Fluorinated analogues of lipidic dialkynylcarbinol pharmacophores: synthesis and cytotoxicity in HCT116 cancer cells

Lipidic alkynylcarbinols (LACs) have been identified as potential antitumor compounds, and a thorough understanding of their pharmacophoric environment is now required to elucidate their biological mode of action. In the dialkynylcarbinol (DAC) series, a specific study of the pharmacophore potential has been undertaken by focusing on the synthesis of three fluorinated derivatives followed by their biological evaluation. This work highlights the requirement of an electron-rich secondary carbinol center as a key structure for cytotoxicity in HCT116 cells

Ethynylogation approach in antitumor lipid pharmacochemistry: from dialkynyl-carbinols to trialkynyl-carbinols

A recently proposed "ethynylogation" pharmacochemical approach, first envisaged in the series of anticancer lipidic dialkynylcarbinols (DACs) H–C≡C–CH(OH)–C≡C–R at the levels of the H–C⋮ and ⋮C–R bonds for R = n-C12H25, is completed here at the level of the (HO)C–H bond. The so-devised mono-lipidic trialkynylcarbinol (TAC) target (HC≡C)2C(OH)–C≡CR and its bis-lipidic counterpart HC≡C–C(OH)(C≡CR)2 were synthesized in 4 steps and with 33 % and 23 % overall yield, respectively. Their antitumor cytotoxicity has been evaluated towards HCT116 cells: while the latter TAC is totally inactive, the former DAC-ethynylogous TAC still exhibits a significant toxicity with an IC50 of 10 µM

Changes of the Membrane Lipid Organization Characterized by Means of a New Cholesterol-Pyrene Probe

We synthesized 3β-hydroxy-pregn-5-ene-21-(1-methylpyrenyl)-20-methylidene (Py-met-chol), consisting of cholesterol steroid rings connected to a pyrene group via a linker without polar atoms. This compound has interesting spectroscopic properties when probing membranes: 1), The pyrene has hypochromic properties resulting from probe self-association processes in membranes. Using liposomes of various lipid compositions, we determined the association constants of the probe (K): KDOPC ≫ KPOPC ≫ KDMPC > KDMPC/15 mol % Chol > KDMPC/30 mol % Chol. This indicates a better probe solvation in saturated than in unsaturated lipids, and this effect is enhanced as the cholesterol concentration increases. 2), The pyrene fluorophore is characterized by monomer (I1–I5) and excimer (IE) emission bands. In model membranes, I1/I3 and IE/I3 ratios revealed a correlation between the polarity of the lipid core of the membrane and the amount of cholesterol. 3), Using this probe, we monitored the first steps of the signaling pathway of the mouse δ-opioid receptor, a G-protein-coupled receptor. The thickness of the membrane around this receptor is known to change after agonist binding. Fluorescence spectra of living Chinese hamster ovary cells overexpressing mouse δ-opioid receptor specifically revealed the agonist binding. These results indicate that Py-met-chol may be useful for screening ligands of this family of receptors

From natural to artificial antitumor lipidic alkynylcarbinols: Asymmetric synthesis, enzymatic resolution, and refined SARs

International audienceAmong 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

( R )‐BINOL‐6,6’‐bistriflone: Shortened Synthesis, Characterization, and Enantioselective Catalytic Applications

International audienceThe title compound, characterized by X-ray crystallography, was accessed in 4 steps with 92 % ee. and 25 % yield from an O-protected (R)-BINOL precursor. This revised synthetic route relied on a chlorosulfonylation reaction, as a shortcut to a previously developed sequence requiring the use of toxic SO2 gas and bromine. The strongly electron-impoverished (R)-6,6′-Tf2-BINOL proved an effective ligand in metal-catalyzed enantioselective transformations such as a Zr-based Mannich-type reaction. The catalytic species was characterized by X-ray crystallography as a unique tetrameric metal cluster. The 6,6′-bistriflone groups also allowed to exalt the H-bond donor capacity of the BINOL moiety, as illustrated in an organocatalyzed Morita-Baylis-Hillman transformation. Theoretical study indicated that the 6,6′-bistriflone groups induce a drop of the phenol acidity of 5 pKa units in DMSO. Overall, this work simplified the access, completed the characterization, and confirmed the potential of (R)-6,6′-Tf2-BINOL as a promising platform to further elaborate activated chiral metal ligands or organocatalysts

Bio-inspired antitumor acetylenic lipids bearing alkynylcarbinol pharmacophores

International audienc

Bio-inspired antitumor acetylenic lipids bearing alkynylcarbinol pharmacophores

International audienc

Asymmetric Synthesis and Biological Evaluation of Natural or Bioinspired Cytotoxic <i>C</i>₂‑Symmetrical Lipids with Two Terminal Chiral Alkynylcarbinol Pharmacophores

Bidirectional syntheses of <i>C</i>₂-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 (3<i>R</i>,4<i>E</i>,16<i>E</i>,18<i>R</i>)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from <i>Callyspongia pseudoreticulata</i>. Two synthetic analogues embedding the recently uncovered (<i>S</i>)-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

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids

International audienceA series of 25 chiral anti-cancer Lipidic AlkynylCarbinols (LACs) was devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting Phenyl-diAlkynylCarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC 50 down to 40 nM for resolved eutomers. A clickable probe allowed confirming the PACs prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 Short-chain Dehydrogenase/Reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin-proteasome system inhibition and apoptosis. Insights into the design of LAC prodrugs specifically bioactivated by HSD17B11 vs. its paralogue HSD17B13 were obtained. The HSD17B11/HSD17B13-dependent cytotoxicity of PACs was exploited to develop a cellular assay to identify specific inhibitors of these enzymes. A docking study was performed with the HSD17B11 AlphaFold model providing molecular basis of the SDR substrates mimicry by PACs. The safety profile of a representative PAC was established in mice

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids

A series of 25 chiral anti-cancer lipidic alkynylcarbinols (LACs) were devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting phenyl-dialkynylcarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC50 down to 40 nM for resolved eutomers. A clickable probe was used to confirm the PAC prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 short-chain dehydrogenase/reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin–proteasome system inhibition, and apoptosis. Insights into the design of LAC prodrugs specifically bioactivated by HSD17B11 vs its paralogue HSD17B13 were obtained. The HSD17B11/HSD17B13-dependent cytotoxicity of PACs was exploited to develop a cellular assay to identify specific inhibitors of these enzymes. A docking study was performed with the HSD17B11 AlphaFold model, providing a molecular basis of the SDR substrates mimicry by PACs. The safety profile of a representative PAC was established in mice