Design and synthesis of isatin derivative payloaded peptide-drug conjugate as tubulin inhibitor against colorectal cancer

Guoyang Sun; Zhaoyang Wang; Yanping Li; Jinjin Wang; Futao Liu; Jiajia Yu; Mengzhen Yuan; Ning Wang; Zhen Liu; Cen Xiang; Yongmin Zhang; Nassima Oumata; Peng Yu; Yuou Teng

doi:10.1016/j.ejmech.2025.117276

Design and synthesis of isatin derivative payloaded peptide-drug conjugate as tubulin inhibitor against colorectal cancer

Eur J Med Chem. 2025 Jan 12:285:117276. doi: 10.1016/j.ejmech.2025.117276. Online ahead of print.

Authors

Guoyang Sun¹, Zhaoyang Wang¹, Yanping Li¹, Jinjin Wang¹, Futao Liu¹, Jiajia Yu¹, Mengzhen Yuan¹, Ning Wang¹, Zhen Liu¹, Cen Xiang¹, Yongmin Zhang², Nassima Oumata³, Peng Yu⁴, Yuou Teng⁵

Affiliations

¹ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China.
² China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China; Sorbonne Université, Institut Parisien de Chimie Moléculaire, UMR8232 CNRS, 4 Place Jussieu, 75005, Paris, France.
³ Université Paris Cité, 4, avenue de l'Observatoire, 75006, Paris, France.
⁴ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China. Electronic address: [email protected].
⁵ China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China. Electronic address: [email protected].

PMID: 39818012
DOI: 10.1016/j.ejmech.2025.117276

Abstract

A series of isatin derivatives which could inhibit colorectal cancer (CRC) were synthesized. Among those compounds, 5B exhibited good inhibitory activity of CRC through the inhibition of tubulin expression, inducing apoptosis, and causing G2/M phase cell cycle arrest pathway, which suggested that 5B could be a potential tubulin inhibitor. Based on that, a novel peptide-drug conjugate (PDC), which employed the CRC cells related receptor CD44 ligand peptide A6 coupling to 5B to accomplish A6-5B. The in vitro and in vivo studies showed that A6-5B could significantly inhibit the tumor growth and metastasis in CRC cells. Mechanistic studies revealed that both 5B and A6-5B exert their antitumor effects by inhibiting tubulin, demonstrating that 5B might play a payload role and A6 could act as a targeting moiety for selective drug delivery to tumor cells.

Keywords: Antitumor; Colorectal cancer; Peptide-drug conjugate; Tubulin inhibitor.