Development of 6H-Chromeno[3,4- c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues

Mykhaylo S Frasinyuk; Svitlana P Bondarenko; Vitaliy M Sviripa; Ravshan Burikhanov; Vivek M Rangnekar; Chunming Liu; David S Watt

doi:10.1016/j.tetlet.2015.01.028

Development of 6H-Chromeno[3,4- c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues

Tetrahedron Lett. 2015 Jun 3;56(23):3382-3384. doi: 10.1016/j.tetlet.2015.01.028.

Authors

Mykhaylo S Frasinyuk¹, Svitlana P Bondarenko², Vitaliy M Sviripa³, Ravshan Burikhanov⁴, Vivek M Rangnekar⁵, Chunming Liu⁶, David S Watt⁷

Affiliations

¹ Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv 02094, Ukraine.
² Taras Shevchenko Kyiv National University, Kyiv 01033, Ukraine.
³ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States ; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, United States.
⁴ Department of Radiation Medicine, College of Medicine; University of Kentucky, Lexington, KY 40536-0096, United States.
⁵ Department of Radiation Medicine, College of Medicine; University of Kentucky, Lexington, KY 40536-0096, United States ; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
⁶ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States ; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
⁷ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States ; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, United States ; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.

Abstract

Nitrosation and cyclization of 4-(3-aminothieno[2,3-b]pyridine-2-yl)-2H-chromen-2-ones 1 afforded substituted 6H-chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones 2 that inhibited the intermediary filament protein, vimentin, at low micromolar concentrations. This inhibition promoted the secretion of Prostate Apoptosis Response-4 protein (Par-4), which selectively triggered apoptosis in prostate cancer cells such as CWR22Rv1, LNCaP-derivative C4-2B, PC-3 and its aggressive analog, PC-3 MM2.

Keywords: Par-4; Prostate Apoptosis Response-4 protein; coumarin; prostate cancer; pyridazine; vimentin.

Abstract

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