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Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors.

Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors.

Authors :
Jójárt R
Laczkó-Rigó R
Klement M
Kőhl G
Kecskeméti G
Özvegy-Laczka C
Mernyák E
Source :
Bioorganic chemistry [Bioorg Chem] 2021 Jul; Vol. 112, pp. 104914. Date of Electronic Publication: 2021 Apr 20.
Publication Year :
2021

Abstract

Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific membrane transporter mediating the cellular uptake of various exo- and endobiotics, including drugs and steroid hormones. Increased uptake of steroid hormones by OATP2B1 may increase tumor proliferation. Therefore, understanding OATP2B1's substrate/inhibitor recognition and inhibition of its function, e.g., in hormone-dependent tumors, would be highly desirable. To identify the crucial structural features that correlate with OATP2B1 inhibition, here we designed modifications at four positions of the estrane skeleton. 13α- or 13β-estrone phosphonates modified at ring A or ring D were synthesized. Hirao and Cu(I)-catalyzed azide-alkyne click reactions served in the syntheses as key steps. 13β-Derivatives displayed outstanding OATP2B1 inhibitory action with IC <subscript>50</subscript> values in the nanomolar range (41-87 nM). A BODIPY-13α-estrone conjugate was additionally synthesized, modified at C-3-O of the steroid, containing a four-carbon linker between the triazole moiety and the BODIPY core. The fluorescent conjugate displayed efficient, submicromolar OATP2B1 inhibitory potency. The newly identified inhibitors and the structure-activity relationships specified here promote our understanding about drug recognition of OATP2B1.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1090-2120
Volume :
112
Database :
MEDLINE
Journal :
Bioorganic chemistry
Publication Type :
Academic Journal
Accession number :
33932771
Full Text :
https://doi.org/10.1016/j.bioorg.2021.104914