# Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold

## TL;DR

Researchers developed new piperazine-based compounds that can inhibit two proteins involved in cancer drug resistance, potentially improving cancer treatment effectiveness.

## Contribution

The study introduces dual inhibitors of P-gp and hCA XII with a synergistic mechanism to overcome multidrug resistance in cancer cells.

## Key findings

- Compound 33 showed the best activity in reversing multidrug resistance by enhancing doxorubicin's cytotoxicity and accumulation in resistant cells.
- Compounds 13, 27, and 32 induced collateral sensitivity in multidrug-resistant cancer cells.
- The compounds demonstrated good inhibitory activity against both P-gp and hCA XII proteins individually.

## Abstract

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.