- Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1
-
Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3β-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.
- Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, Teresa,Heuze, Yvonne,Sánchez, Araceli,Soriano, Juan,Cabeza, Marisa
-
-
Read Online
- The first syntheses of 16β-chloro- and 16β-bromo-cyproterone acetate
-
The first syntheses of 16β-chloro- and 16β-bromo-cyproterone acetate is described. The preparation of 16β-chlorocyproterone acetate was accomplished in eight steps (6.5% overall yield) from commercially available 16-dehydropregnenolone acetate. 16β-Bromocyproterone acetate was prepared from 16β-chlorocyproterone acetate with base-induced epoxide formation as the key step.
- Sakee, Uthai,Kongkathip, Ngampong,Kongkathip, Boonsong
-
-
Read Online
- Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells
-
The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied. Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1). The results showed that only the derivatives with an alicyclic ester at C-3 showed 5α-R2 enzyme inhibition activity, the most potent of them being 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-cyclohexanecarboxylate with an IC50of 29?nM. This is important because prostatic benign hyperplasia is directly associated with the presence of 5α-R2. However, all the derivatives failed to inhibit 5α-R1 or bind to the AR. These alicyclic ester derivatives decreased the weight and size of androgen-dependent glands in the hamster, indicating they are very active in vivo and are not toxic. In addition, the 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-acetate derivative showed the highest cytotoxic activity on the three cancer cell lines studied. It is therefore important in the synthesis of steroidal compounds to consider the size of the ester moiety at C-3 of the steroid skeleton, which is key in obtaining biological activity, as observed in this experiment.
- Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, Teresa,Heuze, Yvonne,Soriano, Juan,Moreno, Isabel,Bravo, Marisol,Bautista, Lucero,Cabeza, Marisa
-
-
Read Online
- Synthesis and biological activity of two pregnane derivatives with a triazole or imidazole ring at C-21
-
Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3β-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3β-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21. These derivatives were synthesized from 16-dehydropregnenolone acetate. The activity on cell proliferation of the compounds was measured on three human cancer cells lines: prostate cancer (PC-3), breast cancer (MCF7) and lung cancer (SK-LU-1). The cytotoxic and antiproliferative effects of T-OH and I-OH were assessed by using SBR and XTT methods, respectively. The gene expressions were evaluated by real time PCR. In addition, results were complemented by docking studies and transactivation assays using an expression vector to progesterone and androgen receptor. Results show that the two compounds inhibited the three cell lines proliferation in a dose-dependent manner. Compound I-OH downregulated the gene expression of the cyclins D1 and E1 in PC-3 and MFC7 cells; however, effect upon Ki-67, EAG1, BIM or survivin genes was not observed. Docking studies show poor interaction with the steroid receptors. Nevertheless, the transactivation assays show a weak antagonist effect of I-OH on progesterone receptor but not androgenic or antiandrogenic actions. In conclusion, the synthesized compounds inhibited cell proliferation as well as genes key to cell cycle of PC-3 and MCF7 cell lines. Therefore, these compounds could be considered a good starting point for the development of novel therapeutic alternatives to treat cancer.
- Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, María Teresa,García-Becerra, Rocío,Ordaz-Rosado, David,Noyola-Martínez, Nancy,Castillo-Bocanegra, Rafael,Barrera, David
-
-
Read Online
- Synthesis and transformations of 20-isoxazolylsteroids with modified D ring: I. Synthesis of 16α,17α-epoxyderivatives
-
Synthesis of 16α,17α-epoxy-20-isoxazolylsteroids was carried out starting with dehydropregnenolone acetate. Transformation procedures for preparation therefrom of open-chain compounds were considered. Physico-chemical characteristics of compounds synthesized were investigated.
- Litvinovskaya,Drach,Khripach
-
-
Read Online
- Practical synthesis of 16α-bromo-17α-hydroxysteroids via a Raney Ni-catalyzed bromide exchange reaction
-
D-ring modified glucocorticoids are attractive synthetic targets owing to their broad application in medicinal chemistry. Herein, we reported a practical synthesis of 16α-bromo-17α-hydroxysteroids from easily available 16β-bromo isomers via a Raney Ni-catalyzed bromide exchange reaction. The catalytic Finkelstein-type reaction features high yield, mild reaction condition, short reaction time and simple operation. The method provided an efficient approach to prepare 17α-hydroxy-15-pregnen-20-ones.
- Xu, Fei-Fei,Li, Hong-Ping,Wang, Mao-Chang,Ma, Hai-Yan,Zhao, Mei-Xin,Ding, Kai
-
supporting information
p. 1710 - 1714
(2019/06/05)
-
- Synthesis and cytotoxic effect of pregnenolone derivatives with one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3
-
Four series of pregnenolone derivatives having one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3 were synthetized to compare their cytotoxicity effect. The final compounds were evaluated on three human cancer cell lines: PC-3 (prostate cancer), MCF-7 (breast cancer), SKLU-1 (lung cancer) and a noncancerous cell line HGF (human gingival fibroblast). Two steroids with a 4-fluorinated benzoic acid ester at C-21 were the most active against lung cancer cell line with IC50 of 13.1 ± 1.2 and 12.8 ± 0.5 μM and showed a low percentage of cytotoxicity for noncancerous cells (27.63 ± 2.3 and 18.39 ± 1.2% in the screening at 50 μM).
- Chávez-Riveros, Alejandra,Cruz Noriega, Abigail,Ramírez Apan, María Teresa,Miranda, Luis D.,Bratoeff, Eugene
-
-
- Synthetic method for drug intermediate 5-pregnene-16alpha,17alpha-epoxy-3beta-ol-20-one
-
The invention discloses a synthetic method for the drug intermediate 5-pregnene-16alpha,17alpha-epoxy-3beta-ol-20-one. The synthetic method comprises the following steps: adding 5-pregnene-16-hydroxy-17-bromo-3-methoxy-20-one and a sodium chloride solution into a reaction vessel, raising the temperature of the obtained solution, controlling a stirring speed, adding lead dioxide and a dodecanol solution and continuing a reaction; and then adding zinc benzoate powder, raising the temperature of the obtained solution, continuing the reaction, carrying out cooling, subjecting the solution to standing so as to realize layering of the solution, carrying out washing with a potassium sulfate solution, carrying out washing with a trichlorotoluene solution, then carrying out recrystallization in a triethylene glycol monomethyl ether solution, and then carrying out dehydration with a dehydrating agent to obtain finished 5-pregnene-16alpha,17alpha-epoxy-3beta-ol-20-one.
- -
-
Paragraph 0012; 0014-0025
(2018/07/30)
-
- Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α-Reductase
-
Hyperplasia of the prostate gland and prostate cancer have been associated with high levels of serum 5α-dihydrotestosterone. This steroid is formed from testosterone by the activity of the enzyme 5α-reductase (5α-R) present in the prostate. Thus, inhibition of this enzyme could be a goal for therapies to treat these diseases. This study reports the synthesis and effects of five different 21-esters of pregnenolone derivatives as inhibitors of 5α-R types 1 and 2. The activity of these steroidal compounds was determined using in vivo and in vitro experiments. The results indicate that of the five steroids studied, the 21(p-fluoro)benzoyloxypregna-4,16-diene-3,6,20-trione derivative, whose structure has not yet been reported, has the best molecular conformation to inhibit the in vitro activity of both types of 5α-R. In addition, this steroid also displayed activity in vivo. Apparently, its pharmacological effect was increased by the presence of a keto group at C-6, because this group decreased the possibility that the steroid would be metabolized by hepatic enzymes. In addition, the double bond present at C-4 of this compound also enhanced its inhibitory activity on 5α-R, and the C-21 ester moiety increased its liphophilicity. Therefore, its solubility in the cell membrane and its pharmacological activity were both increased.
- Chávez-Riveros, Alejandra,Bratoeff, Eugene,Heuze, Yvonne,Soriano, Juan,Moreno, Isabel,Sánchez-Márquez, Araceli,Cabeza, Marisa
-
p. 808 - 816
(2015/11/10)
-
- Proficient synthesis of biologically active pregnane derivatives and its glycoside - Experimental and theoretical approach
-
Synthesis of a number of pregnane derivatives including the glycoside has been described in detail. These compounds were synthesized by reaction of 3β-acetoxy-5, 16-pregnadiene-20-one, derived from diosgenin and then treating it with different nucleophilic reagents. The structures of these newly synthesized compounds were established on the basis of their physical, chemical and spectral data. The molecular geometry of compounds were calculated in ground state by density functional theory method (DFT/B3LYP) using 6-31G (d,p) basis set. 1H NMR chemical shifts were also studied using gauge-including atomic orbital (GIAO) approach, which were found in good agreement with the experimental values. The study of electronic properties such as UV-Vis spectral analysis, HOMO and LUMO energy calculations were performed with time dependent DFT (TD-DFT). Global and local reactivity descriptors were calculated to study the reactive sites within the molecules. These compounds were also evaluated for their anti-dyslipidemic (Triton model) and in vitro anti-oxidant activities. Out of these, compound 9 showed potent anti-dyslipidemic and anti-oxidant activity.
- Sethi, Arun,Bhatia, Akriti,Maurya, Atul,Panday, Anil,Bhatia, Gitika,Shrivastava, Atul,Singh, Ranvijay Pratap,Prakash, Rohit
-
p. 112 - 124
(2013/10/08)
-
- Bismuth(III) triflate-catalyzed rearrangement of 16α,17α-epoxy-20-oxosteroids. Synthesis and structural elucidation of new 16α-substituted 17α-alkyl-17β-methyl-Δ13-18-norsteroids
-
The use of bismuth(III) triflate for the rearrangement of 16α,17α-epoxy-20-oxosteroids is reported. The reactions occur under truly catalytic conditions to afford novel 17α-alkyl-17β-methyl-Δ13-18-nor products bearing different O-containing substituents at C16. When the reaction is performed in the absence of acylation agent a mixture of isomeric 16α- and 16β-hydroxy derivatives is obtained, whereas when carried out in the presence of such reagents, the reaction selectively affords the corresponding 16α-acyl rearranged products. The chemoselective rearrangement of 5β,6β;16α,17α-diepoxy-20-oxopregnan-3β-yl acetate to afford a 'backbone' rearranged product bearing the 16α,17α-epoxide group is also reported. Some mechanistic considerations are provided. All rearranged products were the subject of comprehensive structural elucidation, by the use of X-ray crystallography and 2D NMR.
- Pinto, Rui M.A.,Salvador, Jorge A.R.,Le Roux, Christophe,Carvalho, Rui A.,Beja, Ana Matos,Paix?o, José A.
-
experimental part
p. 6169 - 6178
(2011/03/22)
-
- Process for preparing Guggulsterones
-
The present invention provides an improved process for the preparation of Guggulsterones which comprises epoxidising 16-dihydropegnenolone acetate (16 DPA) by reacting 16DPA with hydrogen peroxide reagent adduct in the presence of a co-base in a polar solvent to obtain 3 β hydroxy-16 α, 17-oxido-5 pregnen-20-one, converting the 3 β hydroxy-16α, 17-oxido-5-pregnen-20-one by reacting with hydrazine in the presence of a strong base at refluxing temperature followed by oxidation to obtain desired guggulsterones viz. to 5, 17-(20)-cis and trans pregnadiene-3 β, 16-diol of the formula Ia and Ib.
- -
-
-
- PROCESS FOR PREPARING GUGGULSTERONES
-
The present invention provides an improved process for the preparation of Guggulsterones which comprises epoxidising 16-dihydropegnenolone acetate (16 DPA) by reacting 16DPA with hydrogen peroxide reagent adduct in the presence of a co-base in a polar solvent to obtain 3 β hydroxy-16 α, 17-oxido-5 pregnen-20-one, converting the 3 β hydroxy-16α, 17-oxido-5-pregnen-20-one by reacting with hydrazine in the presence of a strong base at refluxing temperature followed by oxidation to obtain desired guggulsterones viz. to 5, 17 - (20)-cis and trans pregnadiene - 3 β, 16-diol of the formula Ia and Ib.
- -
-
Page/Page column 6
(2008/06/13)
-
- Further syntheses of cyproterone acetate
-
The present invention relates to improved methods for synthesising cyproterone acetate (17α-Acetoxy-6-chloro-1α, 2α-methylene-4,6-pregnadiene-3,20-dione) from solasodine. The methods of the invention are shorter as those of the prior art and therefore more economic.
- -
-
Page/Page column 5; 15; 27; 29; 31
(2010/02/07)
-
- Evaluation of new pregnane derivatives as 5α-reductase inhibitor
-
The objective of this study was to synthesize several new pregnane derivatives and evaluate them as antiandrogens. From the commercially available 16-dehydropregnenolone acetate (7), two new steroidal compounds were synthesized: 17α-hydroxy-17β-methyl-16β-phenyl-D-homoandrosta-1,4.6- triene-3,20-dione (18) and 17α-acetoxy-17β-methyl-16β-phenyl-D-homoandrosta-1,4.6- triene-3,20-dione (19). The 5α-reductase inhibitory effect of the new compounds 18 and 19 together with the previously synthesized intermediates 7, 8, 13, 16, and 17 was determined in three different models: gonadectomized hamster flank organs diameter size, incorporation of [1,2-14C]sodium acetate into lipids in flank organs and conversion of [3H]testosterone (T) to [3H]dihydrotestosterone (DHT) by Penicillium crustosum. The evaluation of these steroids was carried out with three different controls: one group was treated with vehicle, the second with T and the third group with T plus finasteride. The pharmacological results from this work demonstrated that T significantly increases the diameter of the pigmented spot on the flank organs (p3H]T to [3H]DHT in a manner comparable to that of the flank organs. All experiments indicated that finasteride as well as steroids 7, 8, 13, 16-19 reduced significantly the conversion of T to DHT in P. crustosum. These compounds also decrease the size of the pigmented spot in the flank organs as well as reducing the incorporation of radiolabeled sodium acetate into lipids; T and the control sample (treated with vehicle only) were used for comparison. Apparently the presence of the 4,6-diene-3,20-dione moiety and also the C-17 ester group produce a higher inhibitory effect on the parameters used. PPThe data from this study indicated also that the three models used for the pharmacological evaluation exhibited comparable results.
- Cabesa,Heuze,Bratoeff,Ramirez,Martinez
-
p. 525 - 530
(2007/10/03)
-
- Androgenic and anti-androgenic effects of progesterone derivatives with different halogens as substituents at the C-6 position
-
The pharmacological activities of four pregnane derivatives:17α- hydroxy-16β-methylpregna-4,6-diene-3,20-dione (7), 17α-acetoxy-16β- methylpregna-4,6-diene-3,20-dione (8), 17α-acetoxy-6-bromo-16β- methylpregna-4,6-diene-3,20-dione (10), and 17α-acetoxy-6-chloro-16β- methylpregna-4,6-diene-3,20-dione (11), were determined. The derivatives were evaluated on gonadectomized male hamster flank organs and seminal vesicles. The results indicate that topical applications of testosterone (T) on the flank organs increased the diameter of the pigmented spot. Similarly, the same phenomenon occurred on the glands treated with compound 11, whereas compound 10 decreased the size of the spot significantly. In this study, we determined the effects of several new steroids on the conversion of T to DHT in flank organs and seminal vesicles. The results show that compound 10 inhibited T conversion to DHT, but compound 11, at a dose of 200 μg, stimulated T conversion in both flank organs and seminal vesicles. However, when 2 mg of compound 11 was applied, it inhibited the conversion of T to DHT, suggesting that this compound also represses gonadotropin release. The difference between compounds 10 and 11 involves the electronegativity of the halogen at the C-6 position of the progesterone skeleton. These data clearly indicate that by decreasing the electronegativity of the halogen at C-6 (compound 10), 5α-reductase is inhibited in both tissues and at different pHs. On the other hand, when the electronegativity of the halogen atom was increased (11), there was a much lower inhibitory effect on the conversion of T to DHT.
- Cabeza,Gutierrez,Miranda,Heuze,Bratoeff,Flores,Ramirez
-
p. 413 - 421
(2007/10/03)
-
- The first synthesis of the aglycone of the potent anti-tumor steroidal saponin OSW-1
-
The protected aglycone (21e-β) of the potent anti-tumor agent OSW-1 (1) was synthesized in 9 steps from 5-androsten-3β-ol-17-one (10) in 55% overall yield. Key reactions involve ene installation of the side chain, regio and stereoselective dihydroxylation and diastereoselective reduction of the C16 ketone.
- Guo, Chuangxing,Fuchs
-
p. 1099 - 1102
(2007/10/03)
-
- 17α-acetoxy-17β-methyl-16β-phenyl-D-homo-4,6-pregnadiene-3, 17a-dione: Synthesis and crystal structure determination of a new rearranged pregnane derivative
-
The title compound is C29H34O4, tetragonal, P43, a = b = 10.310(1), c = 23.871(2)A. The A, B, C, and D rings adopt envelope, half-chair, chair, and distorted chair conformations, respectively. The phenyl ring is planar. The methyl substituents at the A/B, C/D, and at C(17) are axial; and the -OCOCH3 group at C(17) and phenyl ring at C(16) are equatorial. The molecules in the crystal are held together by van der Waals forces and several C - H···O hydrogen bond interactions.
- Soriano-Garcia, Manuel,Hernandez-Ortega, Simon,Bratoeff, Eugene,Valencia, Norma,Ramirez, Elena,Flores, Gregoria
-
p. 487 - 491
(2007/10/03)
-
- 5 α-pregnan-20-ones and 5-pregnen-20-ones and related compounds
-
Compounds of the formulae: STR1 useful as anti-obesity, anti-diabetic, anti-coronary and hypolipidemic agents.
- -
-
-
- Peroxide oxidation of Δ4-3-ketosteroids
-
Treatment of Δ4-3-ketosteroids with tert-butyl hydroperoxide in the presence of lithium hydroxide leads to the formation of the corresponding 4β,5β epoxides stereospecifically and in good yield.The stereospecificity of this reaction is explicable in terms of the accepted mechanism for the hydrogen peroxide epoxidation of Δ4-3-ketosteroids.The use of aqueous sodium peroxide as oxidant leads to the production of the corresponding Δ4-3,6-diones.A mechanism for this reaction is proposed in which the key step is autooxidation of the corresponding deconjugated Δ5-3-ketone, produced from the starting material in situ by the action of the reagents.Lithium peroxide does not oxidize androst-4-ene-3,17-dione at C-6, but produces the 4,5-epoxides in low yield together with an A-nor-3,5-secoacid.
- Holland, Herbert L.,Riemland, Elly,Ulrich, Daum
-
p. 1919 - 1923
(2007/10/02)
-