Pregnane Derivatives Research Articles

Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5α-reductase inhibitors

Normal growth and development of human prostate is regulated by the androgens which balances cell proliferation and apoptosis. Testosterone (T) and dihydrotestosterone (DHT) are the two key androgens that stimulate most of the androgen action in prostate. Testosterone is converted to DHT by the membrane bound NADPH-dependent 5α-reductase enzyme. As a consequence of the important observation that progesterone and deoxycortisone inhibits the synthesis of DHT by competing with 4-en-3-one function of the testosterone for the 5α-reductase enzyme a number of pregnane derivatives were synthesized and have been reported as inhibitors of human 5α-reductase enzyme. Due to lack of information on the crystal structure of human 5α-reductase, ligand-based 3D-QSAR study has been performed on pregnane derivatives using self-organizing molecular field analysis (SOMFA) for rationalizing the molecular properties and human 5α-reductase inhibitory activities. The statistical results having good cross-validated rcv2 (0.881), non-cross-validated r2 (0.893) and F-test value (175.527), showed satisfied predictive ability rpred2 (0.777). Analysis of SOMFA models through electrostatic and shape grids provide useful information for the design and optimization of steroidal structure as novel human 5α-reductase inhibitors.

Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents

Synthesis of a number of novel pregnane derivatives has been described in detail. They were prepared by reaction of 3β-hydroxy-5, 16-pregnadiene-20-one (2) with diethylene glycol, 2-methoxy ethanol, 1,2-propane diol, p-chloroaniline and p-fluoroaniline, respectively. The structures of these newly synthesized compounds have been established on basis of physical, analytical and spectral data. These pregnane derivatives have been evaluated for their anti-dyslipidemic activity (Triton model) and in vitro antioxidant activities. Out of the 12 compounds tested, 3 of them showed potent anti-dyslipidemic activity and 7 showed potent antioxidant and scavenger of oxygen free radicals.

Synthesis of Pregnane Derivatives, Their Cytotoxicity on LNCap and PC-3 Cells, and Screening on 5α-Reductase Inhibitory Activity

A series of epoxy- and/or 20-oxime pregnanes were synthesized from commercially available pregnenolone. Compounds 1, 3, 7, 8 and 11-13 were evaluated for cytotoxicity activity towards LNCaP (androgen-dependent) and PC-3 (androgen-independent) prostate cancer cells. Compound 13 showed the highest activity on both LNCaP (IC50 15.17 μM) and PC-3 (IC50 11.83 μM) cell lines. Compound 11 showed weak activity on LNCaP cells (IC 50 71.85 μM) and 8 showed the weak activity on PC-3 cells (IC50 68.95 μM), respectively. The 5α-reductase II (5AR2) inhibitory effects of compounds 1-3, 5 and 7-13 were investigated in a convenient screening model, in which compounds 5, 8, 11 and 12 were observed to be potential inhibitors of 5α-reductase, in particular, the 4-azasteroid 11, that also inhibited cell proliferation of androgen-dependent cells and 8, that in addition inhibited PC-3 cells more potently than LNCaP cells.

Novel C-6 substituted and unsubstituted pregnane derivatives as 5α-reductase inhibitors and their effect on hamster flank organs diameter size

The present study is addressed to ascertain the inhibitory effect of several progesterone derivatives having a chlorine substituent at C-6 (12a–12d), 15 with a bromine substituent at C-6 and 14a–14d, without any halogen atom at C-6 all having an ester side chain at C-17 (benzoate ester bearing a Cl, F and a Br atom at C-4 position of the phenyl ring) on the 5α-reductase enzyme activity present in human prostate. In addition, it was also of interest to investigate the pharmacological effect on hamster flank organs diameter size.In order to study the structure–activity relationships of steroids 12a–12d, 14a–14d and 15 we determined the concentration of these steroids that inhibited 50% of the activity of human prostate 5α-reductase enzyme (IC50), as well as the in vivo effect of these compounds in the hamster flank organs diameter size. We also ascertained, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol using labeled mibolerone (MIB) for monitoring the binding to the androgen receptor.The results from this study indicated that compounds 12a–12d (having a chlorine substituent at C-6), 14a–14d (lacking a halogen atom at C-6), 13 and 15 (having a bromine atom at C-6) showed an increased antiandrogenic effect (lower value for the diameter of the flank organs) as compared to the flank organs from testosterone-treated hamsters. On the other hand, the series of compounds containing a chlorine substituent at C-6 compounds (12a–12d) showed a higher antiandrogenic activity as compared to the compounds lacking a halogen atom at C-6 (14a, 14b and 14d). Although compounds 13 and 15 decreased the flank organs diameter size, however, this increase was not statistically significant as compared to that of the commercially available product finasteride. The steroidal derivatives 13, 14a–14d (lacking the chlorine substituent at C-6) and 15 (having a bromine atom at C-6) exhibited a higher 5α-reductase inhibitory activity (lower IC50 values) as compared to the series of compounds 12a–12d having the halogen substituent at C-6.Finasteride reduced the diameter size of the flank organs. The effect of this steroid and compounds 12a–12d, 13, 14a–14d and 15 on hamster flank organs can be explained by the fact that these steroids did not bind to the androgens receptor, which indicates that its mechanism of action is an inhibiting for the 5α-reductase activity. This enzyme is present in the hamster flank organs and was inhibited by the novel steroids in the human prostate homogenates.

6β-Hydroxy-5β-methyl-20-oxo-19-norpregn-9(10)-en-3β-yl acetate

In the title compound, C(23)H(34)O(4), which is an intermediate in the synthesis of pregnane derivatives with a modified skeleton that show potent abortion-inducing activity, the conformation of ring B is close to half-chair due to the presence of both the C=C double bond and the axial 5beta-methyl group. Rings A and C have conformations close to chair, while ring D has a twisted conformation around the bridgehead C-C bond. Molecules are hydrogen bonded via the hydroxyl and acetoxy groups into infinite chains. Quantum-mechanical ab initio Roothan Hartree-Fock calculations show that crystal packing might be responsible for the low values of the angles between rings A and B, and between ring A and rings C and D, as well as for a different steric position of the methyl ketone side chain compared to the geometry of the free molecule.

Synthesis of C3, C5, and C7 pregnane derivatives and their effect on NMDA receptor responses in cultured rat hippocampal neurons

The synthesis of several novel 5α- and 5β-20-oxo-pregnane derivatives substituted in the position 3 and 7 of the steroid skeleton is described. Activity of synthesized compounds was studied in voltage-clamped cultured rat hippocampal neurons. Substituted derivatives inhibited NMDA-elicited neuronal activity. The relationship between biological activity and structure is discussed.

Biological activity of novel progesterone derivatives having a bulky ester side chains at C-3

Antiandrogens are widely used agents for the treatment of androgen dependent diseases as inhibitors of androgen receptors (AR) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of the structure of the ligand in relation with the nuclear co-repressors. In the present study, we investigated the relationship between log P (the partition coefficient) of four pregnane derivatives 9a–9d and their biological activity. For this purpose, we determined the relative binding affinity (RBA) of steroids 9a–9d to androgen receptor (AR) obtained from rat prostate cytosol, using labeled mibolerone (MIB) as ligand. The IC 50 value of each compound was calculated according to the plots of concentration versus percentage of binding. The in vivo effect of 9a–9d was determined on the weight of the prostate and seminal vesicles from castrated hamsters treated with dihydrotestosterone. The four compounds bind to the androgen receptor with different relative binding affinity (RBA). Compound 9d having a log P of 4.17 showed the highest RBA > 100% as compared to compound 9a having a log P of 2.92 which exhibited a RBA of only 2.85%. These data show a very good correlation between the lipophilicity of these compounds represented by log P and the percentage of RBA. The in vivo experiments showed that all new compound 9a–9d reduced the weight of the prostate gland as well as the seminal vesicles. Steroids 9c and 9d having a log P of 3.75 and 4.17, respectively, showed the highest antiandrogenic effect.

MICROALGAL BIOTRANSFORMATION OF STEROIDS(1).

Microbial biotransformation of steroids is not a new concept, but most studies in this field have focused on fungal and bacterial systems. Microalgae, despite their photosynthetic ability and immense biodiversity, have not received much attention in this aspect until recently. Since the publication of the first article on microalgal biotransformation of steroids about 20 years ago, there have been many reports describing different modifications, including hydroxylation, reduction, side-chain degradation, and isomerization introduced by these microorganisms on estrane, androstane, and pregnane derivatives. On the other hand, the development of new large-scale cultivation systems, the adaptation of existing fermentation techniques to microalgae, and the introduction of microalgal genetic manipulation methods have made these organisms promising candidates for a wide range of biotechnological processes, including biotransformations. In this review, we have summarized the steroid transformation patterns of several microalgal strains and present a perspective of the future trends in microalgal biotechnology, including the possibility of adapting relatively new techniques, such as organic media catalysis and cell immobilization, to this specific field.

Pregnane derivatives from Hoodia gordonii

Pregnane derivatives from Hoodia gordonii

Mechanism for Conversion of Spirosolane Derivative into Pregnane

Previously, we reported an interesting reaction by which esculeogenin A [(5alpha,22S,23S,25S)-3beta,23,27-trihydroxyspirosolane], a sapogenol of tomato-saponin, esculeoside A, was easily converted into a pregnane derivative, 5alpha-pregn-16-en-3beta-ol-20-one, merely by refluxing with pyridine and water. Its chemical mechanism including air oxidation is here described.

Comparative Crystallographic and Hydrogen-bonding Analysis of Pregnane Derivatives

A crystallographic comparison comprised of some geometrical and structural features of a steroids series (pregnane derivatives) is made in the present paper. Some selected bond distances and bond angles of interest are discussed in detail. Conformations of individual ring systems in a series of 46 pregnane derivatives have been calculated and discussed. Correlation of ring conformations especially the rarer ones, vis-a-vis the multiple bonds and ring junctions has been discussed. Graphical presentations of ring conformations are made for all the five- and six-membered rings to show the relative frequency of their occurrence. 17β-side chain conformation is discussed in some pregn-20-one structures. X–H···A intra- and intermolecular interactions in the identified derivatives have been discussed with the standard distance and angle cut-off criteria. Distance-angle scatter plots for both kinds of interactions are presented for a better understanding of the packing interactions which exist in pregnane molecules.

Efficient Conversion of Tomatidine into Neuritogenic Pregnane Derivative.

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Response to Letter Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”

We thank Drs Micheletti and Chevallier for their interest in our report.1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value ( P <0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects …

Letter by Micheletti and Chevallier Regarding Article, “Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study”

To the Editor: We read with interest the report by Canonico and colleagues1 that shows a differential association of oral and transdermal estrogen with venous thromboembolism (VTE) risk among postmenopausal women. In addition, their data suggest that norpregnane derivatives may be thrombogenic (with a 4-fold-increased VTE risk), whereas micronized progesterone and pregnane derivatives appear safe with respect to …

A New Pregnane and a New Diphenylmethane from the Root Barks of Periploca sepium

AbstractA new polyoxygenated pregnane genin and a new diphenylmethane, along with five known pregnane derivatives, were isolated from the root barks of Periploca sepium. The structures of the new compounds were elucidated as (3β,14β)‐3,14‐dihydroxy‐21‐methoxypregn‐5‐en‐20‐one (1) and 2‐hydroxy‐5‐(2‐hydroxy‐4‐methoxybenzyl)‐4‐methoxybenzaldehyde (2) on the basis of spectroscopic methods, especially 2D‐NMR and MS analyses. The known compounds were identified by comparing their physical and spectroscopic data with those reported in the literature.

Systemic lupus erythematosus and hormone replacement therapy

The indications for hormone replacement therapy (HRT) in postmenopausal women is the treatment of climacteric symptoms and the prevention of osteoporosis. Women with systemic lupus erythematosus (SLE) are more likely to have a premature menopause, osteoporosis and cardiovascular disease. HRT can induce SLE flares and cardiovascular or venous thromboembolic events. Therefore it should not be used in women with active disease or those with antiphospholipid (aPL) antibodies. In general, it should be used only for patients without active disease, a history of thrombosis or aPL antibodies. Non-oral administration of estrogen is recommended because of its lesser effect on coagulation. With regard to the progestogen, progesterone or pregnane derivatives are preferred. Otherwise, non-estrogen-based strategies should be used.

Expeditious and convenient synthesis of pregnanes and its glycosides as potential anti-dyslipidemic and anti-oxidant agents

A series of new pregnane derivatives and its glycosides were synthesized in order to find new ‘leads’ against some important targets. The 3β-hydroxy-16α-(2-hydroxy ethoxy) pregn-5-en-20-one ( 5) was synthesized from 3β-hydroxy-5,16-pregnadiene-20-one ( 2) by adopting general modified procedure using BF 3:Et 2O as a catalyst. Reduction of 5, with sodium borohydride yielded 3β,20β-dihydroxy-16α-(2-hydroxy ethoxy) pregn-5-en ( 7) as the major isolable product. O-alkylation of the C-20-oxime-pregnadiene ( 9) with 1,5-dibromopentane yielded 20-( O-5-bromopentyl)-oximino-3β-hydroxy-pregn-5,16-diene ( 11). Synthesis of C-16 substituted pregnane glycosides ( 20) and ( 21) were accomplished with the imidate method using BF 3:Et 2O. The synthesis of 4-chlorobenzoate ( 3) and 2-chlorobenzoate ( 4), derivatives of 2 were also accomplished. These compounds were evaluated for their anti-dyslipidemic and anti-oxidant activity and amongst them compounds 3 and 7 showed more lipid lowering and anti-oxidant activity.

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

Are Some Types of Hormone Therapy Safer Than Others?

Despite great strides in hormone therapy (HT) research, clinical trial data on the benefit-to-risk profile of different formulations, doses, and routes administration of HT remain lacking. Most of the large-scale clinical trials1–3 have tested oral conjugated equine estrogens with or without medroxyprogesterone acetate, and data on nonoral routes and different types and doses of estrogens and progestogens have been limited. The evidence is mounting that route of delivery and possibly type and dose of HT are important factors, particularly for venous thromboembolism (VTE). Results of clinical trials4,5 and observational studies6 have been concordant in demonstrating an increased risk of VTE with oral exogenous HT. Recent studies suggest that VTE risk may be lower with transdermal than oral estrogen7 and with estrogen alone than with combined therapy.4 However, in the absence of rigorous evidence from large-scale clinical trials on differential effects by hormone formulation or route of delivery, should these findings influence clinical practice? Article p 840 The Estrogen and Thromboembolism Risk (ESTHER) study,7 published in the current issue of Circulation , adds important, relevant data to bolster the case that HT type and route of delivery do indeed make a difference. This well-designed, French, multicenter case-control study of VTE enrolled 271 consecutive cases of VTE in women (age, 45 to 70 years) and matched them to hospital and community controls. Current HT use was present in 46% of the VTE cases compared with 37% of controls. Oral HT users had 4-fold-increased odds of VTE; however, there was no increased risk among transdermal hormone users (odds ratio, 0.9). Previous randomized trials have suggested that the risk of VTE may …

Efficient Conversion of Tomatidine into Neuritogenic Pregnane Derivative

Moderate acetylation of tomatidine with anhydrous acetic acid and pyridine for 20 h at r.t., followed by pseudomerization in ice-water, gave a delta(20(22))-pseudo compound, which was then subjected to ozonolysis to provide a pregnane derivative in a total 54% yield showing neuritogenic and NGF-enhancing activities.