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

Pauline Rullière; François Lizeaux; Etienne Joly; Stéphanie Ballereau; Hafida Gaspard; Valérie Maraval; Remi Chauvin; Yves Genisson

doi:10.17721/fujcV7I1P1-9

Authors

Pauline Rullière
François Lizeaux
Etienne Joly
Stéphanie Ballereau
Hafida Gaspard
Valérie Maraval
Remi Chauvin
Yves Genisson SPCMIB laboratory UMR CNRS 5068 Paul Sabatier Toulouse III University

DOI:

https://doi.org/10.17721/fujcV7I1P1-9

Keywords:

alkynylcarbinol, fluorine, alkyne, pharmacophore design, cytotoxicity

Abstract

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.

References

Kuklev D, Dembitsky V. Epoxy acetylenic lipids: Their analogues and derivatives. Progress in Lipid Research 2014;56:67-91. https://doi.org/10.1016/j.plipres.2014.08.001

Kuklev D, Domb A, Dembitsky V. Bioactive acetylenic metabolites. Phytomedicine 2013;20(13):1145-1159. https://doi.org/10.1016/j.phymed.2013.06.009

Siddiq A, Dembitsky V. Acetylenic Anticancer Agents. Anti-Cancer Agents in Medicinal Chemistry 2008;8(2):132-170. https://doi.org/10.2174/187152008783497073

Shi Shun A, Tykwinski R. Synthesis of Naturally Occurring Polyynes. Angewandte Chemie International Edition 2006;45(7):1034-1057. https://doi.org/10.1002/anie.200502071

Dembitsky V. Anticancer activity of natural and synthetic acetylenic lipids. Lipids 2006;41(10):883-924. https://doi.org/10.1007/s11745-006-5044-3

El Arfaoui D, Listunov D, Fabing I, Oukessou M, Frongia C, Lobjois V, Samson A, Ausseil F, Ben-Tama A, El Hadrami E, Chauvin R, Génisson Y. Identification of Chiral Alkenyl- and Alkynylcarbinols as Pharmacophores for Potent Cytotoxicity. ChemMedChem 2013;8(11):1779-1786. https://doi.org/10.1002/cmdc.201300230

Hallock Y, Cardellina J, Balaschak M, Alexander M, Prather T, Shoemaker R, Boyd M. Antitumor Activity and Stereochemistry of Acetylenic Alcohols from the Sponge Cribrochalina vasculum. Journal of Natural Products 1995;58(12):1801-1807. https://doi.org/10.1021/np50126a001

Aiello A, Fattorusso E, Menna M, Pansini M. Further Bioactive Acetylenic Compounds from the Caribbean Sponge Cribrochalina vasculum. Journal of Natural Products 1992;55(9):1275-1280. https://doi.org/10.1021/np50087a015

Gunasekera S, Faircloth G. New acetylenic alcohols from the sponge Cribrochalina vasculum. The Journal of Organic Chemistry 1990;55(25):6223-6225. https://doi.org/10.1021/jo00312a035

Listunov D, Maraval V, Chauvin R, Génisson Y. Chiral alkynylcarbinols from marine sponges: asymmetric synthesis and biological relevance. Natural Product Reports 2015;32(1):49-75. https://doi.org/10.1039/c4np00043a

Génisson Y, Maraval V, Chauvin R, Listunov D, Joly E, Rullière P, Gaspard H, Bernardes-Génisson V. From Natural to Artificial Antitumor Lipidic Alkynylcarbinols: Asymmetric Synthesis, Enzymatic Resolution, and Refined SARs. Synthesis 2018;50(16):3114-3130. https://doi.org/10.1055/s-0037-1610006

Listunov D, Mazères S, Volovenko Y, Joly E, Génisson Y, Maraval V, Chauvin R. Fluorophore-tagged pharmacophores for antitumor cytotoxicity: Modified chiral lipidic dialkynylcarbinols for cell imaging. Bioorganic & Medicinal Chemistry Letters 2015;25(20):4652-4656. https://doi.org/10.1016/j.bmcl.2015.08.029

Bourkhis M, Gaspard H, Rullière P, de Almeida D, Listunov D, Joly E, Abderrahim R, de Mattos M, de Oliveira M, Maraval V, Chauvin R, Génisson Y. Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols. ChemMedChem 2018;13(11):1124-1130. https://doi.org/10.1002/cmdc.201800118

Listunov D, Billot C, Joly E, Fabing I, Volovenko Y, Génisson Y, Maraval V, Chauvin R. Extended structural modulation of bio-inspired chiral lipidic alkynylcarbinols as antitumor pharmacophores. Tetrahedron 2015;71(41):7920-7930. https://doi.org/10.1016/j.tet.2015.08.003

Madiot V, Grée D, Gree R, Lesot P, Courtieu J. Highly enantioselective propargylic monofluorination established by carbon-13 and fluorine-19 NMR in chiral liquid crystals. Chemical Communications 2000;(2):169-170. https://doi.org/10.1039/a909012f

Prakesch M, Kerouredan E, Grée D, Grée R, DeChancie J, Houk K. The propargylic route as efficient entry to monofluoro and gem-difluoro compounds: mechanistic considerations. Journal of Fluorine Chemistry 2004;125(4):537-541. https://doi.org/10.1016/j.jfluchem.2003.11.027

Fauq A, Singh R, Meshri D. Diethylaminosulfurtrifluoride. Encyclopedia of Reagents for Organic Synthesis 2006;:. https://doi.org/10.1002/047084289x.rd175.pub2

Rives A, Baglai I, Barthes C, Maraval V, Saffon-Merceron N, Saquet A, Voitenko Z, Volovenko Y, Chauvin R. Carbo-cyclohexadienes vs. carbo-benzenes: structure and conjugative properties. Chemical Science 2015;6(2):1139-1149. https://doi.org/10.1039/c4sc02742f

Maraval V, Leroyer L, Harano A, Barthes C, Saquet A, Duhayon C, Shinmyozu T, Chauvin R. 1,4-Dialkynylbutatrienes: Synthesis, Stability, and Perspectives in the Chemistry of carbo-Benzenes. Chemistry - A European Journal 2011;17(18):5086-5100. https://doi.org/10.1002/chem.201002769

Hsieh M, Kuo S, Lin H. Solvent- and Transition Metal Catalyst-Dependent Regioselectivity in the [3+2] Cyclocondensation of Trifluoromethyl-α,β-ynones with Hydrazines: Switchable Access to 3- and 5-Trifluoromethylpyrazoles. Advanced Synthesis & Catalysis 2015;357(4):683-689. https://doi.org/10.1002/adsc.201400853

Linderman R, Lonikar M. Addition of organocuprates to acetylenic di- and trifluoromethyl ketones. Regiospecific synthesis of .beta.,.beta.-disubstituted unsaturated fluoro ketones. The Journal of Organic Chemistry 1988;53(26):6013-6022. https://doi.org/10.1021/jo00261a006

Grée D, Grée R. Effect of fluorine or oxygen atom(s) in propargylic position on the reactivity in click chemistry. Tetrahedron Letters 2010;51(17):2218-2221. https://doi.org/10.1016/j.tetlet.2010.02.083

El Dine A, Khalaf A, Grée D, Tasseau O, Fares F, Jaber N, Lesot P, Hachem A, Grée R. Synthesis of enones, pyrazolines and pyrrolines withgem-difluoroalkyl side chains. Beilstein Journal of Organic Chemistry 2013;9:1943-1948. https://doi.org/10.3762/bjoc.9.230