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

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 IC 50 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. [Display omitted] • Discovering lead compound 68 from the metabolites for anti-osteosarcoma. • 68 shows an obviously improved metabolic stability with 115 % bioavailability in vivo. • Compound 68 possesses 44.6 % inhibition osteosarcoma growth and low toxicity in mice. • Compound 68 significantly suppresses osteosarcoma cell migration in vitro. [ABSTRACT FROM AUTHOR]