2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3)

Gazvoda, Martin; Beranič, Nataša; Turk, Samo; Burja, Bojan; Kočevar, Marijan; Rižner, Tea Lanišnik; Gobec, Stanislav; Polanc, Slovenko

doi:10.1016/j.ejmech.2012.12.045

Cited by 10 publications

(8 citation statements)

References 30 publications

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“…AKR1C3 represents a rational target due to its vital role as “gatekeeper” for the production of potent androgens regardless of the pathway used and its ability to function as a coactivator for the AR. This underscores the intense attention the search for AKR1C3 inhibitors has generated. ,,,− …”

Section: Discussionmentioning

confidence: 99%

Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor

et al. 2016

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Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ4-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor

et al. 2016

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“…Our group and others have studied different classes of inhibitors for AKR1C3 in order to develop new therapeutics for the treatment of CRPC based on NSAID scaffolds [13, 14, 25, 26, 37, 39, 41–45]. Although inhibitors with nanomolar potency and high selectivity to AKR1C3 have been identified from these studies, the discovery of new compounds for preclinical development is still required.…”

Section: Discussionmentioning

confidence: 99%

Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)

Zang

Verma

Chen

et al. 2015

Chemico-Biological Interactions

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Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub- micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4′-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.

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“…N ‐Acylsulfonamides 2a ,12 2b ,13 2c ,12 2d ,12 2e ,12 2f ,14 2i ,1f 2l 12 and 2n 12 were prepared by the procedures described in the literature.…”

Section: Methodsmentioning

confidence: 99%

In Situ Formation of Vilsmeier Reagents Mediated by Oxalyl Chloride: a Tool for the Selective Synthesis of N‐Sulfonylformamidines

Gazvoda¹,

Kočevar²,

Polanc³

2013

Eur J Org Chem

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N‐Sulfonylformamidines were produced from sulfonamides or N‐acylated sulfonamides using Vilsmeier reagent obtained in situ from N,N‐disubstituted formamides and oxalyl chloride. Optically active substrates did not racemize during the process. The efficient and mild cleavage of N‐sulfonylformamidines can be achieved with hydrazine hydrate in ethanol. The entire procedure constitutes a simple method for protecting, and deprotecting, the sulfonamide moiety.

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2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3)

Cited by 10 publications

References 30 publications

Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor

Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor

Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)

In Situ Formation of Vilsmeier Reagents Mediated by Oxalyl Chloride: a Tool for the Selective Synthesis of N‐Sulfonylformamidines

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