Design, synthesis of auristatins-glucuronide conjugates targeting the β-glucuronidase in tumor microenvironment

Yujie Wang; Keshi Xu; Hongchun Liu; Wei Zhang; Chun Hu; Yingxia Li

doi:10.1016/j.bmcl.2023.129493

Design, synthesis of auristatins-glucuronide conjugates targeting the β-glucuronidase in tumor microenvironment

Bioorg Med Chem Lett. 2023 Oct 15:95:129493. doi: 10.1016/j.bmcl.2023.129493. Epub 2023 Oct 2.

Authors

Yujie Wang¹, Keshi Xu², Hongchun Liu³, Wei Zhang², Chun Hu⁴, Yingxia Li⁵

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai 201203, China.
² Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education of China, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education of China, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
⁵ School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].

PMID: 37793497
DOI: 10.1016/j.bmcl.2023.129493

Abstract

Auristatins-glucuronide conjugates designed targeting the β-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase pretreated and untreated cancer cells (IC₅₀ = 5.7 nM ∼ 9.7 nM, IC₅₀ (-Enz) > 1 μM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects.

Keywords: Antiproliferation; Auristatin E; Tumor microenvironment; β-Glucuronidase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Glucuronidase*
Glucuronides* / pharmacology
Humans
Mice
Oligopeptides / pharmacology
Tumor Microenvironment

Substances

Glucuronides
Glucuronidase
auristatin
Oligopeptides