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An efficient four-step procedure is described for the synthesis of 3β,25-dihydroxy-5α-cholest-7-ene from 3β-hydroxy-5α-cholesta-7,24-diene in an overall yield of 34%. This product can serve as a precursor for the synthesis of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The 3β-toluene-p-sulfonate ester of 5α-cholesta-7,24-diene was obtained from natural lanolin followed by treatment with toluene-p-sulfonyl chloride. The key step in the synthesis is a very mild method for the hydroxybromination of this ester with N-bromosuccinimide in water, followed by reduction with LiAlH4 to obtain the 3β-toluene-p-sulfonate ester of 25-hydroxy-5α-cholesta-7-ene. The final product was obtained after desulfonation of 3β-toluene-p-sulfonyoxy-25-hydroxy-5α-cholesta-7-ene to afford 3β,25-dihydroxy-5α-cholest-7-ene in excellent yield. The reagents are all relatively cheap, non-toxic and stable. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid dehydrogenase type 1 (3β-HSD1) is selectively expressed in human placenta, mammary glands and breast tumors in women. Human 3β-HSD2 is selectively expressed in adrenal glands and ovaries. Based on AutoDock 3 and 4 results, we have exploited key differences in the amino acid sequences of 3β-HSD1 (Ser194, Arg195) and 3β-HSD2 (Gly194, Pro195) by designing a selective inhibitor of 3β-HSD1. 2,16-Dicyano-4,5-epoxy-androstane-3,17-dione (16-cyano-17-keto-trilostane or DiCN-AND) was synthesized in a 4-step procedure from androstenedione. In purified 3β-HSD inhibition studies, DiCN-AND competitively inhibited 3β- HSD1 with K i = 4.7 μM and noncompetitively inhibited 3β-HSD2 with a 6.5-fold higher K i = 30.7 μM. We previously reported similar isoenzyme-specific inhibition profiles for trilostane. Based on our docking results, we created, expressed and purified the chimeric S194G-1 mutant of 3β-HSD1. Trilostane inhibited S194G-1 (K i = 0.67 μM) with a noncompetitive mode compared to its 6.7-fold higher affinity, competitive inhibition of 3β-HSD1 (K i = 0.10 μM). DiCN-AND inhibited S194G-1 with a 6.3-fold higher K i (29.5 μM) than measured for 3β-HSD1 (K i = 4.7 μM) but with the same competitive mode for both enzyme species. Since DiCN-AND noncompetitively inhibits 3β-HSD2, which has the Gly194 and Pro195 of 3β-HSD2 in place of the Ser194 and Arg195 in 3β-HSD1, this suggests that Arg195 alone in 3β-HSD1 or S194G-1 is required to bind DiCN-AND in the substrate binding site (competitive inhibition). However, both Ser194 and Arg195 are required to bind trilostane in the 3β-HSD1 substrate site based on its noncompetitive inhibition of S194G-1 and 3β-HSD2. In support of this hypothesis, DiCN-AND inhibited our chimeric R195P-1 mutant noncompetitively with a K i = 41.3 μM (similar to the 3β-HSD2 inhibition profile). Since DiCN-AND competitively inhibited S194G-1 that still contains R195 but noncompetitively inhibited R195P-1 that still contains S194, our data provides strong evidence that the Arg195 being mutated to Pro195 (as present in 3β-HSD2) shifts the inhibition mode from competitive to noncompetitive in 3β-HSD1. This supports the key role of Arg195 in 3β-HSD1 for the high affinity, competitive binding of the trilostane analogs. Our new structure/function information for the design of targeted 3β-HSD1 inhibitors may lead to important new treatments for the prevention of spontaneous premature birth. [ABSTRACT FROM AUTHOR]

Astilbe chinensis ( A. chinensis ) is a perennial herb that is used to treat chronic bronchitis and pain. The anticancer activity of 3β,6β‑dihydroxyurs‑12‑en‑27‑oic acid (ACT‑3), a major component isolated from A. chinensis , has not yet been investigated in detail. The purpose of the present study was to investigate the histone deacetylase (HDAC) inhibitory and anticancer activities of ACT‑3 compared with suberoylanilide hydroxamic acid (SAHA) in MCF‑7 human breast cancer cells. The purity of ACT‑3 was determined using high‑performance liquid chromatography. In the present study, the effects of ACT‑3 on anticancer effects of MCF‑7 cells were determined by measuring the level of apoptotic cell death and cell cycle regulator using flow cytometry analysis and western blot analysis, respectively. The effects of ACT‑3 on HDAC enzyme activity were measured using assay kits. ACT‑3 and SAHA increased the levels of acetylated histone H3 and reduced the levels of HDAC1 and HDAC3 in MCF‑7 cells. ACT‑3 significantly decreased the cell viability in a concentration‑dependent manner and induced different morphological changes at high concentrations. ACT‑3 and SAHA significantly inhibited the colony formation in MCF‑7 cells. ACT‑3 inhibited total HDAC activity in a dose‑dependent manner. ACT‑3 significantly reduced the expression levels of cyclin D1 and cyclin‑dependent kinase 4, and upregulated the expression levels of p21 WAF1 and p53. A significant increase in the G1 phase cell population was observed in MCF‑7 cells and ACT‑3 induced apoptosis by reducing the ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2‑associated X (Bax) and releasing cleaved caspase 9. Additionally, ACT‑3 significantly increased autophagic cell death by inhibiting the serine‑threonine kinase/mammalian target of the rapamycin pathway. Autophagy induction was confirmed via acridine orange staining. ACT‑3 significantly increased the pERK1/2 and p21 in MCF‑7 cells. Thus, the activated ERK pathway played an important role in cell cycle arrest and apoptosis via ERK‑dependent induction of p21 in MCF‑7 cells. These data indicated that ACT‑3 can be used as a promising anticancer agent to overcome the limitations and reduce the side effects of conventional anticancer drugs.

Methanol extract of Alafia barteri leaves showed cytotoxic activity on leukaemia carcinoma K562, and hepatic liver cancer cells WRL (IC50 values 193.1 and 225.0 μM respectively). Isolation of the extract gave ursane triterpenoid, 28-acety-urs-5,20-dien-2β,3β,24α-triol, 1, together with undecanol, 2, stigmasterol, 3 and octadecanoic acid, 4. The structures of these compounds were identified by spectroscopic analysis, including MS, 1D and 2D NMR, and supported with literature data. Compound 1 exhibited cytotoxic activity against K-562 at 50 and 100 μM concentrations with IC50 74.22 μM, while compounds 2, 3 and 4 showed low inhibition of WRL, MCF-7 and COLO cell lines. [ABSTRACT FROM AUTHOR]

Background: The 3β, 6β, 16β-trihydroxylup-20(29)-ene (TTHL) is a pentacyclic triterpene obtained from the medicinal plant Combretum leprosum Mart. In folk medicine, this plant is popularly known as mofumbo, cipoaba or mufumbo, and is used to treat several diseases associated with inflammation and pain. Methods: We investigated the antitumor efficacy of TTHL isolated from C. leprosum. The TTHL cytotoxic effect was investigated in MRC5, MCF-7, HepG2, T24, HCT116, HT29, and CACO-2 cells after 24, 48, 72 and 120 h of treatment. The mechanisms of cell death and DNA damage induction were investigated by flow cytometry and comet assay, respectively. Results: The results indicated that TTHL induced a time- and concentration-dependent growth inhibition in all human cancer cell lines. The cytotoxicity was more pronounced in MCF-7 breast cancer cells, with an IC50 of 0.30 µg/mL at 120 h. We therefore evaluated the cell death mechanism induced by TTHL (IC20, IC50, and IC80) in MCF-7 cells at 24 h. We found that the treatment with IC50 and IC80 TTHL for 24 h induced apoptosis in 14% (IC50) and 52% (IC80) of MCF-7 cells. The apoptosis induced by TTHL was accompanied by increased levels of both cleaved caspase-9 and intracellular ROS. In order to further understand the biological mechanism of TTHL-induced cytotoxicity, we have also investigated its effect on different Saccharomyces cerevisiae yeast strains. The mutant strains sod1Δ, sod2Δ, and sod1Δsod2Δ, which are deficient in superoxide dismutase antioxidant defenses, were hypersensitive to TTHL, suggesting that its capacity to disturb cellular redox balance plays a role in drug toxicity. Moreover, TTHL induced mutagenicity in the yeast strain XV185-14c. Conclusions: Taken together, the results suggest that TTHL forms covalent adducts with cellular macromolecules, potentially disrupting cellular function and triggering apoptosis. [ABSTRACT FROM AUTHOR]

Our ongoing investigations on the stem bark of Uncaria macrophylla afforded a new ursolic triterpene, 3β,6β,19α-trihydroxy-urs-12-en-28-oic acid-24-carboxylic acid methyl ester (1), named uncariursanic acid, and three known ursolic triterpenes including 3β,6β,19α-trihydroxy-23-oxo-urs-12-en-28-oic acid (2), 3β,6β,19α-trihydroxy-urs-12-en-28-oic acid (3) and ursolic acid (4). Their structures were elucidated by extensive spectral methods, including 1D and 2D NMR and HR-ESI-MS. The cytotoxicities of the four compounds were evaluated against two cancer cell lines (MCF-7 and HepG2) by the MTT method, and only compound 4 exhibited potent activity. Keywords: triterpene; 3β,6β,19α-trihydroxy-urs-12-en-28-oic acid-24-carboxylic acid methyl ester; Uncaria macrophylla; Rubiaceae; antitumor activity. [ABSTRACT FROM AUTHOR]

Glycosylation of 3 β,12 β-dihydroxy-20 R,25-epoxydammarane (panaxadiol) ( 1) under Koenigs-Knorr, Helferich, and ortho-ester reaction conditions was studied. Condensation of panaxadiol and 2,3,4,6-tetra- O-acetyl- α-D-glucopyranosylbromide ( 2) in the presence of silver oxide and 4-Å molecular sieves in dichloroethane gave a mixture of acetylated panaxadiol 3- and 12- O-β-D-glucopyranosides (3:1 ratio). Reaction of diol 1 and D-glucose tert-butylorthoacetate ( 3) in the presence of 2,4,6-collidinium perchlorate in chlorobenzene resulted in regioselective formation of panaxadiol 12- O-β-D-glucopyranoside tetraacetate. Reaction of equimolar amounts of 1 and glycosyl donor 2 in the presence of Hg(II) cyanide in nitromethane at 90°C was accompanied by opening of the tetrahydropyran ring and gave 3 β,12 β,25-trihydroxydammar20(22) E-ene 12- O- β-D-glucopyranoside tetraacetate. Panaxadiol 3- and 12- O- β-D-glucopyranosides and 3 β,12 β,25-trihydroxydammar-20(22) E-ene 12- O- β-D-glucopyranoside tetraacetate were synthesized for the first time. [ABSTRACT FROM AUTHOR]

New derivatives of steroidal 6-ketoximes containing α-chloropyridine neonicotinoid groups characteristic of bioactive compounds were synthesized by formation of oximes of cholestane and stigmastane 3 β,5-dihydroxy-6-ketosteroids with O-(2-chloropyridin-5-ylmethyl)hydroxylamine in the presence of zinc or tin(IV) chloride. [ABSTRACT FROM AUTHOR]

The heartwood of Azadirachta indica (Meliaceae) yielded a new steroid (2α, 3β, 4β -trihydroxypregnan- 16-one) and 2 known steroids (2β, 3β, 4β -trihydroxypregnan-16-one and 2α, 3α, 4β -trihydroxypregnan- 16-one). Their structures were elucidated through spectral studies including 2D NMR (COSY, NOESY, J -resolved, HMQC, HMBC) experiments. [ABSTRACT FROM AUTHOR]

New esters of 3β,5α,6β-trihydroxysteroids and 3β,5-dihydroxy-6-ketosteroids containing 6-chloropyridine groups characteristic of the alkaloid epibatidine were synthesized by acylation with 6-chloronicotinoylchloride. [ABSTRACT FROM AUTHOR]

New steroid derivatives containing 6-chloropyridine groups characteristic of the alkaloid epibatidine and neonicotinoid insecticides were synthesized by reacting 3β,5α,6β-trihydroxysteroids or 3β,5-dihydroxy-6ketosteroids with 2-chloro-5-chloromethylpyridine. [ABSTRACT FROM AUTHOR]

Abstract: Since isoprostanes are thought to participate in the pathogenesis of thrombosis, presumably through their interaction with thromboxane receptors (TPRs), we examined the ability of 8-iso-PGF2α to bind/signal through TPRs. Using TPR expressing HEK cells, it was found that 8-iso-PGF2α mobilized calcium and bound TPRs with a dissociation constant (K d) of 57nM. Interestingly, site-directed-mutagenesis revealed that 8-iso-PGF2α has a unique coordination profile with TPRs. Thus, while Phe184 and Asp193 are shared by both 8-iso-PGF2α and classical TPR ligands, Phe196 was found to be required only for 8-iso-PGF2α binding. Functional studies also revealed interesting results. Namely, that 8-iso-PGF2α signals in human platelets through both a stimulatory (TPR-dependent) and an inhibitory (cAMP-dependent) pathway. Consistent with the existence of two signaling pathways, platelets were also found to possess two separate binding sites for 8-iso-PGF2α. While the stimulatory site is represented by TPRs, the second cAMP inhibitory site is presently unidentified, but does not involve receptors for PGI2, PGD2 or PGE2. In summary, these studies provide the first documentation that: (1) 8-iso-PGF2α coordinates with Phe184, Asp193 and Phe196 on platelet TPRs; (2) Phe196 serves as a unique TPR binding site for 8-iso-PGF2α; (3) 8-iso-PGF2α signals through both stimulatory and inhibitory pathways in platelets; (4) 8-iso-PGF2α inhibits human platelet activation through a cAMP-dependent mechanism; (5) 8-iso-PGF2α interacts with platelets at two separate binding sites. Collectively, these results provide evidence for a novel isoprostane function in platelets which is mediated through a cAMP-coupled receptor. [Copyright &y& Elsevier]

Abstract: Two new lathyrane diterpenes, 3β,5α-dihydroxy-15β-cinnamoyloxy-14-oxolathyra-6Z,12E -diene (1) and 3β,5α,20-trihydroxy-15β-cinnamoyloxy-14-oxolathyra-6Z,12E-diene (2), were isolated from the roots of Euphorbia kansuensis. Their structures were determined by spectroscopic methods. [Copyright &y& Elsevier]

Abstract: Three triterpenoids, 16β-hydroxy-2,3-seco-lup-20(29)-ene-2,3-dioic acid (1), 3β,21β,24-trihydroxy-30-noroleana-12,20(29)-dien-28-oic acid (2) and 16β-hydroxylupane-1,20(29)-dien-3-one (3), along with eleven known triterpenes were isolated from stems of Stauntonia obovatifoliola Hayata subsp. intermedia (Y.C. Wu) T. Chen. Their structures were determined by analysis of HR-EI/FAB-MS and 1D and 2D NMR spectroscopic data and comparison with those in the literature. Ten of the compounds showed inhibitory activity against HIV-1 protease. [Copyright &y& Elsevier]

Abstract: Two compounds were isolated from the leaves of Panax ginseng. Their structures were identified as 3β,6α,12β-triol-22,23,24,25,26,27-hexanordammaran-20-one, and dammar-20(22),24-diene-3β,6α,12β-triol by spectral and chemical methods. The complete signal assignments of the two compounds were carried out by means of 2D NMR spectral analysis. [Copyright &y& Elsevier]

Abstract: Investigation of the methanol extract of the roots of Serratula wolffii resulted in an ecdysone-related compound, 2β,3β,20R,22R,25-pentahydroxy-5β-cholest-6,8(14)-dien (1), a new ecdysteroid, 24-methylene-shidasterone (2), the known compound stachysterone B (3) and its 14,15-α-epoxide (4), a novel natural product. The structures of compounds 1–4 were established by spectral analysis (1H NMR, 13C NMR, COSY, NOESY, HMQC, HMQC-TOCSY and HMBC). [Copyright &y& Elsevier]

Abstract: Ultraviolet light is the most common cause of skin cancers in human and several effects of ultraviolet light B (UVB) are thought to contribute to skin photocarcinogenesis. The generation of seven triterpenoids from the cones of Liquidamber styraciflua (Hamamelidaceae were examined for their nitric oxide (NO) scavenging activity as the first screening of an in vivo mouse skin anti-initiating assay. 3β,25-epoxy-3α-hydroxylup-20(29)-en-28-oic acid (1), which showed the strongest inhibitory effect among these compounds, was studied further for its anti-tumor initiating activity on mouse models initiated with ultraviolet-B (UVB) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). Oral administration of the compound 1 during a period before and after the three times of UVB irradiation exhibited a remarkable effect: administration of 0.0025% solution of the compound 1 given orally only to the test group, which started 1 week before and ended 1 week after the irradiation, showed approximately 50% inhibition of tumor incidence and tumor multiplicity in comparison to the control group. Thus, compound 1 could act as a potent anti-tumor initiator in UVB radiation photocarcinogenesis. [Copyright &y& Elsevier]

Abstract: Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3α-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3α-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3α-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3α, 5α-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. [Copyright &y& Elsevier]

Abstract: One new and three known triterpenes were isolated from roots of Angelica cartilagino-marginata var. foliata Yuan et Shan. The structures of the new compounds were determined by modern spectroscopic techniques, including 2D NMR experiments. These triterpenes are important characters in chemosystematics of Umbelliferae. [Copyright &y& Elsevier]

Abstract: A novel oleanene triterpenetetrol was isolated from the chloroform extract of the aerial parts of Leontodon filii. Its structure was shown to be 2β,3β,15α,21β-olean-12-ene-2,3,15,21-tetrol by chemical and spectroscopic methods. The fungicidal efficacy of the chloroform and methanol extracts of the plant was also evaluated, a protective effect being found against Plasmopara viticola, Botrytis cinerea, particularly powerful against Pyricularia oryzae. [Copyright &y& Elsevier]

Abstract: Two new steryl esters with a polyhydroxylated ergostane-type nucleus, 3β,5α-dihydroxy-(22E,24R)-ergosta-7,22-dien-6β-yl oleate (1) and 3β,5α-dihydroxy-(22E,24R)-ergosta-22-en-7-one-6β-yl oleate (2), were isolated from the fruiting bodies of the basidiomycete Tricholomopsis rutilans along with three known sterols (3, 4, and 5). The structures of compounds 1 and 2 were established on the basis of spectroscopic means and chemical methods. [Copyright &y& Elsevier]

A scheme using β-sitosterol as an example for synthesizing 2β, 3β, 14α-trihydroxy-Δ4,7-6-ketosteroids and their derivatives from 3β-hydroxy-Δ5-steroids was developed. [ABSTRACT FROM AUTHOR]

The studies were carried out to evaluate the constituents in the aerial part of Isodon excisus var. coreanus (Labiatae). From the aqueous fraction of methanol extract, compound 1 (α-[[3-(3, 4-dihydroxyphenyl)-1-oxo-2-propenyl]oxy]-3,4-dihydroxy-benzenepropanoic acid), compound II (9-methyl-dihydroferulic acid-4-O-β-D-glucopyranosyl (1→2)-α-L- rhamnopyranosyl (1→4)-β-D-glucopyranoside), compound III (ent-7α, 11α, 15β-trihydroxy-kaur-16-en-1-O-β-D-glucopyranoside) and compound IV (2α, 3β, 7α, 23-tetrahydroxy-olean-12-en-28-oic acid 28-O-β-D-glucopyranoside) were isolated and identified on the basis of their physicochemical and spectroscopic evidences[IR, FAB(−)MS,1H-NMR,13C-NMR, HMQC,1H-1H COSY and HMBC (Heteronuclear Multiple Bond Connectivity)]. Especially, New compounds II and III were named isodonin A and Isodonin B respectively. [ABSTRACT FROM AUTHOR]

From the roots of Rubus parvifolius L., four triterpenoidal sapogenins, ursolic acid 1, 2α-hydroxyursolic acid 2, euscapic acid 3, 2α, 3β, 19α-trihydroxyurs-12-en-23,28-dioic acid 4 and one triterpenoidal glycoside, suavissimoside R 5, were isolated. The structures were elucidated by spectroscopic methods and chemical transformations. Compound 4 was first isolated as free form. [ABSTRACT FROM AUTHOR]

Abstract: 3-O-Palmitate of 1β, 3β, 11β-trihydroxy-olean-12-ene (1),was isolated from the stalks of Celastrus rosthornianus. The structure was elucidated by MS, 1D- and 2D-NMR experiments as well as by chemical degradation. [Copyright &y& Elsevier]

An efficient four-step procedure is described for the synthesis of 3β,25-dihydroxy-5α-cholest-7-ene from 3β-hydroxy-5α-cholesta-7,24-diene in an overall yield of 34%. This product can serve as a precursor for the synthesis of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. The 3β-toluene-p-sulfonate ester of 5α-cholesta-7,24-diene was obtained from natural lanolin followed by treatment with toluene-p-sulfonyl chloride. The key step in the synthesis is a very mild method for the hydroxybromination of this ester with N-bromosuccinimide in water, followed by reduction with LiAlH4 to obtain the 3β-toluene-p-sulfonate ester of 25-hydroxy-5α-cholesta-7-ene. The final product was obtained after desulfonation of 3β-toluene-p-sulfonyoxy-25-hydroxy-5α-cholesta-7-ene to afford 3β,25-dihydroxy-5α-cholest-7-ene in excellent yield. The reagents are all relatively cheap, non-toxic and stable. [ABSTRACT FROM AUTHOR]

A correction to the article "Chemical Constituents from Alafia Barteri Oliv. Leaves with Cytotoxic Activity" is presented.

Ten compounds were isolated and purified from the peels of gold-red apple (Malus domestica) for the 1st time. The identified compounds are 3β, 20β-dihydroxyursan-28-oic acid (1), 2α-hydroxyoleanolic acid (2), euscaphic acid (3), 3-O-p-coumaroyl tormentic acid (4), ursolic acid (5), 2α-hydroxyursolic acid (6), oleanolic acid (7), betulinic acid (8), linolic acid (9), and α-linolenic acid (10). Their structures were determined by interpreting their nuclear magnetic resonance and mass spectrometry (MS) spectra, and by comparison with literature data. Compound 1 is new, and compound 2 is herein reported for the 1st time for the genus Malus. α-Glucosidase inhibition assay revealed 6 of the triterpenoid isolates as remarkable α-glucosidase inhibitors, with betulinic acid showing the strongest inhibition (IC50 = 15.19 μM). Ultra-performance liquid chromatography-electrospray ionization MS analysis of the fruit peels, pomace, flesh, and juice revealed that the peels and pomace contained high levels of triterpenes, suggesting that wastes from the fruit juice industry could serve as rich sources of bioactive triterpenes., (© 2014 Institute of Food Technologists®)