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

Jackson, Toby; Woo, L. W. Lawrence; Trusselle, Melanie; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1002/cmdc.200700266

Cited by 27 publications

(31 citation statements)

References 26 publications

(42 reference statements)

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“…This type of interaction is typically recognized by force field-based docking software via a point-charge-term which is most likely not representative of this bond. Therefore, Fe-N constraints are in some cases applied in screening compound libraries against cytochrome P450 enzymes 15 16 32 .…”

Section: Discussionmentioning

confidence: 99%

“…with sp 2 -hybridized nitrogen atoms. Force field-based docking algorithms fail to properly describe this type of semi-covalent bond formation 15 16 . To overcome this problem, density functional theory (DFT) calculations were used to describe the nitrogen-iron interaction 17 in combination with a haem-tailored structure-based virtual screening to suggest novel non-steroidal CYP17A1 inhibitors.…”

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confidence: 99%

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Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Bonomo

Hansen

Petrunak

et al. 2016

Sci Rep

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Cytochrome P450 17A1 (CYP17A1) is an important target in the treatment of prostate cancer because it produces androgens required for tumour growth. The FDA has approved only one CYP17A1 inhibitor, abiraterone, which contains a steroidal scaffold similar to the endogenous CYP17A1 substrates. Abiraterone is structurally similar to the substrates of other cytochrome P450 enzymes involved in steroidogenesis, and interference can pose a liability in terms of side effects. Using nonsteroidal scaffolds is expected to enable the design of compounds that interact more selectively with CYP17A1. Therefore, we combined a structure-based virtual screening approach with density functional theory (DFT) calculations to suggest non-steroidal compounds selective for CYP17A1. In vitro assays demonstrated that two such compounds selectively inhibited CYP17A1 17α-hydroxylase and 17,20-lyase activities with IC 50 values in the nanomolar range, without affinity for the major drugmetabolizing CYP2D6 and CYP3A4 enzymes and CYP21A2, with the latter result confirmed in human H295R cells.Prostate cancer (PCa) is the second most common type of cancer in men and the fifth leading cause of death worldwide 1 . Several treatments have been developed against PCa, but drug resistance occurs rapidly, leading to a disease state known as castration-resistant prostate cancer (CRPC) 2,3 . In CRPC, androgens produced by the tumour and/or the adrenal gland drive disease progression. Thus, reduction or suppression of hormone levels in the cancer cells remains a key point in advanced stages of the disease.Cytochrome P450 17A1 (CYP17A1) is a monooxygenase involved in the synthesis of steroidal hormones. CYP17A1 converts pregnenolone to dehydroepiandrosterone and progesterone to androstenedione by two subsequent reactions, the 17α -hydroxylase and 17,20-lyase reactions (cf. Fig. 1). The hydroxylase reaction generates intermediates in the biosynthesis of glucocorticoids, while both hydroxylase and lyase reactions are required for biosynthesis of androgens and oestrogens 4 . CYP17A1 is therefore a pivotal target in the treatment of hormone-dependent tumours such as prostate cancer [5][6][7] .Several CYP17A1 inhibitors have been developed over the years, but only abiraterone (cf. Fig. 2) has been approved by the FDA for treating CRPC. Abiraterone consists of a steroidal scaffold with a pyridin-3-yl moiety in position 17 that inhibits CYP17A1 through coordination to the haem iron 8 . Oxygen binding to the haem iron is necessary for all CYP17A1 catalysis, so abiraterone binding is inhibitory. Together, the steroidal scaffold and the aromatic nitrogen-containing ring give abiraterone a promiscuous profile with affinity toward steroid receptors and other CYP enzymes, which likely contribute to the undesirable side effects observed in patients receiving abiraterone treatment 9 . Combinatorial synthesis programmes have been started by pharmaceutical companies to identify non-steroidal inhibitors and two such compounds, orteronel 10 and VT-464 11 , have been evaluate...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Bonomo

Hansen

Petrunak

et al. 2016

Sci Rep

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“…One obvious route to take would be to repeat the two aforementioned strategies for designing a DASI and apply them to other reported aromatase and STS inhibitors. However, repetitive application of the same strategies lacks some novelty and so pursuing a new design approach seemed more desirable and challenging .On reviewing computational docking studies of leading DASIs and other related molecules performed with a homology model of aromatase, 19,23,25 we noticed that the molecules docked in different orientations with unoccupied space available within the enzyme site. This observation suggested that further interactions with available amino acid residues might be exploited in principle if additional functionality could be built into the docked molecule in a complementary manner.…”

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Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity

Woo

Bubert

Purohit

et al. 2010

ACS Med. Chem. Lett.

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Single agents against multiple drug targets are highly topical. Hormonedependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS), and several dual aromatase-sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC 50 : aromatase, 15 pM; STS, 830 pM) and 15 (IC 50 : aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.KEYWORDS: Hybrid, dual inhibitors, aromatase, sulfatase, cancer E strogen deprivation has been an effective therapeutic intervention for hormone-dependent breast cancer (HDBC). One established and clinically proven approach involves the inhibition of the aromatase enzyme, 1-3 although the inhibition of steroid sulfatase (STS) is an emerging new strategy, as demonstrated by promising results for STX64 (Irosustat, BN83495), [4][5][6] the first STS inhibitor that entered clinical trials. Since both aromatase and STS are targets for treating HDBC, it has been reasoned that estrogen deprivation may be more comprehensively achieved by dual inhibition of both enzymes.Designing single agents that act against multiple biological targets is of increasing interest and prominence. In recent years, an increasing volume of work has been published exemplifying the successful use of this strategy. [7][8][9][10][11][12][13][14][15][16][17] We have pioneered this approach to augment our strategy directed at the first-in-class clinical target of STS inhibition and successfully developed three series of single agent dual aromatase and sulfatase inhibitors (DASIs) that are sulfamate derivatives of the nonsteroidal aromatase inhibitor (AI) 4-((4-bromobenzyl)-[1,2,4]-triazol-4-ylamino)benzonitrile (1) (e.g., 2 and 3), 18-20 letrozole 4 (e.g., 5), 21,22 and anastrozole 6 (e.g., 7) (Figure 1). 23 The design of these DASIs shares a common principle of engendering the irreversible STS inhibitory pharmacophore (ie. an aryl sulfamate ester, ArOSO 2 NH 2 ) into a clinical or experimental AI with minimal structural change incurred on the original scaffold in order to retain and maximize aromatase inhibition. More recently, a different design approach was employed. A series of biphenyl-based DASIs was developed as a result of incorporating the reversible aromatase inhibitory pharmacophore, which is principally a heme-ligating nitrogen-containing heterocycle, into a known sulfamate-based STS inhibitor (e.g., 8 and 9, Figure 1). 24 On evaluating the lead candidates from these four structural classes of DASI, all of them showed in vitro and in vivo dual inhibito...

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“…=100 n m , IC 50 STS =227 n m ). A previous SAR study on nonsteroidal AIs that are based on a biphenyl template (e.g., 8 , Figure 1) demonstrated that a cyano group substituted at the position on the phenyl ring para to a haem-ligating moiety, such as the triazolylmethyl group, is important for potent aromatase inhibition 41. Either the removal of the cyano group or the replacement of it with a fluorine or a chlorine atom leads to derivatives that are significantly weaker AIs 41.…”

Section: Resultsmentioning

confidence: 99%

“…A previous SAR study on nonsteroidal AIs that are based on a biphenyl template (e.g., 8 , Figure 1) demonstrated that a cyano group substituted at the position on the phenyl ring para to a haem-ligating moiety, such as the triazolylmethyl group, is important for potent aromatase inhibition 41. Either the removal of the cyano group or the replacement of it with a fluorine or a chlorine atom leads to derivatives that are significantly weaker AIs 41. Docking studies on this class of biphenyl-based AIs into a homology model of human aromatase (PDB code: 1TQA) revealed that the cyano group might interact favourably with Ser478 of the active site through hydrogen bond interactions 41…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

Woo¹,

Wood²,

Bubert³

et al. 2013

ChemMedChem

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4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nm, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nm in the same assay.

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

Cited by 27 publications

References 26 publications

Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity

Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

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