http://hdl.handle.net/10033/108395 Leiter Prof. Dr. Rolf W. Hartmann Wed, 22 May 2013 03:34:22 GMT 2013-05-22T03:34:22Z http://hdl.handle.net/10033/269912 Title: 3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2. Authors: Yin, Lina; Hu, Qingzhong; Hartmann, Rolf W Abstract: Aldosterone synthase (CYP11B2) is a promising therapeutic target for the treatment of cardiovascular diseases related to abnormally high aldosterone levels. On the basis of our previously identified lead compounds I-III, a series of 3-pyridinyl substituted aliphatic cycles were designed, synthesized and tested as CYP11B2 inhibitors. Aromaticity abolishment of the core was successfully applied to overcome the undesired CYP1A2 inhibition. This study resulted in a series of potent and selective CYP11B2 inhibitors, with compound 12 (IC(50) = 21 nM, SF = 50) as the most promising one, which shows no inhibition toward CYP1A2 at 2 µM. The design conception demonstrated in this study can be helpful in the optimization of CYP inhibitor drugs regarding CYP1A2 selectivity. Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/10033/269912 2012-01-01T00:00:00Z http://hdl.handle.net/10033/266712 Title: Synthesis and aromatase inhibitory activity of some new 16E-arylidenosteroids. Authors: Bansal, Ranju; Thota, Sridhar; Karkra, Nalin; Minu, Maninder; Zimmer, Christina; Hartmann, Rolf W Abstract: A new series of 16E-arylidene androstene derivatives has been synthesized and evaluated for aromatase inhibitory activity. The impact of various aryl substituents at 16 position of the steroid skeleton on aromatase inhibitory activity has been observed. The 16E-arylidenosteroids 6, 10 and 11 exhibited significant inhibition of the aromatase enzyme. 16-(4-Pyridylmethylene)-4-androstene-3,17-dione (6, IC(50): 5.2 μM) and 16-(benzo-[1,3]dioxol-5-ylmethylene)androsta-1,4-diene-3,17-dione (11, IC(50): 6.4 μM) were found to be approximately five times more potent in comparison to aminoglutethimide. Sat, 01 Dec 2012 00:00:00 GMT http://hdl.handle.net/10033/266712 2012-12-01T00:00:00Z http://hdl.handle.net/10033/249356 Title: Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). Authors: Spadaro, Alessandro; Negri, Matthias; Marchais-Oberwinkler, Sandrine; Bey, Emmanuel; Frotscher, Martin Abstract: 17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC₅₀-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics. Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/10033/249356 2012-01-01T00:00:00Z http://hdl.handle.net/10033/246211 Title: Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties. Authors: Bansal, Ranju; Guleria, Sheetal; Thota, Sridhar; Bodhankar, Subhash L; Patwardhan, Moreshwar R; Zimmer, Christina; Hartmann, Rolf W; Harvey, Alan L Abstract: As a part of our investigations into the structural-activity relationship studies of a novel class of medicinally active 16-substituted steroids, several new 16-imidazolyl substituted steroidal derivatives have been synthesized and pharmacologically evaluated in the current study. The new steroidal analogues 5, 6, 8, 9, 11 and 12 exhibited moderate cytotoxic effects in sixty cancer cell lines derived from nine cancers types. The imidazolyl substituted steroidal derivatives 6 (DPJ-RG-1241) and 7 (RB-401) were obtained as the powerful inhibitors of aromatase with IC50=0.18 μM and IC50=0.168 μM, respectively, approximately 1.2 and 1.4 times more potent in comparison to standard drug exemestane. The bis-quaternary steroids 13 and 14 displayed potent skeletal muscle relaxant properties. An affinity constant of 0.007 μM was observed for compound 14 on frog rectus abdominis muscle preparation and 13 displayed a very high anticholinesterase activity K(i)=25 nM, approximately 115-fold higher in comparison to standard drug galanthamine (K(i)=2.9 μM). Tue, 01 May 2012 00:00:00 GMT http://hdl.handle.net/10033/246211 2012-05-01T00:00:00Z