# Synthesis of Novel Podophyllotoxin–Benzothiazole Congeners and Their Biological Evaluation as Anticancer Agents

## TL;DR

Researchers created new cancer-fighting compounds by combining podophyllotoxin and benzothiazole, showing strong cell-killing effects and unique interactions with cancer cells.

## Contribution

The study introduces novel podophyllotoxin–benzothiazole derivatives with enhanced anticancer activity and unique structural insights.

## Key findings

- Compounds 7 and 11 showed strong cytotoxicity against multiple cancer cell lines with IC50 values of 0.68–2.88 µM.
- The compounds induce G2/M phase arrest in HeLa cells, inhibiting cancer cell proliferation.
- Molecular docking studies revealed distinct binding modes to β-tubulin compared to podophyllotoxin.

## Abstract

A series of novel podophyllotoxin derivatives containing benzothiazole scaffolds were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (MCF-7, SKOV-3, B16F10, LOVO, and HeLa). Two compounds, 7 and 11, which are different only by the absence or presence of the ester group, showed the strongest cytotoxic effect towards all tested cancer cell lines with the IC50 0.68–2.88 µM. In addition, it was demonstrated that these compounds inhibit cancer cell proliferation by inducing G2/M phase arrest in HeLa cells. The structure–activity relationship was analyzed and it confirmed the importance of the core structural features like a dioxolane ring and free-rotating trimethoxyphenyl group for cytotoxicity. Moreover, the R configuration of the ester group at the C-8′ position proved to be substantial since its epimer was inactive. The molecular docking studies revealed that the most potent compounds have a different binding mode to β-tubulin than podophyllotoxin; however, the benzothiazole fragment docked in a similar location as the trimethoxyphenyl group of podophyllotoxin, exhibiting similar hydrophobic interactions. These findings clearly indicate that podophyllotoxin–benzothiazole derivatives could be addressed for further pharmacological studies in anticancer research.