2. Academic Validation
  3. Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

  • ACS Omega. 2023 Jul 13;8(29):26479-26496. doi: 10.1021/acsomega.3c03181.
Ezequiel F Bruna-Haupt 1 2,  Marcelle D Perretti 3,  Hugo A Garro 1 2 4 5,  Romen Carrillo 3,  Félix Machín 6 7,  Isabel Lorenzo-Castrillejo 6,  Lucas Gutiérrez 1,  Esteban G Vega-Hissi 1,  Macarena Mamberto 5 8,  Mauricio Menacho-Marquez 5 8,  Claudio O Fernández 4 5,  Celina García 3,  Carlos R Pungitore 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, San Luis 5700, Argentina.
  • 2 Chemical Technology Research Institute-National Council for Scientific and Technical Research (INTEQUI-CONICET), San Luis 5700, Argentina.
  • 3 Institute of Bio-Organics Antonio González, Department of Organic Chemistry, University of La Laguna, Institute of Natural Products and Agrobiology, IPNA-CSIC, La Laguna 38206, Spain.
  • 4 Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC), and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Rosario 2002, Argentina.
  • 5 National University of Rosario, Rosario, Santa Fe 3100, Argentina.
  • 6 Research Unit, Nuestra Señora de Candelaria University Hospital, Santa Cruz de Tenerife 38010, Spain, Institute of Biomedical Technologies, University of La Laguna, Tenerife 38200, Spain.
  • 7 Faculty of Health Sciences, Fernando Pessoa Canarias University, Las Palmas de Gran Canaria 35450, Spain.
  • 8 Institute of Clinical and Experimental Immunology of Rosario (IDICER; CONICET-UNR), Center for Research and Production of Biological Reagents (CIPReB; FCM-UNR), Faculty of Medical Sciences, Rosario, Santa Fe 3100, Argentina.
PMID: 37521653 DOI: 10.1021/acsomega.3c03181
Abstract

A library of structurally related Coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both in vivo and in vitro. Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in in vitro tests against Taq DNA Polymerase with IC50 values lower than 250 μM. The derivatives 4-(chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (2d) and 4-((acetylthio)methyl)-2-oxo-2H-chromen-7-yl acetate (3c) showed the most promising anti-polymerase activity with IC50 values of 20.7 ± 2.10 and 48.25 ± 1.20 μM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the most promising, with an IC50 value of 8.47 μM and a selectivity index of 1.87. In addition, the derivatives were evaluated against Saccharomyces cerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2H-chromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitro antiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 μM with an IC50 value of 134.22 ± 2.37 μM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.

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