# Biological Evaluation and SAR Exploration of Bile Acid–Dihydroartemisinin Hybrids as Potential Anticancer Agents for Colorectal Cancer

## TL;DR

Researchers designed and tested new bile acid-DHA hybrids that show stronger anticancer effects against colorectal cancer cells than DHA alone.

## Contribution

A novel library of bile acid-DHA hybrids was synthesized and evaluated, revealing enhanced anticancer activity through structure-activity relationship analysis.

## Key findings

- BA-DHA hybrids synthesized via click chemistry showed 2- to 20-fold higher activity than DHA in colorectal cancer cell lines.
- Click-derived hybrids displayed enhanced anticancer and antimetastatic potential at lower concentrations than DHA.
- Conjugation site and linker type significantly influenced the activity of the hybrids.

## Abstract

Dihydroartemisinin (DHA), a first-line treatment for uncomplicated malaria, has demonstrated antitumor activity against a variety of human cancers, emphasizing its potential for repurposing as an anticancer agent. However, its short half-life and poor bioavailability hinder its application in cancer therapy. We previously demonstrated that the molecular hybridization of DHA with bile acids (BAs) enhances its anticancer activity by improving stability and reducing toxicity. Based on this rationale, here, we designed and synthesized a library of DHA-based hybrids through conjugation with ursodeoxycholic and chenodeoxycholic bile acids. Different conjugation sites and both cleavable and non-cleavable linkages were explored to enable a comprehensive structure–activity relationship analysis. The resulting BA-DHA hybrids were evaluated in vitro for their anticancer activity against HCT116 and RKO colorectal cancer cell lines. As a result of the synergistic effect of the linker type and conjugation site, the BA-DHA hybrids synthesized via click chemistry emerged as the most active compounds in both cell lines, displaying 2- to 20-fold higher activity than the parent DHA. Mechanistic investigations further revealed that the click-derived BA-DHA hybrids possess enhanced anticancer activity and antimetastatic potential, achieving comparable or even superior efficacy to the parent compound at markedly lower concentrations.