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

Maroua Bourkhis, Dymytrii Listunov, Hafida Gaspard, Etienne Joly, Raoudha Abderrahim, Valérie Maraval, Yves Génisson, Remi Chauvin

Abstract


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.

Keywords


alkyne; antitumor agent; ethynylogation; lipid; pharmacophore design; trialkynylcarbinol

Full Text:

PDF

References


Neumeyer J. Book Review of The Practice of Medicinal Chemistry. Third Edition The Practice of Medicinal Chemistry. Third Edition . Edited by Camille G. Wermuth . Academic Press/Elsevier, Amsterdam, The Netherlands. 2008. xxvi + 942 pp. 22 × 28.5 cm. ISBN 978-0-12-374194-3. $175.00.. Journal of Medicinal Chemistry 2008;51(22):7323-7323. https://doi.org/10.1021/jm801122c

Patrick GL. An Introduction to Medicinal Chemistry, Fifth Edition, Oxford University Press, 2013, 816.

Wermuth C, Ganellin C, Lindberg P, Mitscher L. Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998). Pure and Applied Chemistry 1998;70(5):1129–1143. https://doi.org/10.1351/pac199870051129

Cancer.gov [homepage on the Internet]. Bethesda, MD: NIH National Cancer Institute [updated August 18 2016]. Available from: https://www.cancer.gov/about-cancer/treatment/drugs

Andriamialisoa R, Langlois N, Langlois Y, Potier P. Composés antitumoraux du groupe de la vinblastine: nouvelle méthode de préparation. Tetrahedron 1980;36(20-21):3053-3060. https://doi.org/10.1016/0040-4020(80)88032-x

Listunov D, Saffon-Merceron N, Joly E, Fabing I, Génisson Y, Maraval V, Chauvin R. Ethynylogation approach in pharmacophore design: from alkynyl-to butadiynyl-carbinols vs antitumoral cytotoxicity. Tetrahedron 2016;72(42):6697-6704. https://doi.org/10.1016/j.tet.2016.09.001

Hafner K, Neuenschwander M. Ethynylogous Amides and Urethanes. Angewandte Chemie International Edition in English 1968;7(6):459-460. https://doi.org/10.1002/anie.196804591

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

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

Isaacs S, Kashman Y, Loya S, Hizi A, Loya Y. Petrosynol and petrosolic acid, two novel natural inhibitors of the reverse transcriptase of human immunodeficiency virus from petrosia sp.. Tetrahedron 1993;49(45):10435-10438. https://doi.org/10.1016/s0040-4020(01)80571-8

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

Seo Y, Cho K, Rho J, Shin J, Sim C. Petrocortynes and petrosiacetylenes, novel polyacetylenes from a sponge of the genus Petrosia. Tetrahedron 1998;54(3-4):447-462. https://doi.org/10.1016/s0040-4020(97)10290-3

Shin J, Seo Y, Cho K. Five New Polyacetylenes from a Sponge of the Genus Petrosia . Journal of Natural Products 1998;61(10):1268-1273. https://doi.org/10.1021/np9802015

Kim J, Lim Y, Im K, Jung J, Shim C, Lee C, Hong J, Lee H. Cytotoxic Polyacetylenes from the Marine Sponge Petrosia sp. . Journal of Natural Products 1999;62(4):554-559. https://doi.org/10.1021/np9803427

Watanabe K, Tsuda Y, Yamane Y, Takahashi H, Iguchi K, Naoki H, Fujita T, Van Soest R. Strongylodiols A, B and C, new cytotoxic acetylenic alcohols isolated from the Okinawan marine sponge of the genus Strongylophora as each enantiomeric mixture with a different ratio. Tetrahedron Letters 2000;41(48):9271-9276. https://doi.org/10.1016/s0040-4039(00)01692-0

Nuzzo G, Ciavatta M, Villani G, Manzo E, Zanfardino A, Varcamonti M, Gavagnin M. Fulvynes, antimicrobial polyoxygenated acetylenes from the Mediterranean sponge Haliclona fulva. Tetrahedron 2012;68(2):754-760. https://doi.org/10.1016/j.tet.2011.10.068

Legrave N, Hamrouni-Buonomo S, Dufies M, Guérineau V, Vacelet J, Auberger P, Amade P, Mehiri M. Nepheliosyne B, a New Polyacetylenic Acid from the New Caledonian Marine Sponge Niphates sp.. Marine Drugs 2013;11(7):2282-2292. https://doi.org/10.3390/md11072282

Gung B. Total synthesis of polyyne natural products. Comptes Rendus Chimie 2009;12(3-4):489-505. https://doi.org/10.1016/j.crci.2008.08.014

Sui B, Yeh E, Curran D. Assignment of the Structure of Petrocortyne A by Mixture Syntheses of Four Candidate Stereoisomers. The Journal of Organic Chemistry 2010;75(9):2942-2954. https://doi.org/10.1021/jo100115h

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

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

Listunov D, Maraval V, Saffon-Merceron N, Mallet-Ladeira S, Voitenko Z, Volovenko Y, Génisson Y, Chauvin R. On terminal alkynylcarbinols and derivatization thereof. Fr. Ukr. J. Chem. 2015;3(1):21-28. https://doi.org/10.17721/fujcV3I1P21-28

Listunov D, Fabing I, Saffon-Merceron N, Gaspard H, Volovenko Y, Maraval V, Chauvin R, Génisson Y. Asymmetric Synthesis and Biological Evaluation of Natural or Bioinspired CytotoxicC2-Symmetrical Lipids with Two Terminal Chiral Alkynylcarbinol Pharmacophores. The Journal of Organic Chemistry 2015;80(11):5386-5394. https://doi.org/10.1021/acs.joc.5b00494

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

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

DETTY M, LUSS H. Addition of Disodium Chalcogenides to 1,5-Bis(trimethylsilyl)penta-1,4-diyn-3-one. Syntheses, Structure, and Reactivity of the Parent δ-4H-Chalcogenapyran-4-ones. Organometallics 1992;11:2157-2162.

Tedeschi C, Saccavini C, Maurette L, Soleilhavoup M, Chauvin R. 1,4-Diynes from alkynyl–propargyl coupling reactions. Journal of Organometallic Chemistry 2003;670(1-2):151-169. https://doi.org/10.1016/s0022-328x(02)02183-6

Tropsha A. Best Practices for QSAR Model Development, Validation, and Exploitation. Molecular Informatics 2010;29(6-7):476-488. https://doi.org/10.1002/minf.201000061




DOI: https://doi.org/10.17721/fujcV5I1P24-34

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

ISSN 2312-3222 (Online)

Creative Commons License
 French-Ukrainian Journal of Chemistry is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright (c) 2013 French-Ukrainian Journal of Chemistry