Synthesis of Structurally Related Coumarin Derivatives as Antiproliferative Agents

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 IC 50 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 IC 50 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 IC 50 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)-2Hchromen-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 IC 50 value of 134.22 ± 2.37 μM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.

Latest developments in coumarin-based anticancer agents: mechanism of action and structure–activity relationship studies

“…Besides the above-mentioned coumarin hybrids, coumarin-hydroxamic acid, 217 coumarin–ergosterol peroxide, 218 coumarin–formonontin, 219 coumarin–costunolide, 220 coumarin–curcuminoid, 221 coumarin–furan, 222 coumarin–maltol, 223 coumarin–carbazole, 224 coumarin–quinazoline, 225 coumarin-steroidal, 226,227 coumarin-sugar, 228–232 coumarin-thiazin-2-thione, 233 coumarin–thiophosphate, 234 coumarin-triazolothiadiazines, 235 N -heterocyclocoumarin, 236 hydroxymercapto-methylcoumarin, 237 triazole-tethered coumarin–isatin, 238 and others 239–241 also showed certain anticancer activities.…”

l-Proline-catalysed synthesis of chromeno[2,3-b]chromene from 4-hydroxy-2H-chromene-2-thione and an anti-proliferative study

“…4 Moreover, various coumarin compounds display a wide range of biological activities. 3 In addition to diverse applications in industries such as food additives, agrochemicals, fragrances, cosmetics, and fluorescent dyes, 5–9 they also possess pharmacological properties such as antibacterial, 10 antiproliferative, 11,12 anticoagulant 13 and antioxidant 14 activities. The chemistry of 4-hydroxycoumarin was explored extensively for new compounds, including warfarin, dicoumarol, and flocoumafen, which have significant pharmacological importance and are used as anticoagulants in medicine.…”