Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

Sainas, Stefano; Pippione, Agnese Chiara; Giorgis, Marta; Lupino, Elisa; Goyal, Parveen; Ramondetti, Cristina; Buccinnà, Barbara; Piccinini, Marco; Braga, Rodolpho C.; Andrade, Carolina Horta; Andersson, Mikael; Moritzer, Ann Christin; Friemann, Rosmarie; Mensa, Stefano; Al-Karadaghi, Salam; Boschi, Donatella; Lolli, Marco Lucio

doi:10.1016/j.ejmech.2017.02.017

Cited by 51 publications

(57 citation statements)

References 37 publications

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“…[20,21] Recently, we successfully applied a scaffold hopping strategy based on the replacement of quinolinecarboxylate moiety of brequinar with a hydroxyazolecarboxamidic scaffold for the design of new potent human dihydroorotate dehydrogenase (hDHODH) inhibitors. [22] In the present study, we applied a similar scaffold hopping strategy to the FLU benzoic acid moiety ( Figure 2). Specifically, three hydroxyazoles (hydroxyfurazan, hydroxythiadiazole and a series of N-substituted hydroxyl-1,2,3-triazoles) were used to design compounds 1 -8 ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Pippione

Giraudo

Bonanni

et al. 2017

European Journal of Medicinal Chemistry

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The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.

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Section: Introductionmentioning

confidence: 99%

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Pippione

Giraudo

Bonanni

et al. 2017

European Journal of Medicinal Chemistry

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“…We have recently demonstrated that the regio‐substituted hydroxytriazole scaffold is an effective bioisosteric scaffold with a wide range of applications for drug design . We herein describe a variety of optimized strategies for the preparation of regio‐substituted hydroxytriazole derivatives that can be used as useful building blocks.…”

Section: Discussionmentioning

confidence: 99%

“…) has recently been successfully used to mimic the carboxylic function in the design of new potential drugs, as it can be deprotonated at physiological pH . As the search for new agents that are active in the central nervous system gathers pace, this moiety has led to promising glutamate analogues , novel sortilin inhibitors , new anticancer drugs , and new immunosuppressive agents being produced . Unlike with other hydroxyazole systems that are frequently used to mimic the carboxylic function , regio‐substitution at the nitrogen atoms of the hydroxytriazole ring allows for improved exploration of the chemical space of the biological target .…”

Section: Introductionmentioning

confidence: 99%

“…We have recently reported the preparation of N‐alkyl derivatives of ethyl 4‐benzyloxy‐1,2,3‐triazolcarboxylate 19 in ACN and potassium carbonate in which it was shown that alkylation only occurred on N(b) and N(c) , while the N(b)/N(c) alkylation ratio was governed by a combination of the electronic and steric effects of the alkyl bromine (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

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Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

Sainas

Pippione

Giraudo

et al. 2018

Journal of Heterocyclic Chem

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Acidic 4‐hydroxy‐1,2,3‐triazole is a proven bioisostere of acidic functions that has recently been used to replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis of the three possible N‐alkylated 4‐hydroxy‐1,2,3‐triazole regioisomers have been designed and reported herein, by identifying the optimal conditions under which the alkylation of ethyl 4‐benzyloxy‐1,2,3‐triazolecarboxylate (compound 19) can be regiodirected to the triazole N(b) position and thus produce the only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform for parallel synthesis, called Arachno and which has been patented by the authors' group, has been used to speed up the process, and an NMR study has been carried out to better understand the reactivity of compound 19 towards the N(b) position. A library of benzyloxy protected 4‐hydroxy‐1,2,3‐triazoles has been prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the N(a) isomers; the processes are described herein. The three N‐alkylated regioisomer series have been characterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4‐benzyloxy protective group on the N‐alkylated‐4‐benzyloxy‐5‐ethoxycarbonyl‐1,2,3‐triazoles provided the corresponding substituted 4‐hydroxy‐1,2,3‐triazoles.

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“…Since carboxylic acids are likely to be transported into cells by carrier-mediated processes rather than passive diffusion [57] , there are potential advantages in finding non-carboxylate inhibitors [58,59] . Following this rationale, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold [60] .…”

Section: Akr1c3mentioning

confidence: 99%

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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Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

Cited by 51 publications

References 37 publications

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

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

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