PMID- 35074339
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20220217
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 354
DP  - 2022 Feb 25
TI  - Reduction of photoswitched, nitrogen bridged N-acetyl diazocines limits 
      inhibition of 17betaHSD3 activity in transfected human embryonic kidney 293 cells.
PG  - 109822
LID - S0009-2797(22)00027-8 [pii]
LID - 10.1016/j.cbi.2022.109822 [doi]
AB  - Testosterone depletion is a common aim in the treatment of hormone-dependent 
      prostate cancer, since the steroid boosts the tumor's proliferation. Therefore, 
      inhibition of 17beta-hydroxysteroid dehydrogenase type 3 (17betaHSD3), which catalyzes 
      the carbonyl reduction of androstenedione to testosterone, represents an 
      expedient therapeutic drug target. Among the compounds targeting 17betaHSD3, 
      tetrahydrodibenzazocines have been reported to be highly potent inhibitors. Thus, 
      we hypothesized that structural analogs to the tetrahydrodibenzazocine scaffold, 
      namely diazocines, which contain an azo group instead of the ethylene moiety, are 
      also able to inhibit 17betaHSD3. Diazocines consist of a photoresponsive core and 
      can be isomerized from Z into E configuration by irradiation with a specific 
      wavelength. In the present study, 17betaHSD3 inhibition by diazocine photoisomers 
      was examined in transfected human embryonic kidney 293 cells (HEK-293) and 
      isolated microsomes. For this purpose, cells or microsomes were treated with 
      androstenedione and incubated for 2 or 24 h in the presence or absence of 
      irradiated and non-irradiated diazocines. Testosterone formation was determined 
      by uHPLC. We report a weak inhibition of 17betaHSD3 activity by diazocines in 
      HEK-293 cells and microsomes. Furthermore, we found no significant difference 
      between samples treated with irradiated and non-irradiated diazocines in terms of 
      inhibition. However, we detected a new compound by HPLC analysis, which only 
      appeared in light-treated samples, indicating a chemical modification of the 
      photoswitched diazocines, presumably rendering them ineffective. Further 
      investigations revealed that this modification occurs in the presence of reducing 
      agents like dithiothreitol and glutathione. A preliminary mass-spectrometric 
      analysis suggests that the N-N double bond is reduced, resulting in a dianiline 
      derivative. Nevertheless, optimized photoswitchable diazocine derivatives, which 
      are stable in a cellular environment, might serve as potent 17betaHSD3 inhibitors, 
      effective only in irradiated tissue.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Wages, F
AU  - Wages F
AD  - Institute of Toxicology and Pharmacology for Natural Scientists, University 
      Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105, Kiel, 
      Germany.
FAU - Lentes, P
AU  - Lentes P
AD  - Otto Diels Institute of Organic Chemistry, Christian Albrechts University Kiel, 
      Otto Hahn Platz 4, 24118, Kiel, Germany.
FAU - Griebenow, T
AU  - Griebenow T
AD  - Otto Diels Institute of Organic Chemistry, Christian Albrechts University Kiel, 
      Otto Hahn Platz 4, 24118, Kiel, Germany.
FAU - Herges, R
AU  - Herges R
AD  - Otto Diels Institute of Organic Chemistry, Christian Albrechts University Kiel, 
      Otto Hahn Platz 4, 24118, Kiel, Germany.
FAU - Peifer, C
AU  - Peifer C
AD  - Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstrasse 
      76, 24118, Kiel, Germany.
FAU - Maser, E
AU  - Maser E
AD  - Institute of Toxicology and Pharmacology for Natural Scientists, University 
      Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105, Kiel, 
      Germany. Electronic address: maser@toxi.uni-kiel.de.
LA  - eng
PT  - Journal Article
DEP - 20220121
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.- (17beta-hydroxysteroid dehydrogenase type 3)
SB  - IM
MH  - *17-Hydroxysteroid Dehydrogenases
OTO - NOTNLM
OT  - 17beta-hydroxysteroid dehydrogenase 3
OT  - Glutathione
OT  - Irradiation
OT  - N-acetyl diazocine
OT  - Photopharmacology
OT  - Photoswitch
OT  - Prostate cancer
EDAT- 2022/01/26 06:00
MHDA- 2022/02/19 06:00
CRDT- 2022/01/25 05:40
PHST- 2021/09/11 00:00 [received]
PHST- 2022/01/11 00:00 [revised]
PHST- 2022/01/18 00:00 [accepted]
PHST- 2022/01/26 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2022/01/25 05:40 [entrez]
AID - S0009-2797(22)00027-8 [pii]
AID - 10.1016/j.cbi.2022.109822 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2022 Feb 25;354:109822. doi: 10.1016/j.cbi.2022.109822. Epub 
      2022 Jan 21.