Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

EZEQUIEL F. BRUNA-HAUPT; MARCELLE D. PERRETTI; GARRO, HUGO A.; C. R. PUNGITORE

ACS Omega

American Chemical Society

Año: 2023 vol. 8 p. 26479 - 26496

ABSTRACT: A library of structurally related coumarins was generatedthrough synthesis reactions and chemical modification reactions toobtain derivatives with antiproliferative activity both in vivo and in vitro.Out of a total of 35 structurally related coumarin derivatives, seven ofthem showed inhibitory activity in in vitro tests against Taq DNApolymerase 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 themost promising anti-polymerase activity with IC50 values of 20.7 ± 2.10and 48.25 ± 1.20 μM, respectively. Assays with tumor cell lines (HEK293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the mostpromising, with an IC50 value of 8.47 μM and a selectivity index of 1.87.In addition, the derivatives were evaluated against Saccharomycescerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that causereplicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2Hchromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most importantfunctionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitroantiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 μM with an IC50 valueof 134.22 ± 2.37 μM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.