title: Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases.
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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA. mykhaylo.frasinyuk@ukr.net.|Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA. mykhaylo.frasinyuk@ukr.net.|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.
authors.forename: Mykhaylo S
authors.initials: MS
authors.lastname: Frasinyuk
authors.affiliation: Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv, 02094, Ukraine.
authors.forename: Galyna P
authors.initials: GP
authors.lastname: Mrug
authors.affiliation: Department of Chemistry, Taras Shevchenko Kyiv National University, Kyiv, 01601, Ukraine.
authors.forename: Svitlana P
authors.initials: SP
authors.lastname: Bondarenko
authors.affiliation: Department of Chemistry, Taras Shevchenko Kyiv National University, Kyiv, 01601, Ukraine.
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Khilya
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA.|Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA.
authors.forename: Vitaliy M
authors.initials: VM
authors.lastname: Sviripa
authors.affiliation: Central Laboratory for Quality Control of Medicines and Medical Products, Kyiv, 04053, Ukraine.
authors.forename: Oleksandr A
authors.initials: OA
authors.lastname: Syrotchuk
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA.|Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA.|Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Fiandalo
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA.|Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, 40536-0596, USA. dwatt@uky.edu.|Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0509, USA. dwatt@uky.edu.|Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0093, USA. dwatt@uky.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D061565:Cycloaddition Reaction; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis* / Q000494:pharmacology; D008352:Mannich Bases / Q000737:chemistry*; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014966:Xanthenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007529:Isoflavones; D008352:Mannich Bases; D011714:Pyrans; D014966:Xanthenes
keywords: Mannich reactions; inverse electron-demand Diels-Alder reaction; isoflavonoids; ortho-quinone methides; prostate cancer PC-3 cell line