# Design, Synthesis, Structure–Activity Relationships, and Preliminary Anticancer Properties of Menthol-Modified Coumarin Esters and 3,4-Dihydrocoumarin Derivatives

## TL;DR

This paper describes the design and testing of new coumarin-based compounds with anticancer potential, showing promising activity and low toxicity.

## Contribution

The study introduces novel menthol-modified coumarin esters and dihydrocoumarin derivatives with anticancer properties.

## Key findings

- Compounds 2b, 4a, and 4b showed strong anticancer activity and selectivity against cancer cell lines.
- Compound 2b was non-toxic to zebrafish larvae in in vivo tests.
- In silico analysis predicted favorable ADME and pharmacokinetic profiles for the compounds.

## Abstract

Menthol-modified
coumarin esters (1a–e) and 3-phosphorylated
coumarins (2a, 2b, 3) were
synthesized. The Michael addition
of P­(O)H groups to the coumarin skeleton offered access to 3,4-dihydrocoumarin
derivatives (4a–4d, 5a–5b). The addition reaction proceeded with high
yields (89–98%) in a short time under mild temperature conditions
and environmentally friendly solvents such as CH3CN or
water. The resulting compounds (1a–1f, 2a, 2b, 3, 4a–4d, 5a–5b)
were subjected to in vitro cytotoxicity evaluation
against human cancer cell lines: colorectal (SW480, SW620), prostate
(PC3), breast (MDA-MB-231), and human keratinocytes (HaCaT) by MTT
assay. Doxorubicin and cisplatin were used as reference compounds.
Based on the findings, the three most promising compounds (2b, 4a, 4b) were selected for further biological
studies, which included evaluation of their ability to induce apoptosis,
inhibit IL-6 secretion, and antiproliferative activity. Compounds
such as 4a and 4b were tested as diastereomeric
mixtures due to the limited possibility of separating them into individual
isomers at this stage. Nevertheless, promising activity and selectivity
against selected cancer cell lines were observed. The in vivo toxicological evaluation performed on zebrafish larvae indicated
that coumarin 2b did not present toxic effects. In addition,
the prediction of physicochemical properties, ADME, and pharmacokinetic
profiles was performed by in silico methods. The
results indicate the significant potential of the selected compounds
as candidates for further research toward the design of new bioactive
compounds.