Issue 31, 2020

Pictet–Spengler condensations using 4-(2-aminoethyl)coumarins


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.

Graphical abstract: Pictet–Spengler condensations using 4-(2-aminoethyl)coumarins

Supplementary files

Article information

Article type
27 May 2020
20 Jul 2020
First published
22 Jul 2020

New J. Chem., 2020,44, 13415-13429

Author version available

Pictet–Spengler condensations using 4-(2-aminoethyl)coumarins

V. M. Sviripa, M. V. Fiandalo, K. L. Begley, P. Wyrebek, L. M. Kril, A. G. Balia, S. R. Parkin, V. Subramanian, X. Chen, A. H. Williams, C. Zhan, C. Liu, J. L. Mohler and D. S. Watt, New J. Chem., 2020, 44, 13415 DOI: 10.1039/D0NJ02664F

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