Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives

Sinreih, Maša (author), Jójárt, Rebeka (author), Kele, Zoltán (author), Büdefeld, Tomaž (author), Paragi, Gábor (author), Mernyák, Erzsébet (author), Lanišnik-Rižner, Tea (author)

Enzymes AKR1C regulate the action of oestrogens, androgens, and progesterone at the pre-receptor level and are also associated with chemo-resistance. The activities of these oestrone halides were investigated on recombinant AKR1C enzymes. The oestrone halides with halogen atoms at both C-2 and C-4 positions (13β-, 13α-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC$_{50}$ values were for the 13α-epimers 2_2I,4Br and 2_2I,4Cl (IC$_{50}$, 0.7 μM, 0.8 μM, respectively), both of which selectively inhibited the AKR1C1 isoform. The 13α-methyl-17-keto halogen derivatives 2_2Br and 2_4Cl were the most potent inhibitors of AKR1C2 (IC$_{50}$, 1.5 μM, 1.8 μM, respectively), with high selectivity for the AKR1C2 isoform. Compound 1_2Cl,4Cl showed the best AKR1C3 inhibition, and it also inhibited AKR1C1 (Ki: AKR1C1, 0.69 μM; AKR1C3, 1.43 μM). These data show that halogenated derivatives of oestrone represent a new class of potent and selective AKR1C inhibitors as lead compounds for further optimisations.

• Language: English
• Keywords: aldo-keto reductases, inhibition, halogenated oestrone derivatives, structure–activity relationships
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: Str. 1499–1507
• Numbering: Vol. 36, no. 1
• PID: 20.500.12556/RUL-144791
• UDC: 616-006
• ISSN on article: 1475-6366
• DOI: 10.1080/14756366.2021.1937142
• COBISS.SI-ID: 67617027
• Publication date in RUL: 13.03.2023

Record is a part of a journal

• Title: Journal of enzyme inhibition and medicinal chemistry
• Shortened title: J. enzyme inhib. med. chem.
• Publisher: Taylor & Francis
• ISSN: 1475-6366
• COBISS.SI-ID: 512255001

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: aldo-keto reduktaze, halogenirani derivati estrona, zaviranje