Mykhaylo S Frasinyuk1,2,3, Galyna P Mrug4, Svitlana P Bondarenko5, Volodymyr P Khilya5, Vitaliy M Sviripa6,7, Oleksandr A Syrotchuk8, Wen Zhang6,9, Xianfeng Cai6,9, Michael V Fiandalo10, James L Mohler10, Chunming Liu6,9, David S Watt11,12,13. 1. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA. mykhaylo.frasinyuk@ukr.net. 2. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA. mykhaylo.frasinyuk@ukr.net. 3. Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, 02094, Ukraine. mykhaylo.frasinyuk@ukr.net. 4. Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, 02094, Ukraine. 5. Department of Chemistry, Taras Shevchenko Kyiv National University, Kyiv, 01601, Ukraine. 6. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA. 7. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA. 8. Central Laboratory for Quality Control of Medicines and Medical Products, Kyiv, 04053, Ukraine. 9. Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA. 10. Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. 11. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA. dwatt@uky.edu. 12. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA. dwatt@uky.edu. 13. Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA. dwatt@uky.edu.
Abstract
The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6-substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μm concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.
The regioselective condensations of various 7-hydroxyisoflavonoids with n class="Chemical">bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6-substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μm concentration range in an in vitro proliferation assay using the PC-3prostate cancer cell line.
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