- Synthesis and Biological Evaluation of Vitamin D3 Metabolite 20S,23S-Dihydroxyvitamin D3 and Its 23R Epimer
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The vitamin D3 metabolite, 20S,23S-dihydroxyvitamin D3, was chemically synthesized for the first time and identified to be the same as the enzymatically produced metabolite. The C23 absolute configurations of both 20S,23S/R-dihydroxyvitamin D3 epimers were unambiguously assigned by NMR and Mosher ester analysis. Their kinetics of CYP27B1 metabolism were investigated during the production of their 1α-hydroxylated derivatives. Bioactivities of these products were compared in terms of vitamin D3 receptor activation, anti-inflammatory, and antiproliferative activities.
- Lin, Zongtao,Marepally, Srinivasa R.,Ma, Dejian,Kim, Tae-Kang,Oak, Allen Sw.,Myers, Linda K.,Tuckey, Robert C.,Slominski, Andrzej T.,Miller, Duane D.,Li, Wei
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- Enzymatic deacetylation of steroids bearing labile functions
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Lipase from Candida cylindracea and Candida antarctica catalyzes the removal of acetyl groups from 3β-acetoxypregn-5-en-20-one and 3β-acetoxy-20-(S)-hydroxycholest-5-en-23-one through a transesterification reaction in organic solvents.
- Baldessari, Alicia,Maier, Marta S.,Gros, Eduardo G.
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- 1,5-Hydride shift in Wolff-Kishner reduction of (20R)-3β,20, 26-trihydroxy-27-norcholest-5-en-22-one: Synthetic, quantum chemical, and NMR studies
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Heating (20R)-3β,20,26-trihydroxy-27-norcholest-5-en-22-one (1) with hydrazine and KOH at 160°C completely converted the steroid to a diastereoisomeric mixture of the new (20R,22RS)-27-norcholest-5-ene-3β,20,22-triols (2). Exclusive formation of 2 suggest
- Szendi, Zsuzsanna,Forgo, Peter,Tasi, Gyula,Boecskei, Zsolt,Nyerges, Levente,Sweet, Frederick
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- Ile351, Leu355 and Ile461 residues are essential for catalytic activity of bovine cytochrome P450scc (CYP11A1)
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Cytochrome P450scc (CYP11A1) is a mammalian mitochondrial enzyme which catalyzes cholesterol side chain cleavage to form pregnenolone. Along with cholesterol, some other steroids including sterols with a branched side chain like β-sitosterol are the substrates for the enzyme, but the activity towards β-sitosterol is rather low. Modification of the catalytic site conformation could provide more effective β-sitosterol bioconversion by the enzyme. This study was aimed to find out the amino acid residues substitution of which could modify the conformation of the active site providing possible higher enzyme activity towards β-sitosterol. After structural and bioinformatics analysis three amino acid residues I351, L355, I461 were chosen. Molecular dynamics simulations of P450scc evidenced the stability of the wild type, double (I351A/L355A) and triple (I351A/L355A/I461A) mutants. Mutant variants of cDNA encoding P450scc with the single, double and triple mutations were obtained by site-directed mutagenesis. However, the experimental data indicate that the introduced single mutations Ile351A, Leu355A and Ile461A dramatically decrease the target catalytic activity of CYP11A1, and no activity was observed for double and triple mutants obtained. Therefore, isoleucine residues 351 and 461, and leucine residue 355 are important for the cytochrome P450scc functioning towards sterols both with unbranched (cholesterol) and branched (sitosterol) side chains.
- Glyakina, Anna V.,Strizhov, Nicolai I.,Karpov, Mikhail V.,Dovidchenko, Nikita V.,Matkarimov, Bakhyt T.,Isaeva, Ludmila V.,Efimova, Vera S.,Rubtsov, Mikhail A.,Novikova, Ludmila A.,Donova, Marina V.,Galzitskaya, Oxana V.
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- Discovery of novel steroidal-chalcone hybrids with potent and selective activity against triple-negative breast cancer
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A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 μM and 0.52 μM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.
- Bai, Chengfeng,Hou, Qiangqiang,Lin, Xin,Lu, Xiang,Luo, Guoshun,Wei, Hanlin,Xiang, Hua
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- A new mild PTSA-catalyzed method for sulfate ester hydrolysis and acid-catalyzed rearrangement of 12-acetyl-diene-11-ol tetracyclic triterpenoids involving an angular methyl migration
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Tetracyclic triterpenoids containing the 12-acetyl-Δ8,14-diene-ll-ol moiety undergo a series of acid-catalyzed rearrangements. The rearrangement products have been characterized, plausible mechanisms for the rearrangement have been elucidated and conditions have been developed to give high yields of the rearrangement products. A new and general PTSA·H2O and PPTS-catalyzed sulfate hydrolysis method has been developed. (C) 2000 Elsevier Science Ltd.
- Singh
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- Inhibition of bovine adrenocortical cytochrome P-450scc by 3,3'-dimethoxybenzidine
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The effect of 3,3'-dimethoxybenzidine (o-dianisidine) on the conversion of cholesterol to pregnenolone was investigated in a reconstituted side chain cleavage system using enzymes purified from bovine adrenal cortex; d-p-aminoglutethimide was also assayed under similar conditions for comparison. 3,3'-Dimethoxybenzidine was found to be a potent inhibitor of pregnenolone formation, causing 50% inhibition at a concentration of 1.5 μM when using 70 μM cholesterol - this does is approximately one fourth that required of 3-methoxybenzidine and one twentieth that required of benzidine for equal inhibition. In the same system, d-p-aminoglutethimide exhibited an I50 value of about 55 μM. No effects of 3,3'-dimethoxybenzidine on adrenodoxin reductase or adrenodoxin activities could be detected, and inhibition of side chain cleavage could be relieved by dilution suggesting that the inhibitor acts by reversibly binding to cytochrome P-450 scc.
- Duval,Vickery
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- Mild deprotection of steroid esters by bis(tributyltin)oxide
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Bis(tributyltin)oxide (BBTO) has been utilized for the first time for the deprotection of steroid esters. The best results were obtained for 3β-esters, in particular the selective hydrolysis of the 3β-acetyl group in 3β,6α-diacetoxy-5α-pregnan-20-one to give 6α-acetoxy-3β-hydroxy-5α-pregnan-20-one.
- Perez, Marina G.,Maier, Marta S.
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- Human placental cholesterol side-chain cleavage: enzymatic synthesis of (22R)-20α,22-dihydroxycholesterol
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(22R)-20α,22-Dihydroxycholesterol is the second intermediate in the conversion of cholesterol to pregnenolone by cytochrome P450scc in steroidogenic tissues.We report a rapid method for the enzymatic synthesis of (22R)-20α,22-dihydroxycholesterol from (22R)-20-hydroxycholesterol using mitochondria from the human placenta. (Steroids 58:230-233, 1993) Keywords: steroids; cytochrome P450scc; placental mitochondria; (22R)-20α,22-dihydroxycholesterol; (22R)-22-hydroxycholesterol; pregnenolone
- Tuckey, Robert C.,Cameron, Kathryn J.
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- Proline-promoted dehydroxylation of α-ketols
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A new single-step proline-potassium acetate promoted reductive dehydroxylation of α-ketols is reported. We introduce the unexplored reactivity of proline and, for the first time, reveal its ability to function as a reducing agent. The developed metal-free and open-flask operation generally results in good yields. Our protocol allows the challenging selective dehydroxylation of hydroxyketones without affecting other functional groups.
- Mostinski, Yelena,Lankri, David,Konovalov, Yana,Nataf, Riva,Tsvelikhovsky, Dmitry
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- Cholesterol side-chain cleavage activity in human placenta and bovine adrenals: An one-step method for separation of pregnenolone formed in vitro
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Cholesterol side-chain cleavage (CSCC) activity towards exogenous cholesterol was quantified by an one-step reversed-phase minicolumn method for the separation of pregnenolone formed in the reaction. The assay is rapid and reproducible. The method is linear for up to 2 mg of placental mitochondrial protein and up to 1 mg of bovine adrenal mitochondrial protein in the incubate over 30 min and 5 min reaction times, respectively. Average Km and Vmax values were 14.1 μM and 3.4 pmol/min/mg for the placental preparation and 1.5 μM and 20.7 pmol/min/mg for the bovine adrenal mitochondrial preparation. In human placenta, the mitochondrial fraction contained most of the CSCC activity. Inhibition studies showed that aminoglutethimide (500 μM) inhibited both placental and bovine adrenal activities at the same level (about 80-90% inhibition) but androstenedione (500 μM), metyrapone (500 μM), benzo(a)pyrene (800 μM) and Emulgen 911 (0.05%) were more effective in human placental preparations. Neither of the activities were inhibited to any great extent by α-naphthoflavone (500 μM), SKF 525A (500 μM) or 7-ethoxycoumarin (1 mM).
- Pasanen,Pelkonen
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- Microbial hydroxylation of pregnenolone derivatives
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Pregnenolone (1) and pregnenolone acetate (2) were incubated with the fungi Cunninghamella elegans, Rhizopus stolonifer and Gibberella fujikuroi. Incubation of 1 with C. elegans yielded metabolites, 3 β,7 β,11 α-trihydroxypreg-5-en-20-one (3), 3 β,6 α,11 α,12 β,15 β-pentahydroxypreg-4-en-20-one (4) and 3 β,6 β,11 α-trihydroxypreg-4-en-20-one (5), while incubation with G. fujikuroi yielded two known metabolites, 3 β,7 β-dihydroxypregn-5-en-20-one (6) and 6 β,15 β-dihydroxypreg-4-ene-3,20-dione (7). Metabolites 4 and 5 were found to be new. Fermentation of 2 by C. elegans yielded four known oxidative metabolites, 1, androsta-1,4-diene-3,17-dione (8), 6 β,15 β-dihydroxyandrost-4-ene-3,17-dione (9) and 11 α,15 β-dihydroxypreg-4-ene-3,20-dione (10). Fermentation of 2 with R. stolonifer yielded two known metabolites, 11 α-hydroxypreg-4-ene-3,20-dione (11) and 7. Compounds 1-11 were screened for their cholinesterase inhibitory activity in a mechanism-based assay.
- Choudhary, Muhammad Iqbal,Batool, Iffat,Shah, Syed Adnan Ali,Nawaz, Sarfraz Ahmad,Atta-ur-Rahman
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- From organocatalysed desilylations to high-yielding benzylidenations of electron-deficient benzaldehydes
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A new type of organoprecatalyst (MeSCH2Cl/KI) for desilylation and benzylidenation reactions has been designed. Both reactions are user friendly and high yielding (71->99%) and have fast reaction rates. The desilylation of iodo silyl ethers was achieved with no sequential etherification side reactions like those seen for reactions when using TBAF. In the application of the catalytic system to a 6-TBDMS ether of a glucoside, glucoside benzylidenations using electron-deficient benzaldehydes were achieved in 87% yield compared with the previously reported yields of 69-77%. Altogether, 14 benzylidenation reactions were realised using silyloxy alcohols and electrondeficient benzaldehydes instead of their activated acetal forms. In terms of reaction rates and yields, the order of the benzylidenations is p-fluorobenzaldehyde > benzaldehyde > p-anisaldehyde, and a possible mechanism is discussed. These experiments have preliminarily differentiated this cost-effective catalytic system from the classic Lewis acids.
- Niu, Qun,Xing, Linlin,Li, Chunbao
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- Stereoselective synthesis of (22R,23R,24S)-3β-Hydroxy-5-ene-22,23-dihydroxy-24-methyl-cholestane: A Brassinolide Intermediate from 16-Dehydropregnenolone Acetate
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A new synthesis of the important aldehyde 1 from easily available 16-Dehydropregnenolone acetate (16-DPA) in high yield is described.The aldehyde 1 is converted to triol 24, involving a stereoselective generation of all the four chiral centers in the brassinolide side chain.The important features of this synthesis is stereospecific generation of the acetate 14 through ene reaction using three different catalysts as well as regioselective wittig reaction on the acetoxy aldehyde 20.Conversion of triol 24 to brassinolide is known, hence this constitutes a formal total synthesis of brassinolide.
- Hazra, Braja G.,Joshi, Padmakar L.,Bahule, Bharat B.,Argade, Narshinha P.,Pore, Vandana S.,Chordia, Mahendra D.
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- A Dual Role Reductase from Phytosterols Catabolism Enables the Efficient Production of Valuable Steroid Precursors
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4-Androstenedione (4-AD) and progesterone (PG) are two of the most important precursors for synthesis of steroid drugs, however their current manufacturing processes suffer from low efficiency and severe environmental issues. In this study, we decipher a dual-role reductase (mnOpccR) in the phytosterols catabolism, which engages in two different metabolic branches to produce the key intermediate 20-hydroxymethyl pregn-4-ene-3-one (4-HBC) through a 4-e reduction of 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) and 2-e reduction of 3-oxo-4-pregnene-20-carboxyl aldehyde (3-OPA), respectively. Inactivation or overexpression of mnOpccR in the Mycobacterium neoaurum can achieve exclusive production of either 4-AD or 4-HBC from phytosterols. By utilizing a two-step synthesis, 4-HBC can be efficiently converted into PG in a scalable manner (100 gram scale). This study deciphers a pivotal biosynthetic mechanism of phytosterol catabolism and provides very efficient production routes of 4-AD and PG.
- Peng, Haidong,Wang, Yaya,Jiang, Kai,Chen, Xinru,Zhang, Wenlu,Zhang, Yanan,Deng, Zixin,Qu, Xudong
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p. 5414 - 5420
(2021/02/05)
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- ENABLING CHOLESTEROL CATABOLISM IN HUMAN CELLS
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Compositions, methods, and systems for modifying sterol metabolism in a subject is disclosed. In some embodiments, the subjects may be administered one or more mammalian cells modified to express at least one sterol degrading enzyme derived from a bacterium. In many embodiments, the cell is a macrophage or monocyte stably expressing three or more enzymes that aid in opening the β ring of cholesterol. The disclosed compositions and methods may be useful in lowering cholesterol levels in a subject in need thereof. In some embodiments, the subject may have a genetic predisposition to atherosclerosis.
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Paragraph 0029
(2020/07/05)
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- Steroid compound as well as preparation method and application thereof (by machine translation)
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The compounds have the structure shown in the general formula (I) or the general formula (II); and experiments prove that the compounds can treat three-negative breast cancer by promoting apoptosis. (by machine translation)
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Paragraph 0058-0059; 0062-0063
(2020/10/29)
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- Design and synthesis of novel steroidal imidazoles as dual inhibitors of AR/CYP17 for the treatment of prostate cancer
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Both AR and CYP17 are important targets for blocking androgen signaling, and it has been accepted that multifunctional drugs have a low risk of drug resistance in the treatment of cancer. Thus, herein a series of steroidal imidazoles were designed, synthesized and evaluated as dual AR/CYP17 ligands. Several compounds displayed good biological profiles in both enzymatic and cellular assays. SAR studies showed that introducing oximino at the C-3 position of steroidal scaffold is beneficial to the enhancement of AR antagonistic activity. Among these compounds, the most potent compound 13a exhibited the best AR inhibition (IC50 = 0.5 μM) that was 27-fold increase compared with the hit compound 5 as well as comparable CYP17 inhibition (IC50 = 11 μM). Additionally, 13a displayed promising anti-proliferative effects on LNCap cell lines with the IC50 value of 23 μM which was superior to positive control Flutamide (IC50 = 28 μM). Furthermore, the docking results of 13a revealed that the oxygen atom at the position of C-3 connected to the heme of CYP17, which may be helpful for its satisfactory dual-target inhibition. In summary, this study provides an efficient strategy for multi-targeting drug discovery in the treatment of prostate cancer.
- Hou, Qiangqiang,He, Conghui,Lao, Kejing,Luo, Guoshun,You, Qidong,Xiang, Hua
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- The desA and desB genes from Clostridium scindens ATCC 35704 encode steroid-17,20-desmolase
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Clostridium scindens is a gut microbe capable of removing the side-chain of cortisol, forming 11?-hydroxyandrostenedione. A cortisol-inducible operon (desABCD) was previously identified in C. scindens ATCC 35704 by RNA-Seq. The desC gene was shown to encode a cortisol 20?-hydroxysteroid dehydrogenase (20?-HSDH). The desD encodes a protein annotated as a member of the major facilitator family, predicted to function as a cortisol transporter. The desA and desB genes are annotated as N-terminal and C-terminal transketolases, respectively. We hypothesized that the DesAB forms a complex and has steroid-17,20-desmolase activity. We cloned the desA and desB genes from C. scindens ATCC 35704 in pETDuet for overexpression in Escherichia coli. The purified recombinant DesAB was determined to be a 142 ± 5.4 kDa heterotetramer. We developed an enzyme-linked continuous spectrophotometric assay to quantify steroid- 17,20-desmolase. This was achieved by coupling DesABdependent formation of 11?-hydroxyandrostenedione with the NADPH-dependent reduction of the steroid 17-keto group by a recombinant 17?-HSDH from the filamentous fungus, Cochliobolus lunatus. The pH optimum for the coupled assay was 7.0 and kinetic constants using cortisol as substrate were Km of 4.96 ± 0.57 μM and kcat of 0.87 ± 0.076 min?1. Substrate- specificity studies revealed that rDesAB recognized substrates regardless of 11?-hydroxylation, but had an absolute requirement for 17,21-dihydroxy 20-ketosteroids.- Devendran, S., S. M. Mythen, and J. M. Ridlon. The desA and desB genes from Clostridium scindens ATCC 35704 encode steroid-17,20-desmolase.
- Devendran, Saravanan,Mythen, Sean M.,Ridlon, Jason M.
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p. 1005 - 1014
(2018/06/22)
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- 20-triazole-20-hydroxyl-pregnane derivatives, method for preparing same and medical application of 20-triazole-20-hydroxyl-pregnane derivatives
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The invention belongs to the field of medicines, and particularly relates to a series of 20-triazole-20-hydroxyl-pregnane derivatives, a method for preparing the same and medical application of the 20-triazole-20-hydroxyl-pregnane derivatives. The 20-triazole-20-hydroxyl-pregnane derivatives are particularly used for preparing medicines for treating androgen receptor related diseases such as cellproliferation, prostate cancer, polytrichia, acne and androgenic alopecia which are dependent on androgens. Structural general formulas of compounds of the 20-triazole-20-hydroxyl-pregnane derivativesare shown. Details of definition of various groups in the general formulas are attached to specifications.
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Paragraph 0086; 0087; 0088
(2018/11/22)
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- Steroid compound 3-site hydroxyl configuration inversion method
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The invention discloses a steroid compound 3-site hydroxyl configuration inversion method. The method specifically comprises the following steps that (1) a steroid compound containing a 3-site hydroxyl reacts with an acyl chloride compound; (2) the product obtained in the step (1) and a substituting agent are subjected to SN2 nucleophilic substitution reaction under existing of a phase transfer catalyst; and (3) the product obtained in the step (2) is subjected to a hydrolysis reaction. Compared with a Mitsunobu method, the method does not need to use triphenylphosphine and azodiformate pricedhigher, and accordingly the production cost is greatly lowered; meanwhile, a p-nitrobenzoic acid derivative which seriously affects the water environment does not need to be used, and therefore the method is more environmentally friendly. The method adopts cesium acetate/18-crown ether-6 system to conduct 3-site hydroxyl configuration inversion, can remarkably reduce occurrence of side reactions,accordingly a higher reaction yield is obtained, and the method is finally applicable to industrialized production.
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Paragraph 0079; 0084; 0085
(2018/12/14)
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- Stereoselective synthesis of α-methyl and α-alkyl ketones from esters and alkenes: Via cyclopropanol intermediates
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Alkenes bearing a stereocenter in the allylic position were found to undergo Kulinkovich hydroxycyclopropanation with good diastereoselectivity. For the isomerization of the resulting cyclopropanols to diastereomerically enriched α-methyl ketones, a new mild regioselective method has been developed. A sequence of stereoselective cyclopropanation and cyclopropanol ring opening was successfully employed for the construction of the C20 stereocenter in steroids.
- Barysevich, Maryia V.,Kazlova, Volha V.,Kukel, Aliaksandr G.,Liubina, Aliaksandra I.,Hurski, Alaksiej L.,Zhabinskii, Vladimir N.,Khripach, Vladimir A.
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supporting information
p. 2800 - 2803
(2018/03/21)
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- Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists
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Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4 h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.
- Lao, Kejing,Sun, Jie,Wang, Chong,Wang, Ying,You, Qidong,Xiao, Hong,Xiang, Hua
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supporting information
p. 4212 - 4217
(2017/08/23)
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- Design, synthesis and biological evaluation of novel androst-3,5-diene-3-carboxylic acid derivatives as inhibitors of 5α-reductase type 1 and 2
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5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25?μM and 0.13?μM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p??0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.
- Lao, Kejing,Sun, Jie,Wang, Chong,Lyu, Weiting,Zhou, Boshen,Zhao, Ruheng,Xu, Qian,You, Qidong,Xiang, Hua
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- Synthesis, Structural Elucidation, and Biological Evaluation of NSC12, an Orally Available Fibroblast Growth Factor (FGF) Ligand Trap for the Treatment of FGF-Dependent Lung Tumors
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NSC12 is an orally available pan-FGF trap able to inhibit FGF2/FGFR interaction and endowed with promising antitumor activity. It was identified by virtual screening from a NCI small molecule library, but no data were available about its synthesis, stereochemistry, and physicochemical properties. We report here a synthetic route that allowed us to characterize and unambiguously identify the structure of the active compound by a combination of NMR spectroscopy and in silico conformational analysis. The synthetic protocol allowed us to sustain experiments aimed at assessing its therapeutic potential for the treatment of FGF-dependent lung cancers. A crucial step in the synthesis generated a couple of diastereoisomers, with only one able to act as a FGF trap molecule and to inhibit FGF-dependent receptor activation, cell proliferation, and tumor growth when tested in vitro and in vivo on murine and human lung cancer cells.
- Castelli, Riccardo,Giacomini, Arianna,Anselmi, Mattia,Bozza, Nicole,Vacondio, Federica,Rivara, Silvia,Matarazzo, Sara,Presta, Marco,Mor, Marco,Ronca, Roberto
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p. 4651 - 4663
(2016/06/13)
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- Steroidal androgen receptor inhibitor as well as preparation method and medical application thereof
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The invention relates to the field of medicinal chemistry, in particular relates to a steroidal androgen receptor inhibitor as well as a preparation method and medical application thereof, and particularly discloses medicines for treating related diseases of an androgen receptor, for example, cell proliferation dependent on androgen, hirsutism, acnes, androgenetic alopecia and the like. The general structural formula of the compound is as shown in the specification; and group definitions in the general formula are specified in the specification.
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Paragraph 0018; 0019; 0020; 0076; 0077; 0078
(2016/12/26)
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- Isotope-Labeling Studies Support the Electrophilic Compound i Iron Active Species, FeO3+, for the Carbon-Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1
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The enzyme cytochrome P450 11A1 cleaves the C20-C22 carbon-carbon bond of cholesterol to form pregnenolone, the first 21-carbon precursor of all steroid hormones. Various reaction mechanisms are possible for the carbon-carbon bond cleavage step of P450 11A1, and most current proposals involve the oxoferryl active species, Compound I (FeO3+). Compound I can either (i) abstract an O-H hydrogen atom or (ii) be attacked by a nucleophilic hydroxy group of its substrate, 20R,22R-dihydroxycholesterol. The mechanism of this carbon-carbon bond cleavage step was tested using 18O-labeled molecular oxygen and purified P450 11A1. P450 11A1 was incubated with 20R,22R-dihydroxycholesterol in the presence of molecular oxygen (18O2), and coupled assays were used to trap the labile 18O atoms in the enzymatic products (i.e., isocaproaldehyde and pregnenolone). The resulting products were derivatized and the 18O content was analyzed by high-resolution mass spectrometry. P450 11A1 showed no incorporation of an 18O atom into either of its carbon-carbon bond cleavage products, pregnenolone and isocaproaldehyde. The positive control experiments established retention of the carbonyl oxygens in the enzymatic products during the trapping and derivatization processes. These results reveal a mechanism involving an electrophilic Compound I species that reacts with nucleophilic hydroxy groups in the 20R,22R-dihydroxycholesterol intermediate of the P450 11A1 reaction to produce the key steroid pregnenolone.
- Yoshimoto, Francis K.,Jung, I-Ji,Goyal, Sandeep,Gonzalez, Eric,Guengerich, F. Peter
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p. 12124 - 12141
(2016/10/03)
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- Direct organocatalytic stereoselective transfer hydrogenation of conjugated olefins of steroids
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Kinetically controlled and organocatalytic syn-selective transfer hydrogenation has been successfully demonstrated for the reduction of the enone functional group of various steroids. Herein, diastereoselective synthesis of many 5β-steroids have been reported through organocatalysis, which have broad medicinal and pharmaceutical applications. The mechanistic studies and the selectivity of the products clearly indicated that the catalyst 1b·d-CSA is mild enough to activate the various chiral cyclic enones through iminium ion formation during the organocatalytic transfer hydrogenations with Hantzsch ester 2a as a hydrogen source. Further, clear evidence for the selective formation of intermediate iminium species [I]+ have been characterized through on-line monitoring of controlled experiments by NMR and ESI-HRMS analyses.
- Ramachary, Dhevalapally B.,Sakthidevi, Rajasekar,Reddy, P. Srinivasa
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p. 13497 - 13506
(2013/09/02)
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- 22-NBD-cholesterol as a novel fluorescent substrate for cholesterol-converting oxidoreductases
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Docking simulations and experimental data indicate that 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β- ol (22-NBD-cholesterol), a common fluorescent sterol analog, binds into active sites of bovine cytochrome P450scc and microbial cholesterol dehydrogenases (CHDHs) and then undergoes regiospecific oxidations by these enzymes. The P450scc-dependent system was established to realize N-dealkylation activity toward 22-NBD-cholesterol, resulting in 7-nitrobenz[c][1,2,5]oxadiazole-4-amine (NBD-NH2) formation as a dominant fluorescent product. Basing on LC-MS data of the probes derivatized with hydroxylamine or cholesterol oxidase, both pregnenolone and 20-formyl-pregn-5-en-3β-ol were deduced to be steroidal co-products of NBD-NH2, indicating intricate character of the reaction. Products of CHDH-mediated conversions of 22-NBD-cholesterol were defined as 3-oxo-4-en and 3-oxo-5-en derivatives of the steroid. Moreover, the 3-oxo-4-en derivative was also found to be formed after 22-NBD-cholesterol incubation with pathogenic bacterium Pseudomonas aeruginosa, indicating a possible application of the reaction for a selective and sensitive detection of some microbes. The 3-keto-4-en derivative of 22-NBD-cholesterol may be also suitable as a new fluorescent probe for steroid hormone-binding enzymes or receptors.
- Faletrov, Yaroslav V.,Bialevich, Katsiarina I.,Edimecheva, Irina P.,Kostsin, Dzmitry G.,Rudaya, Elena V.,Slobozhanina, Ekaterina I.,Shkumatov, Vladimir M.
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- Novel oxysterols activate the Hedgehog pathway and induce osteogenesis
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Localized induction of bone formation is essential during orthopedic procedures that involve skeletal repair, such as surgical treatment of non-union bone fractures and degenerative disk disease. Herein we disclose the synthesis and biological evaluation of novel oxysterol derivatives designed as anabolic bone growth agents. Structure-activity relationship studies of oxysterol 4 have identified analogues such as 18, 21 and 30. These new analogues are characterized by higher potency in an osteoblast differentiation assay and/or by increased metabolic stability in human liver microsomes. Oxysterols 4, 18 and 21 were evaluated in vivo in a rat spinal fusion model.
- Stappenbeck, Frank,Xiao, Wei,Epperson, Matt,Riley, Mariko,Priest, Aaron,Huang, Danwen,Scott Thies, R.,Farouz, Francine,Nguyen, Khanhlinh,Jung, Michael E.
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p. 5893 - 5897,5
(2020/07/31)
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- PROGESTERONE RECEPTOR ANTAGONISTS AND USES THEREOF
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The present invention relates to a compound of formula (I): for its use as progesterone receptor antagonist, in particular for its use for the prevention and/or the treatment of cancer or uterine pathologies.
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Page/Page column 44
(2011/11/30)
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- Stereoselective synthesis and antimicrobial activity of steroidal C-20 tertiary alcohols with thiazole/pyridine side chain
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Stereoselective synthesis of novel steroidal C-20 tertiary alcohols with thiazole and pyridine side chain using Grignard reaction of steroidal ketones and thiazole/pyridine magnesium bromide have been realized. These molecules were evaluated in vitro for their antifungal and antibacterial activities. Most of the compounds exhibited significant antifungal and antibacterial activity against all the tested strains.
- Shingate, Bapurao B.,Hazra, Braja G.,Salunke, Deepak B.,Pore, Vandana S.,Shirazi, Fazal,Deshpande, Mukund V.
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experimental part
p. 3681 - 3689
(2011/11/06)
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- Ethylenediamine: An effective reagent for deacetylation of natural products
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The use of ethylenediamine in methanol is described for the selective cleavage of the acetate group in nimbin (1) to 6-deacetyl nimbin (1a) under microwave irradiation. This method enables to deacetylate without affecting other functional groups such as ,α,β-unsaturated ketone, ester, ether, etc. in certain tetranortriterpenoids and other acetate-containing natural compounds.
- Mohankumar, Ramasamy,Ilango, Kaliappan,Santhanakrishnan, Vichangal Pridiuldi,Radhakrishnan, Viswanathan,Narasimhan, Srinivasan
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experimental part
p. 851 - 858
(2010/12/25)
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- D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation
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A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the 'click chemistry' approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study.
- Banday, Abid H.,Shameem, Shameem A.,Gupta,Kumar, H.M. Sampath
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scheme or table
p. 801 - 804
(2010/10/01)
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- Highly efficient epoxidation of unsaturated steroids using magnesium bis(monoperoxyphthalate) hexahydrate
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Fast generation of epoxides from the corresponding homoallylic and allylic steroidal olefins was developed by using magnesium bis(monoperoxyphthalate) hexahydrate (MMPP) as oxidant suspended in acetonitrile (CH3CN) at reflux temperature. The protocol involves the use of a safe readily available oxidant along with an easy work-up, which renders the process very efficient. Selective 4,5- and 5,6-epoxidations of steroids are reported. Among them, highly stereoselective epoxidation of Δ5-B-nor-cholestanes was achieved. Moreover, the method is chemoselective for the 5,6-position and can be applied to the epoxidation of ring-A enones.
- Carvalho, Jo?o F.S.,Silva, M. Manuel Cruz,Sá e Melo, M. Luisa
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experimental part
p. 2773 - 2781
(2009/08/15)
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- Aspects of the progesterone response in Hortaea werneckii: Steroid detoxification, protein induction and remodelling of the cell wall
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Progesterone in sublethal concentrations temporarily inhibits growth of Hortaea werneckii. This study investigates some of the compensatory mechanisms which are activated in the presence of progesterone and are most probably contributing to escape from growth inhibition. These mechanisms lead on the one hand to progesterone biotransformation/detoxification but, on the other, are suggested to increase the resistance of H. werneckii to the steroid. Biotransformation can detoxify progesterone efficiently in the early logarithmic phase, with mostly inducible steroid transforming enzymes, while progesterone biotransformation/detoxification in the late logarithmic and stationary phases of growth is not very efficient. The relative contribution of constitutive steroid transforming enzymes to progesterone biotransformation is increased in these latter phases of growth. In the presence of progesterone, activation of the cell wall integrity pathway is suggested by the overexpression of Pck2 which was detected in the stationary as well as the logarithmic phase of growth of the yeast. Progesterone treated H. werneckii cells were found to be more resistant to cell lysis than mock treated cells, indicating for the first time changes in the yeast cell wall as a result of treatment with progesterone.
- Krizancic Bombek, Lidija,Lapornik, Ajda,Ukmar, Marjeta,Matis, Maja,Cresnar, Bronislava,Katalinic, Jasna Peter,Zakelj-Mavric, Marija
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experimental part
p. 1465 - 1474
(2009/04/06)
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- Stereoselective syntheses of 20-epi cholanic acid derivatives from 16-dehydropregnenolone acetate
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A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropregnenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these products revealed C-5α and C-17α configurations of the hydrogen atoms.
- Shingate, Bapurao B.,Hazra, Braja G.,Pore, Vandana S.,Gonnade, Rajesh G.,Bhadbhade, Mohan?M.
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p. 5622 - 5635
(2008/01/06)
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- Synthesis of 21,21-difluoro-3β-hydroxy-20-methylpregna-5,20-diene and 5,16,20-triene as potential inhibitors of steroid C17(20) lyase
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Novel 21,21-difluorovinyl steroids, designed as difluorinated C20(21) enol mimics of pregnenolone, were targeted as potential mechanism-based inhibitors of C17(20)lyase, a crucial enzyme in the biosynthesis of testosterone. Addition of (difluoromethyl)diphenylphosphine oxide reagent to 17-acetyl steroids was the approach chosen for the construction of these compounds. Of particular interest were the abnormal Wittig products which formed during attempted preparation of the triene 9. The target difluoroolefin 3 was found to be a moderately potent, time-dependent inhibitor of the enzyme.
- Weintraub, Philip M.,Holland, Amy K.,Gates, Cynthia A.,Moore, William R.,Resvick, Robert J.,Bey, Philippe,Peet, Norton P.
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p. 427 - 431
(2007/10/03)
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- Regio- and stereoselective synthesis of isoxazolines via cycloaddition reactions using pregnenolone as chiral auxiliary
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The asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides 2a-b to olefins 1a-c has been acccomplished by employing pregnenolone as chiral auxiliary. The optically pure 3-aryl-5-isoxazoline esters 9 are obtained from the major diastereomer in good yield.
- Sharma, Utpal,Bora, Utpal,Chetia, Apurba,Boruah, Romesh C.,Sandhu, Jagir Singh
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p. 1012 - 1014
(2007/10/03)
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- Use of sigma receptor agonists for the treatment of depression
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Method for the prevention or treatment of depression comprising administering to a steroid-depleted patient suffering therefrom and in need of treatment an effective amount of a sigma 1 receptor agonist.
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- 6,7-oxygenated steroids and uses related thereto
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Steroid compounds having various oxygen substitution on the steroid nucleus are disclosed. A specific functionality present on many of the steroid compounds is oxygen substitution at both of positions 6 and 7. Thus, certain steroids have oxygen substitution at C6 and C7, and some have specific stereochemistries such as 6 alpha and 7 beta oxygen substitution, and an alpha hydrogen at the 5 position in addition to having 6 alpha and 7 beta oxygen substitution. Steroids having 3,4-epoxy functionality are also disclosed. In addition, steroids having C17 pyran and delta -lactone functionality, with oxygen substitution at C6 and C7, or at C15, of the steroid nucleus, are disclosed.
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- Stereoselective synthesis of a new hexanor(C23-C28) castasterone-20,22-ethyl diether from 16-dehydropregnenolone acetate and its plant growth promoting activity
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Stereoselective synthesis of a new hexanor(C23-C28)castasterone-20,22-ethyl diether 22 has been achieved in sixteen steps from cheap and readily available 16-dehydropregnenolone acetate. This new brassinosteroid has shown typical brassin activity in mung bean epicotyl bioassay.
- Hazra, Braja G.,Basu, Sourav,Bahule, Bharat B.,Pore, Vandana S.,Vyas, Brahmanand N.,Ramraj, Velaswamy M.
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p. 4909 - 4920
(2007/10/03)
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- A Mechanism-Based Fluorogenic Probe for the Cytochrome P-450 Cholesterol Side Chain Cleavage Enzyme
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The rate-limiting step of steroid biosynthesis is the enzymatic conversion of cholesterol to pregnenolone by cytochrome P-450scc (side chain cleavage) located in the inner mitochondrial membrane of all steroid producing cells.We report here the synthesis and application of a fluorogenic probe which is a cholene-based steroid with a fluorogenic moiety (resorufin) strategically located at the site of side chain cleavage.Synthesis of the probe required four steps starting from 3β-acetoxy-22,23-bisnor-5-cholenic acid and resorufin.Reaction of the probe with P-450scc yields pregnenolone and the highly fluorescent resorufin, thus providing a sensitive fluorescent signal representative of enzyme activity.The fluorescence quantum yield of this probe is approximately 40-fold lower (Φ = 0.006) than resorufin (Φ = 0.23) and is essentially nonfluorescent at wavelengths used to excite resorufin.The utility of the probe is demonstrated biochemically by incubation with mitochondria known to contain the P-450scc enzyme, and its specificity for this enzyme is shown by regulation of the enzyme activity with inhibitors and through the use of a nonspecific substrate.
- Simpson, Daniel J.,Unkefer, Clifford J.,Whaley, Thomas W.,Marrone, Babetta L.
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p. 5391 - 5396
(2007/10/02)
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- A facile route to 20-hydroxyecdysone and side chain homologues from poststeron
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A flexible approach to ecdysteroids, chain elongated at C-26 and C-27, is reported. Key features are the addition of 5-lithio 2,3-dihydrofurans (3) to poststeron (10) and a stereoselective reduction of the 22-∞ group.
- Hedtmann, Udo,Klintz, Ralf,Hobert, Kurt,Frelek, Jadwiga,Vlahov, Iontscho,Welzel, Peter
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p. 3753 - 3772
(2007/12/18)
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- Sterols in Marine Invertebrates. Part 57. Stereostructure, Synthesis, and Acid-catalysed Isomerization of Hebesterol - A Biosynthetically Significant Cyclopropyl-containing Marine Sterol
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Three new cyclopropane-containing sterols hebesterol (11), petrostanol (8), and 23,24-dihydro-5α-calystanol (10) have been isolated from the sponge, Petrosia hebes, together with the principal sterol, petrosterol (7), and 21 known sterols.The structure elucidation of the new trace sterols was accomplished by spectroscopic methods and partial synthesis.Hebesterol (11) and its trans-diastereoisomers (31)-(33) have been synthesized and their acid-catalysed cyclopropane ring-opening studied.Each hebesterol isomer (11), (31)-(33) was correlated with the recently synthesized ficisterol isomers (5), (53), (56), and (58) of known absolute stereochemistry, thus leading to an unambiguous assignment of the absolute stereochemistry of hebesterol.The other products from the acid-catalysed isomerizations were characterized by spectroscopic methods, synthesis, and mechanistic considerations.Two of these products, (23R)-23-ethyldesmosterol (51) and (23S)-23-ethyldesmosterol (59), provided a relay to the absolute stereochemistry of the 23-ethylcholestanols, which had previously been synthesized without assignment of absolute stereochemistry.Hebesterol (11) is the key 'missing link' with the predicted stereochemistry in a proposed biosynthetic sequence encompassing the unusual marine sterols dihydrocalysterol (9), petrosterol (7), and ficisterol (5).
- Cho, Jin-Ho,Djerassi, Carl
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p. 1307 - 1318
(2007/10/02)
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- CONVERSION OF THE CHOLESTEROL SIDECHAIN TO A 17-ACETYL GROUP BY REMOTE CHLORINATION REACTIONS
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Two methods to convert cholesterol to pregnane derivatives are described.In one, template directed chlorination of C-20 with an iodoaryl ester attached at the 6 β position was used to convert i-cholesterol to pregnenolone.
- Maitra, Uday,Breslow, Ronald
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p. 3087 - 3090
(2007/10/02)
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- Mild and Effective Removal of Dithioketal Protecting Groups by Triarylamine Cation Radicals as Homogeneous Electron Transfer Agents
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1,3-Dithianes 2 can effectively be converted into the parent carbonyl compounds 7 by a very mild oxidative procedure using tri-p-tolylammoniumyl (1a+.) or tris(4-bromophenyl)ammoniumyl (1b+.) as homogeneous electron transfer agents.The yields are equally good for the cleavage by stoichiometric amounts of the triarylammoniumyl hexachloroantimonates as well as for the indirect electrochemical procedure using catalytic amounts of the triarylamine together with electrochemical generation and regeneration of the cation radicals.In the case of 1,3-dithiolanes 3 the application of stoichiometric amounts of tris(4-bromophenyl)ammoniumyl hexa chloroantimonate is very effective while during the indirect electrochemical procedure the deposition of polymeric sulfur compounds onto the electrode surface has to be prevented by the use of a flowthrough cell.In all cases the conditions for the cleavage are so mild that hydroxy functions and double bonds are tolerated without problems.
- Platen, Martin,Steckhan, Eberhard
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p. 1679 - 1694
(2007/10/02)
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- STEROIDS AND RELATED PRODUCTS. L. THE SYNTHESIS OF 17-METHOXYMETHYLPROGESTERONE
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A new progesterone analogue, 17-methoxymethylprogesterone, was synthesized from pregnenolone by two pathways, one involving as intermediate a 17-hydroxymethylated adduct, the other one by methoxymethylation of a 17,20-lithium enolate with bromomethoxymethane.The product shows significant progestational activity.
- Boncza-Tomaszewski, Z.,Engel, Ch. R.
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p. 107 - 114
(2007/10/02)
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