# Design, Synthesis, Molecular Docking, Dynamics Simulation, and Biological Evaluation of Novel Thiazolidinedione Derivatives Against Breast Cancer with Apoptosis-Inducing Activity

## TL;DR

This study designs and tests new thiazolidinedione compounds that show strong anticancer effects on breast cancer cells by inducing apoptosis.

## Contribution

The paper introduces novel TZD derivatives with improved antiproliferative and apoptotic activity against breast cancer.

## Key findings

- PZ-11 showed the highest antiproliferative effect on MCF-7 cells with an IC50 of 17.35 μM.
- PZ-11 significantly alters gene expression to promote apoptosis in breast cancer cells.
- Molecular docking and dynamics simulations confirmed strong interactions between PZ-11 and AIF.

## Abstract

Breast cancer remains one of the leading causes of cancer-related
deaths among women worldwide. The chemotherapeutic drugs used in treatment
often have serious side effects. In light of their anticancer potential,
thiazolidinedione (TZD) derivatives are considered to be promising
candidates for the development of novel antitumor agents. The objective
of this study is to synthesize and produce two sets of TZD derivatives
by combining the structural features of microtubule-targeting drugs
used in breast cancer treatment, and to determine their molecular
docking, molecular dynamics simulations, ADMET profile, antiproliferative,
and apoptotic effect potential. In the present study, PZ-11 was determined
by xCELLigence analysis to have the highest antiproliferative potential
among all compounds tested on MCF-7 breast cancer cells. The cytotoxic
activity of the synthesized compounds was evaluated against MCF-7
breast cancer cells, revealing IC50 values of 29.44 μM
for PZ-9 and 17.35 μM for PZ-11, compared to 6.45 μM for
the reference drug vincristine. Analysis of the gene expression of
the PZ-11 compound, which has a stronger cytotoxic effect potential,
showed that PZ-11 significantly downregulates AIFM1, BAG3, and BIRC3, while upregulating pro-apoptotic genes
such as BAD, HRK, CASP10, and CASP14. PZ-11’s binding affinities were screened using a molecular
docking workflow via KNIME. The robust and persistent interactions
between PZ-11 and AIF were substantiated by molecular dynamics simulation.
It is demonstrated by ADMET predictions that PZ compounds possess
suitable pharmacokinetic properties. PZ-11 is a promising TZD-based
anticancer drug candidate against breast cancer cells, as determined
by computational and experimental analysis. However, further validation
is required through in vivo analysis to support these
findings.