Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases

• Published in: ChemMedChem Vol. 11; no. 6; pp. 600 - 611
• Main Authors: Frasinyuk, Mykhaylo S., Mrug, Galyna P., Bondarenko, Svitlana P., Khilya, Volodymyr P., Sviripa, Vitaliy M., Syrotchuk, Oleksandr A., Zhang, Wen, Cai, Xianfeng, Fiandalo, Michael V., Mohler, James L., Liu, Chunming, Watt, David S.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 17.03.2016; Wiley; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Cycloaddition Reaction; Humans; inverse electron-demand Diels-Alder reaction; Isoflavones - chemical synthesis; Isoflavones - pharmacology; isoflavonoids; Life Sciences & Biomedicine; Mannich Bases - chemistry; Mannich reactions; ortho-quinone methides; Pharmacology & Pharmacy; prostate cancer PC-3 cell line; Pyrans - chemical synthesis; Pyrans - pharmacology; Science & Technology; Stereoisomerism; Xanthenes - chemical synthesis; Xanthenes - pharmacology; inverse electron-demand Diels-Alder reaction; DIELS-ALDER REACTIONS; ELECTRON-RICH DIENES; Mannich reactions; CASTRATION; MILD; INHIBITION; FUNGUS XYLARIA SP; PROSTATE-CANCER; ABIRATERONE ACETATE; CYP17; ortho-quinone methides; isoflavonoids; prostate cancer PC-3 cell line
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600008

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. Thermally generated ortho‐quinone methides from Mannich bases of 7‐hydroxyisoflavones or from 8‐methoxymethyl‐ or 8‐hydroxymethyl 7‐hydroxyisoflavones trapped a variety of electron‐rich dienophiles to give various inverse electron‐demand Diels–Alder adducts in good yields. Selected adducts displayed good activity in a proliferation assay using the PC‐3 prostate cancer cells.