# Synthesis and biological activity study of tanshinone I-pyridinium salt derivatives

## TL;DR

Researchers improved the anticancer properties of tanshinone I by creating new pyridinium salt derivatives, with one showing strong activity against several cancers.

## Contribution

A novel tanshinone I-pyridinium salt derivative (a4) was developed as a potent PI3Kα inhibitor with antitumor and immune-activating properties.

## Key findings

- Compound a4 showed potent cytotoxicity against breast, liver, and prostate cancer cell lines with IC50 values of 1.40–1.63 μM.
- a4 inhibits PI3Kα and reduces phosphorylation of key signaling proteins in the PI3K/Akt/mTOR pathway.
- a4 significantly downregulates PD-L1, suggesting potential to enhance tumor immunity.

## Abstract

Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4, bearing a 4-bromobenzoylmethyl substituent at the N-1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC50 values of 1.40–1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC50 of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents.

The online version contains supplementary material available at 10.1007/s13659-025-00534-7.