Vitaliy M Sviripa1,2,3, Michael V Fiandalo4, Kristin L Begley2,5, Przemyslaw Wyrebek2,5, Liliia M Kril2,5, Andrii G Balia2,5, Sean R Parkin6, Vivekanandan Subramanian7, Xi Chen8, Alexander H Williams1, Chang-Guo Zhan1,2, Chunming Liu3,5, James L Mohler4,9, David S Watt2,3,5. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596 USA. 2. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596 USA. 3. Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093 USA. 4. Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263 USA. 5. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509 USA. 6. Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40506 USA. 7. NMR Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596 USA. 8. College of Chemistry and Material Science, South Central University for Nationalities, Wuhan 430074, People's Republic of China. 9. Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263 USA.
Abstract
Androgen-deprivation therapy (ADT) is only a palliative measure, and prostate cancer invariably recurs in a lethal, castration-resistant form (CRPC). Prostate cancer resists ADT by metabolizing weak, adrenal androgens to growth-promoting 5α-dihydrotestosterone (DHT), the preferred ligand for the androgen receptor (AR). Developing small-molecule inhibitors for the final steps in androgen metabolic pathways that utilize 17-oxidoreductases required probes that possess fluorescent groups at C-3 and intact, naturally occurring functionality at C-17. Application of the Pictet-Spengler condensation to substituted 4-(2-aminoethyl)coumarins and 5α-androstane-3-ones furnished spirocyclic, fluorescent androgens at the desired C-3 position. Condensations required the presence of activating C-7 amino or N,N-dialkylamino groups in the 4-(2-aminoethyl)coumarin component of these condensation reactions. Successful Pictet-Spengler condensation, for example, of DHT with 9-(2-aminoethyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one led to a spirocyclic androgen, (3R,5S,10S,13S,17S)-17-hydroxy-10,13-dimethyl-1,2,2',3',4,5,6,7,8,8',9,9',10,11,12,12',13,13',14,15,16,17-docosahydro-7'H,11'H-spiro-[cyclopenta[a]phenanthrene-3,4'-pyrido[3,2,1-ij]pyrido[4',3':4,5]pyrano[2,3-f]quinolin]-5'(1'H)-one. Computational modeling supported the surrogacy of the C-3 fluorescent DHT analog as a tool to study 17-oxidoreductases for intracrine, androgen metabolism.
Androgen-deprivation therapy (ADT) is only a palliative measure, and n class="Disease">prostate cancer invariably recurs in a lethal, castration-resistant form (CRPC). Prostate cancer resists ADT by metabolizing weak, adrenal androgens to growth-promoting 5α-dihydrotestosterone (DHT), the preferred ligand for the androgen receptor (AR). Developing small-molecule inhibitors for the final steps in androgen metabolic pathways that utilize 17-oxidoreductases required probes that possess fluorescent groups at C-3 and intact, naturally occurring functionality at C-17. Application of the Pictet-Spengler condensation to substituted 4-(2-aminoethyl)coumarins and 5α-androstane-3-ones furnished spirocyclic, fluorescent androgens at the desired C-3 position. Condensations required the presence of activating C-7 amino or N,N-dialkylamino groups in the 4-(2-aminoethyl)coumarin component of these condensation reactions. Successful Pictet-Spengler condensation, for example, of DHT with 9-(2-aminoethyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one led to a spirocyclic androgen, (3R,5S,10S,13S,17S)-17-hydroxy-10,13-dimethyl-1,2,2',3',4,5,6,7,8,8',9,9',10,11,12,12',13,13',14,15,16,17-docosahydro-7'H,11'H-spiro-[cyclopenta[a]phenanthrene-3,4'-pyrido[3,2,1-ij]pyrido[4',3':4,5]pyrano[2,3-f]quinolin]-5'(1'H)-one. Computational modeling supported the surrogacy of the C-3 fluorescent DHT analog as a tool to study 17-oxidoreductases for intracrine, androgen metabolism.
Authors: Lara Sellés Vidal; Ciarán L Kelly; Paweł M Mordaka; John T Heap Journal: Biochim Biophys Acta Proteins Proteom Date: 2017-11-10 Impact factor: 3.036
Authors: Michael V Fiandalo; John J Stocking; Elena A Pop; John H Wilton; Krystin M Mantione; Yun Li; Kristopher M Attwood; Gissou Azabdaftari; Yue Wu; David S Watt; Elizabeth M Wilson; James L Mohler Journal: Oncotarget Date: 2018-01-10