Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

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.

This research was supported by CONICET (PIP 11220200101091CO 2021-2023), PICT 2017-0785 Type D of the National Agency for Scientific and Technological Promotion, UNSL (PROICO 02-2620), and RGLP from AvH Foundation. E.F.B.-H. thanks CONICET for doctoral fellowship and specially to Graphic Designer Bruna-Haupt L. for his help. H.A.G. thanks CONICET for belonging to the CIC. We wish thank to Dr. Di Marco N. I. for the genetic material gently provided. C.R.P. thanks CONICET for belonging to the CIC and Alexander von Humboldt Foundation for the different subsidies. We appreciate language revision by staff from the Instituto de Lenguas, UNSL, and specially Mg. Rezzano S.F.M. thanks to the Spanish Ministry of Science (research grant BFU2017-83954-R), ACIISI (research grant ProID2017010167), and FIISC (research grant PIFIIS19/04). C.G. thanks Ministerio de Ciencia, Innovación y Universidades (MCIU) of Spain-European Regional Development Fund (ERDF) (PGC2018-094503-B-C22). This work is a part of the cotutelled (UNSL-ULL) Ph.D. of E.F.B.-H.

Peer reviewed