35843-32-4Relevant academic research and scientific papers
In silico and in vitro insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template
Choi, Inkyu,Park, Yujin,Ryu, Il Young,Jung, Hee Jin,Ullah, Sultan,Choi, Heejeong,Park, Chaeun,Kang, Dongwan,Lee, Sanggwon,Chun, Pusoon,Young Chung, Hae,Moon, Hyung Ryong
, p. 37 - 50 (2021)
The β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold confers tyrosinase inhibitory activity, and in the present study, 16 (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxooxazolidin-4-one analogues containing this scaffold were synthesized. Mushroom tyrosinase inhibitory activities were examined. Compound 1c (IC50 = 4.70 ± 0.40 μM) and compound 1j (IC50 = 11.18 ± 0.54 μM) inhibited tyrosinase by 4.9 and 2.1-fold, respectively, and did so more potently than kojic acid (IC50 = 23.18 ± 0.11 μM). Kinetic analysis of tyrosinase inhibition revealed that 1c and 1j inhibited tyrosinase competitively. Results of docking simulation with mushroom tyrosinase using four docking programs suggested that 1c and 1j bind more strongly than kojic acid to the active site of tyrosinase and supported kinetic findings that both compounds are competitive inhibitors. The docking results of human tyrosinase homology model indicated that 1c and 1j can also strongly inhibit human tyrosinase. EZ-cytox assays revealed 1c and 1j were not cytotoxic to B16F10 melanoma cells. The effects of 1c and 1j on cellular tyrosinase activity and melanin production were also investigated in α-MSH- and IBMX-co-stimulated these cells. Both compounds significantly and dose-dependently reduced tyrosinase activity, and at 10 μM were more potent than kojic acid at 20 μM. Compounds 1c and 1j also inhibited melanogenesis, which suggested that the inhibitory effects of these compounds on melanin production were mainly attributable to their inhibitions of tyrosinase. These results indicate that compounds 1c and 1j with the PUSC scaffold have potential use as whitening agents for the treatment of hyperpigmentation-associated diseases.
Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors
Harada, Koichiro,Kubo, Hideki,Abe, Jun,Haneta, Mari,Conception, Arnel,Inoue, Shinichi,Okada, Satoshi,Nishioka, Kazuhiko
experimental part, p. 3242 - 3254 (2012/07/27)
We have previously reported the discovery of a new class of potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17β-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17β-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100 mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4 h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer.
