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

Vitaliy M. Sviripa, Michael V. Fiandalo, Kristin L. Begley, Przemyslaw Wyrebek, Liliia M. Kril, Andrii G. Balia, Sean R. Parkin, Vivekanandan Subramanian, Xi Chen, Alexander H. Williams, Chang Guo Zhan, Chunming Liu, James L. Mohler, David S. Watt

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)13415-13429
Number of pages15
JournalNew Journal of Chemistry
Volume44
Issue number31
DOIs
StatePublished - Aug 21 2020

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)
  • Materials Chemistry

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