974-23-2Relevant articles and documents
Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1
Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, Teresa,Heuze, Yvonne,Sánchez, Araceli,Soriano, Juan,Cabeza, Marisa
, p. 7535 - 7542 (2015)
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.
The first syntheses of 16β-chloro- and 16β-bromo-cyproterone acetate
Sakee, Uthai,Kongkathip, Ngampong,Kongkathip, Boonsong
, p. 1695 - 1706 (2003)
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.
Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells
Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, Teresa,Heuze, Yvonne,Soriano, Juan,Moreno, Isabel,Bravo, Marisol,Bautista, Lucero,Cabeza, Marisa
, p. 1600 - 1607 (2017)
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.
Synthesis and biological activity of two pregnane derivatives with a triazole or imidazole ring at C-21
Silva-Ortiz, Aylin Viviana,Bratoeff, Eugene,Ramírez-Apan, María Teresa,García-Becerra, Rocío,Ordaz-Rosado, David,Noyola-Martínez, Nancy,Castillo-Bocanegra, Rafael,Barrera, David
, p. 8 - 18 (2016)
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.
Synthesis and transformations of 20-isoxazolylsteroids with modified D ring: I. Synthesis of 16α,17α-epoxyderivatives
Litvinovskaya,Drach,Khripach
, p. 787 - 792 (2001)
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.
Practical synthesis of 16α-bromo-17α-hydroxysteroids via a Raney Ni-catalyzed bromide exchange reaction
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)
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.
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
Chávez-Riveros, Alejandra,Cruz Noriega, Abigail,Ramírez Apan, María Teresa,Miranda, Luis D.,Bratoeff, Eugene
, p. 37 - 45 (2018/02/06)
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).
Synthetic method for drug intermediate 5-pregnene-16alpha,17alpha-epoxy-3beta-ol-20-one
-
Paragraph 0012; 0014-0025, (2018/07/30)
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.
Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α-Reductase
Chávez-Riveros, Alejandra,Bratoeff, Eugene,Heuze, Yvonne,Soriano, Juan,Moreno, Isabel,Sánchez-Márquez, Araceli,Cabeza, Marisa
, p. 808 - 816 (2015/11/10)
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.
Proficient synthesis of biologically active pregnane derivatives and its glycoside - Experimental and theoretical approach
Sethi, Arun,Bhatia, Akriti,Maurya, Atul,Panday, Anil,Bhatia, Gitika,Shrivastava, Atul,Singh, Ranvijay Pratap,Prakash, Rohit
, p. 112 - 124 (2013/10/08)
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.
