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

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.