Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3

Endo, Shunsuke; Hu, Dawei; Matsunaga, Toshiyuki; Otsuji, Yoko; El‐Kabbani, Ossama; Kandeel, Mahmoud; Ikari, Akira; Hara, Akira; Kitade, Yukio; Toyooka, Naoki

doi:10.1016/j.bmc.2014.08.007

Cited by 21 publications

(19 citation statements)

References 36 publications

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“…In addition, recent studies have shown that polar substitutions (e.g. hydroxyl and carboxylate group) on the phenyl ring of cinnamic acid or the phenyl ring of the 4-dihydroxycinnamoyloxy group decreased the inhibition for AKR1C3 [37, 46, 47]. For example, the displacement of 4-dihydrocinnamoyloxy group by a hydroxyl group to form drupanin (see Table 1) resulted in a loss of inhibitory potency (IC 50 : 15 μM) and only a 7-fold selectivity for AKR1C3 versus AKR1C2.…”

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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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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“…Because of its structural differences with HSD17B3, an enzyme belonging to SDR family and catalysing the same reaction of AKR1C3 in testis [46] , AKR1C3 could be a good target for selective inhibition.…”

Section: Akr1c3mentioning

confidence: 99%

“…The structure activity relationship (SAR) of propolis-derived cinnamic acids suggested that the 3-prenyl moiety of baccharin is responsible for the selective binding to AKR1C3 [56] . Endo et al [46] also reported on the commercially available 3,4-dihydroxybenzaldehyde, derivatives configured with 3-aliphatic and aryl ethers instead of the 3-prenyl moiety. Within the series of aliphatic ethers, AKR1C3 inhibition was shown to decrease proportionally with increase in the aliphatic chain lengths.…”

Section: Akr1c3mentioning

confidence: 99%

“…The carboxylic group at position-3 provided selective inhibition ofSRD5A2, as all the compounds of this series showed minimal inhibition against the type I enzyme.4-azasteroid-2-oximes (structures [45][46][47] were reported to be active against the SRD5A enzymes present on rat ventral prostate extract (both type 1 and the type 2 isozymes were present) [99] . .…”

Section: Srd5amentioning

confidence: 99%

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Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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“…The presence of AKR1C3 expression in malignant cells has prompted numerous laboratories to synthesize AKR1C3-specific inhibitors which could be effective in solid tumors or leukemia. [42][43][44][45] Although synthesis of targeted inhibitors is a common approach to control malignant cell growth, Khanim et al found that the use of a specific inhibitor to AKR1C3 did not prevent tumor growth in an AML cell line following a high-throughput screen for AKR1C3 inhibitors. 45 The value of a preprodrug such as PR-104 is that it specifically targets cells expressing AKR1C3, without requiring the malignant cell to be reliant on this pathway for survival.…”

Section: Primary T-all Mononuclear Cells Are More Sensitive To Pr-104mentioning

confidence: 99%

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

Manesh

El-Hoss

Evans

et al. 2015

Blood

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Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3

Cited by 21 publications

References 36 publications

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

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

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

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