Derivatives of Exemestane — Synthesis and Evaluation of Aromatase Inhibition.

Goerlitzer, K.; Bonnekessel, Ch.; Jones, Peter G.; Palusczak, Anja; Hartmann, Robert C.

doi:10.1002/chin.200644185

Cited by 4 publications

(6 citation statements)

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“…Although the stereochemistry at the 6-position was not assigned in the current paper, we speculate the stereo orientation for the 6 substitute is “ α ” for both synthesized 6-EXE-cys and 6-17 β -DHE-cys based on the proton coupling constant between the proton at the 4-position and the proton at the 6-position of both EXE-cys and 17 β -DHE-cys conjugates. For 6-substituted steroids, long-distance coupling between H-4 and H-6 in 1 H NMR will be observed only when the 6-substituent is in the α position ( Chin and Warren, 1972 ; Schneider et al, 1973 ; Numazawa and Oshibe, 1994 ; Numazawa and Yamaguchi, 1998 ; Görlitzer et al, 2006 ). In an analysis of a series of 6-substituted phenylaliphatic steroids, Numazawa and Yamaguchi (1998) demonstrated that proton coupling between the hydrogens at the 4- and 6-positions was only observed for the 6 α -substituted, but not the 6 β -substituted, phenylaliphatic steroids.…”

Section: Discussionmentioning

confidence: 99%

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

et al. 2018

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Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although the known major metabolic pathway for EXE is reduction to form the active 17b-dihydro-EXE (17b-DHE) and subsequent glucuronidation to 17b-hydroxy-EXE-17-O-b-D-glucuronide (17b-DHE-Gluc), previous studies have suggested that other major metabolites exist for exemestane. In the present study, a liquid chromatography-mass spectrometry (LC-MS) approach was used to acquire accurate mass data in MS E mode, in which precursor ion and fragment ion data were obtained simultaneously to screen novel phase II EXE metabolites in urine specimens from women taking EXE. Two major metabolites predicted to be cysteine conjugates of EXE and 17b-DHE by elemental composition were identified. The structures of the two metabolites were confirmed to be 6-methylcysteinylandrosta-1,4-diene-3,17-dione (6-EXE-cys) and 6-methylcysteinylandrosta-1,4-diene-17b-hydroxy-3-one (6-17b-DHE-cys) after comparison with their chemically synthesized counterparts. Both underwent biosynthesis in vitro in three stepwise enzymatic reactions, with the first involving glutathione conjugation. The cysteine conjugates of EXE and 17b-DHE were subsequently quantified by liquid chromatography-mass spectrometry in the urine and matched plasma samples of 132 subjects taking EXE. The combined 6-EXE-cys plus 6-17b-DHE-cys made up 77% of total EXE metabolites in urine (vs. 1.7%, 0.14%, and 21% for EXE, 17b-DHE, and 17b-DHE-Gluc, respectively) and 35% in plasma (vs. 17%, 12%, and 36% for EXE, 17b-DHE, and 17b-DHE-Gluc, respectively).

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Section: Discussionmentioning

confidence: 99%

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

et al. 2018

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“…SCXRD analysis revealed that EX crystallizes in the orthorhombic space group P2 1 2 1 2 1 (Gö rlitzer et al, 2006), whereas the co-crystal crystallizes in the monoclinic space group P2 1 ; hence EX and TH are independent asymmetric moieties in the unit cell with Z = 2, as depicted in Table 1. Structural analysis revealed that EX and its co-crystal are both composed of four transfused rings (A-D).…”

Section: Resultsmentioning

confidence: 99%

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity

Fatima

Kumar

Choudhary

et al. 2020

IUCrJ

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Co-crystallization is a phenomenon widely employed to enhance the physiochemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methylideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of cocrystals of exemestane with thiourea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thiourea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-HÁ Á ÁO hydrogen bonding between the amine (NH 2 ) groups of thiourea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC 50 = 3.86 AE 0.31 mg ml À1 ) compared with the API (exemestane), which was found to be inactive, and the co-former (thiourea) (IC 50 = 21.0 AE 1.25 mg ml À1 ), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

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“…Compound (I) shares structural and physicochemical similarities with the natural substrate of the enzyme, androstenedione (Busetta et al, 1972), and with exemestane (Gorlitzer et al, 2006), an important aromatase inhibitor, suggesting a common aromatase recognition mechanism. In particular, the three compounds have very hydrophobic scaffolds and two hydrogen-bond acceptors at equivalent positions, viz.…”

Section: Commentmentioning

confidence: 96%

“…The cyclopentane B-nor ring assumes a 9-envelope conformation [puckering parameters: q 2 = 0.435 (2) Å and ' 2 = 288.2 (3) ; pseudorotation and asymmetry parameters: Á = 181.3 (2), ' m = 44.2 (1), ÁC s (9) = 1.0 (2), ÁC 2 (8,9) = 22.4 (2) ]. The pseudo-torsion angle C19-C10Á Á ÁC13-C18 of 6.9 (2) indicates that the B-nor steroid molecule is twisted compared with androstenedione or exemestane, for which values of À1.57 and 0.1 (2) , respectively, were determined by Busetta et al (1972) and Gorlitzer et al (2006). This twist can be understood as a normal consequence of the replacement of the six-membered B ring by a five-membered ring.…”

Section: Figurementioning

confidence: 99%

6β-Methyl-B-norandrostenedione

et al. 2010

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The title compound, C 19 H 26 O 2 , a B-norandrogen with a 6methyl group, is a recently identified and experimentally tested potent new aromatase inhibitor. It shares structural and physicochemical similarities both with the natural substrate of the enzyme, androstenedione, and with exemestane, another potent aromatase inhibitor having a 6-methylidene group. X-ray diffraction results indicate that the B-nor molecule and exemestane have nearly the same oxygen-oxygen and methylmethyl separations, though they have distinct configurations of the hydrophobic groups at the 6-position. These structural comparisons allow correlations to be inferred between the active site geometry of the molecules and the aromatase inhibition power of the studied compound.

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Derivatives of Exemestane — Synthesis and Evaluation of Aromatase Inhibition.

Cited by 4 publications

References 0 publications

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity

6β-Methyl-B-norandrostenedione

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