Lead Optimization Providing a Series of Flavone Derivatives as Potent Nonsteroidal Inhibitors of the Cytochrome P450 Aromatase Enzyme

Gobbi, Silvia; Cavalli, Andrea; Rampa, Angela; Belluti, Federica; Piazzi, Lorna; Paluszcak, Anja; Hartmann, Rolf W.; Recanatini, Maurizio; Bisi, Alessandra

doi:10.1021/jm060186y

Cited by 91 publications

(71 citation statements)

References 14 publications

(35 reference statements)

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“…Many research groups, including our own, are still active in pursuing new entities that possess aromatase inhibitory properties. The latest publications in this field report flavone derivatives, [11] imidazolylmethylbenzophenones, [12] and (AE )-abyssinone II derivatives [13] as AIs; additionally, YM511-, letrozole-, and anastrozole-based derivatives have been reported as dual aromatase and steroid sulfatase inhibitors. [14][15][16] However, to the best of our knowledge, the exploitation of the biphenyl system, a putative steroidal A/C ring mimic, as a scaffold in the design of NSAIs has yet to be realised, although Hartmann et al have previously reported several imidazole-and triazole-substituted biphenyls as highly potent 17a-hydroxylase-C17,20-lyase (Cyp17) inhibitors for the potential treatment of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

et al. 2008

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The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC(50) value of 0.12 nM, although seven of its congeners are also highly potent (IC(50)

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Section: Introductionmentioning

confidence: 99%

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

et al. 2008

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“…Several examples have recently been documented: derivatization with imidazole, triazole, and pyridinyl moieties markedly increased the anti-aromatase potency of flavones and isoflavones through coordination between the nitrogen-containing heterocycle and the Fe 2 + ion of the aromatase heme group. [16,17] However, to fully understand the pharmaceutical and thera-peutic potential of these natural compounds in the treatment of breast cancer, a deeper rational study of the physicochemical determinants of their aromatase binding is needed.…”

Section: Introductionmentioning

confidence: 99%

Combining Computational and Biochemical Studies for a Rationale on the Anti‐Aromatase Activity of Natural Polyphenols

et al. 2007

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Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti‐aromatase activity of a set of natural polyphenolic compounds was evaluated in vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti‐aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques based on grid‐independent descriptors and molecular interaction fields, the major physicochemical features associated with inhibitory activity were disclosed, and a putative virtual active site of aromatase was proposed. Docking of the inhibitors into a 3D homology model structure of the enzyme defined a common binding mode for the small molecules under investigation. The good correlation between computational and biological results provides the first rationalization of the anti‐aromatase activity of polyphenolic compounds. Moreover, the information generated in this approach should be further exploited for the design of new aromatase inhibitors.

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“…Accordingly, introduction of substituents into the benzyloxy moiety might lead to further enhancement of selectivity. While this hypothesis was confirmed by the meta-methoxy (13), dimethoxy (16) and the chloro derivatives (17)(18)(19), the monomethoxy compounds (14)(15) showed different results. Compounds 14 (meta-methoxy, SF = 16) and 15 (para-methoxy, SF = 12) revealed similar selectivity toward 17b-HSD2 as the nonsubstituted benzyloxy compound 12 (SF = 13).…”

Section: Biologymentioning

confidence: 95%

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

et al. 2011

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An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17β-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nM (cell-free assay) and 78 nM (cellular assay), high selectivity for 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.

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Lead Optimization Providing a Series of Flavone Derivatives as Potent Nonsteroidal Inhibitors of the Cytochrome P450 Aromatase Enzyme

Cited by 91 publications

References 14 publications

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

Combining Computational and Biochemical Studies for a Rationale on the Anti‐Aromatase Activity of Natural Polyphenols

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

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