Publications (17) View all
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Article: Drug discovery for breast cancer and co-instantaneous cardiovascular disease: what is the future?
Future medicinal chemistry 03/2013; 5(4):359-62. · 2.52 Impact Factor -
Article: Modulation of cytochromes P450 with xanthone-based molecules: from aromatase to aldosterone synthase and steroid 11beta-hydroxylase inhibition.
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ABSTRACT: Imidazolylmethylflavones previously reported by us as aromatase inhibitors proved to be able to interact with aldosterone synthase (CYP11B2), a cytochrome P450 enzyme involved in the biosynthesis of the mineralcorticoid hormone aldosterone, and were used to obtain a pharmacophore model for this enzyme. Here, in the search for potential ligands for CYP11B2 and the related CYP11B1, a virtual screening of a small compounds library of our earlier synthezised aromatase inhibitors was performed and, according to the results and the corresponding biological data, led to the design and synthesis of a series of xanthones derivatives carrying an imidazolylmethyl substituent in position 1 and different substituents in position 4. Some very potent inhibitors were obtained, in particular the 4-chlorine derivative was active in the low nanomolar or subnanomolar range on CYP11B2 and CYP11B1, respectively, proving that xanthone can be considered as an excellent scaffold, whose activity can be directed to different targets when appropriately functionalized.Journal of Medicinal Chemistry 01/2013; · 4.80 Impact Factor -
Article: Tetrahydropyrroloquinolinone Type Dual Inhibitors of Aromatase/Aldosterone Synthase as a Novel Strategy for Breast Cancer Patients with Elevated Cardiovascular Risks.
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ABSTRACT: The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.Journal of Medicinal Chemistry 01/2013; · 4.80 Impact Factor -
Article: Hits Identified in Library Screening Demonstrate Selective CYP17A1 Lyase Inhibition.
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ABSTRACT: A screening of structurally different steroid hormone synthesis inhibitors was performed in order to find a starting point for the development of a new inhibitor of the bifunctional steroidogenic enzyme CYP17A1. Emphasis was placed on determination of selectivity between the two catalytic steps, namely 17α-hydroxylase and C(17,20)-lyase. For that purpose a new inhibition assay has been developed. Hits identified within this novel assay demonstrated selective inhibition of CYP17A1 lyase activity, and thus mark the basis for the development of selective C(17,20)-lyase inhibitors for the treatment of prostate cancer.The Journal of steroid biochemistry and molecular biology 11/2012; · 2.66 Impact Factor -
Article: Selective dual inhibitors of CYP19 and CYP11B2: targeting cardiovascular diseases hiding in the shadow of breast cancer.
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ABSTRACT: Postmenopausal women are at high risk for cardiovascular diseases because of the estrogen deficiency. As for postmenopausal breast cancer patients, this risk is even higher due to inhibition of estrogens biosyntheses in peripheral tissue by the aromatase (CYP19) inhibitors applied. Because estrogen deficiency results in significantly elevated aldosterone levels, which are a major cause of cardiovascular diseases, dual inhibition of CYP19 and CYP11B2 (aldosterone synthase) is a promising treatment for breast cancer and the coinstantaneous cardiovascular diseases. By combination of important structural features of known CYP19 and CYP11B2 inhibitors, we succeeded in obtaining compounds 3 and 5 as selective dual inhibitors with IC(50) values around 50 and 20 nM toward CYP19 and CYP11B2, respectively. These compounds showed also good selectivity toward CYP11B1 (selectivity factors (IC(50 CYP11B1)/IC(50 CYP11B2)) around 50) and CYP17 (no inhibition).Journal of Medicinal Chemistry 08/2012; 55(16):7080-9. · 4.80 Impact Factor
