# Design, Synthesis, and Evaluation of New 2-Arylpropanoic Acid-l-Tryptophan Derivatives for Mitigating Cisplatin-Induced Nephrotoxicity

## TL;DR

Researchers designed new compounds that protect the kidneys from cisplatin chemotherapy side effects by targeting a specific receptor.

## Contribution

A new class of GRPR-targeting 2-arylpropanoic acid-L-tryptophan derivatives was synthesized and shown to improve kidney protection.

## Key findings

- Compound 3m improved mouse renal cell viability more than existing GRPR antagonists.
- 3m reduced kidney injury markers and inflammatory cytokines in cisplatin-treated models.
- Molecular docking and drug property predictions support 3m's potential as a therapeutic candidate.

## Abstract

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity.