesized. The peralkylated version (m=6) provides experimental access to intrinsic features of the insulated C18 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 C18 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 C18tBu6 happen to be yellow (λmax=379 vs. 472 nm for C18Ph6). In comparison to C18Ph6, the reduction of C18tBu6 remains reversible, but occurs at twice as high an absolute potential (E1/2=−1.36 vs. −0.72 V). Systematic XRD analyses and DFT calculations show that the C18 ring symmetry is the nearest to D6h 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 C18tBu6: NICS(0)=−17.2 ppm versus (−18.0±0.1) ppm for the theoretical references C18H6 and C18F6, and −13.5 ppm for C18Ph6. Accurate correlations of NICS(0) with experimentally recorded or calculated maximum UV/Vis absorption wavelengths, λmax, and chemical hardness, η=ELUMO−EHOMO, are evidenced. [ABSTRACT FROM AUTHOR]

Ethynylogation of a chiral lipidic dialkynylcarbinol (DAC), identified as a lead for cytotoxicity against HCT116 cancer cells, is shown to typify the butadiynyl-alkynylcarbinol (BAC) unit as a new pharmacophore. The enantiomers of the internal BAC have been synthesized with 72–75% yield and 85% ee through the use of a modified Carreira reaction shown here for the first time to be compatible with butadiyne and ynal substrates. One enantiomer of the internal BAC could be characterized by X-ray crystallography. In this particular case, the ‘DAC to BAC’ ethynylogation results in a slight enhancement of the eutomer potency with a preserved vanishing eudismic ratio (IC 50 values from 102±14 nM to 42±12 nM for the (+) enantiomers). [ABSTRACT FROM AUTHOR]

Chiral lipidic dialkynylcarbinols (DACs), recently highlighted as antitumoral pharmacophores, have been conjugated to difluoroboron-dipyrromethene (bodipy), 7-hydroxy-coumarine, and 7-nitro-benzoxadiazole (NBD) fluorophore motifs through triazole clips. The labeled lipids preserve cytotoxic activity against HCT116 cells, and fluorescence microscopy of the stained cells showed clear signals in the intra-cellular membrane system. While the bodipy conjugate also labels lipid droplets very brightly, as expected, the coumarine and NBD probes appear as promising specific tools for the identification of the intra-cellular targets of DACs’ cytotoxicity. [ABSTRACT FROM AUTHOR]

The chiral alkynylcarbinol motif typically found in natural marine products, has been the subject of intense research activity for its pharmacophoric properties, in particular cytotoxicity against tumor cell lines. In a chemical synthesis-driven four-parameter structure–activity relationship (SAR) study from the ( S , E )-eicos-4-en-1-yl-3-ol natural reference 1 , the ( S )-dialkynylcarbinol unit of the non-natural dehydro derivative 2 emerged as an unprecedented anti-tumoral pharmacophore. An extended study of lipidic alkynylcarbinol pharmacophores is presented, addressing additional structural parameters: Z→E isomerization of the alkenyl carbinol substituent of 1 , variation of the lipidic chain length of 2 (C 3n , n =3, 4, 6), oxidation or substitution of the carbinol unit of 2 (to ketone, tertiary methylcarbinol, or methylether), cyclomethylenation of the double bond of 1 . The synthesis of these analogues is described, including the preparation of enantio-enriched chiral alkynylcarbinol derivatives using a modified Carreira procedure for Zn-mediated addition of (trialkylsilyl)acetylene substrates to ynals in the presence of (−)- or (+)- N -methylephedrine. Preliminary cytotoxicity evaluation of 12 new products against the HCT 116 tumor cell line are finally reported and the results compared with those obtained for 1 and 2 . These observations support and refine the relevance of the pharmacophoric character of secondary DAC units. [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]

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. [ABSTRACT FROM AUTHOR]

The reactivity of EWG (electron withdrawing group)-activated methylene group in 1,3-thiazolidin-4-one 1,1-dioxides were investigated. Novel derivatives of 1,3-thiazolidin-4-one 1,1-dioxides were prepared (the heterocyclic core was modified with carboxamide and carboxthioamide moieties as carbonyl group analogues). The products, which have functional groups for possible future modifications, are described and characterized. [ABSTRACT FROM PUBLISHER]

GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions. [Display omitted] • Thiophene amide class of compounds binds selectively to GAS41 YEATS domain • GAS41 inhibitors bind into a channel involved in recognition of acylated lysine • Bivalent analogs have significantly enhanced activity over monomeric inhibitors • Lead compound demonstrates on-target inhibition of GAS41 in cancer cells By employing a fragment screening approach, Listunov et al. developed small molecule inhibitors of GAS41 YEATS domain. They found that dimeric GAS41 inhibitors have significantly enhanced potency over monomeric inhibitors, engage GAS41 in cells, and inhibit growth of lung cancer cells. [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]

Herein, the optical properties of thiophene-functionalized quadrupolar carbo -benzenes and a benzenic parent, of generic structure Th–C C–[core]–C C–Th, Th = R 2 C 4 HS, are comparatively investigated. Beyond the previously unknown dioctylthienylethynylbenzene (core = p -C 6 H 4 , R = n Oct), two bis-dialkylthienylethynyl- carbo -benzenes (core = C 18 Ph 4 , R = n Oct, n Bu) are envisaged for the unique " carbo -aromatic" character of the C 18 macrocycle. The three targets were synthesized from the corresponding ethynylthiophenes in 47, 20 and 10% yield, respectively, then characterized by classical methods such as NMR spectroscopy, and X-ray crystallography for one of the carbo -benzenes. Regarding linear and nonlinear optical properties, our results show that the carbo -merization induces a significant shift to lower energies of the one-photon electronic excitations accompanied by an 8-fold increase of the molar extinction coefficient compared to the parent molecule. Intriguingly, these excitations lead to a broad band of photoluminescence comprising decay transitions of the type S 1 → S 0 but also of the type S 2 → S 0. This phenomenon of emission from higher excited states, which is contrary to Kasha's rule, is assigned to - or revealed by - a reduction of the internal conversion efficiency between S 2 and S 1. Two-photon induced transitions are also enhanced, the two-photon absorption cross-section (σ 2PA) being in average five times larger for the carbo -benzenes than for their benzene parent in the wavelength range 650–950 nm, with a maximum of σ 2PA = 1430 GM (1 GM = 10−50 cm4 s/photon). Beyond a moderate nonlinearity, this comparative study provides quantitative insights about the way carbo -merization or insertion of a π-conjugated macrocycle between chromophoric functions (here thiophene rings) can tune optical properties of organic molecules. The optical properties of the bis-dialkylthienylethynyl- carbo -benzenes are also discussed in regard of recent reports on organic chromophores based on other types of π-conjugated macrocyclic cores. Image 1 • A full core-carbo-meric effect analysis on optical properties is reported for the first time. • Enhancement of 2 PA in a carbo -benzene is demonstrated versus its benzenic parent. • Anomalous luminescence is observed in the carbo- benzene due to simultaneous radiative decays from different excited states. • Janus aromatic softness in a "super-soft" chromophore: atom-governed in thiophene (S), size-governed in carbo-benzene (C18). [ABSTRACT FROM AUTHOR]