Discovery of potent thiazolidin-4-one sulfone derivatives for inhibition of proliferation of osteosarcoma in vitro and in vivo

Xuwen Chen; Zhengli Luo; Zongjing Hu; Donghui Sun; Yingying He; Jiani Lu; Lili Chen; Shunying Liu

doi:10.1016/j.ejmech.2023.116082

Discovery of potent thiazolidin-4-one sulfone derivatives for inhibition of proliferation of osteosarcoma in vitro and in vivo

Eur J Med Chem. 2024 Feb 15:266:116082. doi: 10.1016/j.ejmech.2023.116082. Epub 2024 Jan 3.

Authors

Xuwen Chen¹, Zhengli Luo¹, Zongjing Hu¹, Donghui Sun¹, Yingying He¹, Jiani Lu², Lili Chen², Shunying Liu³

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
² Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: syliu@sist.ecnu.edu.cn.

PMID: 38232462
DOI: 10.1016/j.ejmech.2023.116082

Abstract

Chemotherapy combining with surgical treatment has been the main strategy for osteosarcoma treatment in clinical. Due to unclear pathogenesis and unidentified drug targets, significant progress has not been made in the development of targeted drugs for osteosarcoma during the past 50 years. Our previous discovery reported compound R-8i with a high potency for the treatment of osteosarcoma by phenotypic screening. However, both the metabolic stability and bioavailability of R-8i are poor (T_1/2 = 5.36 min, mouse liver microsome; and bioavailability in vivo F = 52.1 %, intraperitoneal administration) which limits it use for further drug development. Here, we described an extensive structure-activity relationship study of thiazolidine-4-one sulfone inhibitors from R-8i, which led to the discovery of compound 68. Compound 68 had a potent cellular activity with an IC₅₀ value of 0.217 μM, much higher half-life (T_1/2 = 73.8 min, mouse liver microsome) and an excellent pharmacokinetic profile (in vivo bioavailability F = 115 %, intraperitoneal administration). Compound 68 also showed good antitumor effects and low toxicity in a xenograft model (44.6 % inhibition osteosarcoma growth in BALB/c mice). These results suggest that compound 68 is a potential drug candidate for the treatment of osteosarcoma.

Keywords: Inhibitors; Osteosarcoma; Structure-activity relationship; Thiazolidin-4-one sulfone.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Bone Neoplasms* / drug therapy
Cell Line, Tumor
Cell Proliferation
Humans
Mice
Osteosarcoma* / drug therapy
Osteosarcoma* / pathology
Pharmaceutical Preparations
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Pharmaceutical Preparations
Antineoplastic Agents