Novel 2-phenyl-3-(Pyridin-2-yl) thiazolidin-4-one derivatives as potent inhibitors for proliferation of osteosarcoma cells in vitro and in vivo

  • Eur J Med Chem. 2022 Jan 15;228:114010. doi: 10.1016/j.ejmech.2021.114010.
Yaqi Deng  1 ,  Rou Pi  1 ,  Li Niu  1 ,  Yun Zhao  1 ,  Dan Ni  1 ,  Longlong Song  1 ,  Zi Li  1 ,  Wangyujing Han  1 ,  Qinghua Wei  1 ,  Yuqiao Han  1 ,  Tong Zhu  1 ,  Zhengli Luo  1 ,  Donghui Sun  1 ,  Suzhen Dong  2 ,  Shunying Liu  3
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, PR China.
  • 2. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, PR China. Electronic address: [email protected].
  • 3. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, PR China. Electronic address: [email protected].
PMID: 34861640 DOI: 10.1016/j.ejmech.2021.114010
Abstract

Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.

Keywords
Inhibitors; Osteosarcoma; Phenotypic screening; Thiazolidinone.
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