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This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent taccalonolide AJ demonstrated covalent binding to β-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A counter-current chromatography (CCC) method was successfully applied to separate and purify steroid saponins from the traditional Chinese medicine Dioscorea zingiberensis C.H.Wright for the first time. Ethyl acetate-n-butanol-methanol-water (4:1:2:4, v/v) was used as the two-phase solvent system, and evaporative light scattering detector (ELSD) was used as the detector in this method. The method separated in a single run the following five steroid saponins: 26-O-β-d-glucopyranosyl-(25R)-furost-5-en-3β, 22ζ, 26-triol-3-O-[β-d-glucopyranosyl-(1→3)-β-d-glucopyranol-(1→4)-α-l-rhamnopyranosyl-(1→2)]-β-d-glucopyranoside (Compound A); 26-O-β-d-glucopyranosyl-(25R)-furost-5-en-3β, 22ζ, 26-triol-3-O-[β-d-glucopyranosyl(1→3)-α-l-rhamnopyranosyl(1→2)]-β-d-glucopyranoside (Compound B); 26-O-β-d-glucopyranosyl-(25R)-furost-5-en-3β, 22ζ, 26-triol-3-O-[α-l-rhamnopyranosyl(1→4)]-β-d-glucopyranoside (Compound C); 26-O-β-d-glucopyranosyl-(25R)-furost-5, 20(22)-diene-3β, 26-diol-3-O-{α-l-rhamnopyranosyl-(1→4)-[β-d-glucopyranosyl-(1→3)-β-d-glucopyranosyl-(1→2)]}-β-d-glucopyranoside (Compound D); and 26-O-β-d-glucopyranosyl-(25R)-furost-5, 20(22)-diene-3β, 26-diol-3-O-[β-d-glucopyranosyl-(1→4)-α-l-rhamnopyranosyl(1→2)]-β-d-glucopyranoside (Compound E). Their structural identification of the five steroid saponins was performed by means of ESI-MS, and (13)C NMR., (Copyright © 2013. Published by Elsevier B.V.)

Two dimeric steroid derivatives, shishicrellastatin A (1) and B (2), have been isolated as cathepsin B inhibitors from the marine sponge Crella (Yvesia) spinulata. Their structures were determined by interpretation of spectroscopic data. Shishicrellastatins inhibit cathepsin B with an IC(50) value of 8 μg/mL each., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Simultaneous characterization of quaternary alkaloids, 8-oxoprotoberberine alkaloids, and a steroid compound in Coscinium fenestratum was successfully performed by liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LC/IT-TOF MS). A total of 32 compounds, including 2 benzylisoquinoline alkaloids, 3 aporphine alkaloids, 12 quaternary protoberberine alkaloids, 10 8-oxoprotoberberine alkaloids, 3 tetrahydroprotoberberine alkaloids, and a steroid compound were simultaneously separated and characterized by matching the empirical molecular formulae with those published in literature and the multi-stage mass spectrometry (MS(n)) data obtained using structural information from IT, accurate mass measurement obtained from TOF MS, and HPLC separation. A total of 20 compounds, including 4 novel natural products were identified or tentatively identified for the first time from Coscinium fenestratum. In the positive-ion mode, 8-oxoprotoberberines produced [M+H](+) and [M+Na](+); the fragmentation of 8-oxodihydroprotoberberines produced [M+H-*CH(3)](+*), [M+H-*CH(3)-*CH(3)](+), and [M+H-*CH(3)-*CH(3)-CO](+), while 8-oxotetrahydroprotoberberines generated [M+H-*CH(3)](+*), [M+H-*CH(3)-*CH(3)](+), [M+H-*CH(3)-*H](+), and iminium ions from the cleavage of the protoberberine skeleton. The method can be applied for the analysis of 8-oxoberberine and other alkaloids in Coptis japonica, Phellodendron amurense, and other herbal medicines.

Although nerve growth factor (NGF) therapy is an available option for the treatment of Alzheimer's disease, several limitations exist in its medical application. In the present study, we examined the neurotrophic effects of spicatoside A isolated from Liriope platyphylla on PC12 cells as well as the mechanisms involved in this process. Spicatoside A (10 microg/mL) induced neurite outgrowth similar to NGF (50 ng/mL). Furthermore, spicatoside A, a steroidal saponin, activated extracellular signal-regulated kinase 1/2 (ERK 1/2) and phosphatidylinositol 3-kinase (PI 3-kinase/Akt) via tyrosine receptor kinase A (TrkA), which is responsible for the induction of the neuritic process. The effects of NGF and spicatoside A on neurite outgrowth disappeared in TrkA knockdown PC12 cells by siRNA. In conclusion, neuritogenic effects resulting from spicatoside A may be involved in TrkA activation.

Macrostemonoside A, a newly found compound, is derived from Allium macrostemon Bung. However, investigation into its nature is lacking. In this study, the effects of macrostemonoside A on hyperglycemia, hyperlipidemia, visceral fat accumulation, and related enzyme activities in high-fat diet-fed C57BL/6 mice are examined. The results showed that mice fed with a high-fat diet had a significant increase in fasting blood glucose, liver glycogen, serum total cholesterol, and visceral fat accumulation, but were mildly or moderately inhibited by macrostemonoside A at a dose of 4 mg/kg/d after 30 days of treatment. This hypoglycemic effect might be associated with the potential increase in insulin sensitivity and visfatin expression, although it needs further validation in future studies. Its anti-obesity effect might be associated with elevated total lipase activity in visceral adipose cells. The up-regulation in the expression of peroxisome proliferators-activated receptor gamma 2 might be responsible for the increased lipase activity in visceral adipose cells. Furthermore, we supposed that its action mechanisms might promote energy metabolism in muscles. Macrostemonoside A, with its steroid-like structure, has no significant cortisone-like side effects on the immune system but has potential cardiovascular protective effects. These results suggested that a potential compound to treat hyperglycemia, hyperlipidemia, and visceral obesity could be developed. However, its underlying mechanisms need further investigation in future studies.

Dehydroepiandrosterone (DHEA), the most abundant steroid in human circulating blood, is metabolized to sex hormones and other C19-steroids. Our previous collaborative study demonstrated that androst-5-ene-3beta,17beta-diol (Adiol) and androst-4-ene-3,17-dione (Adione), metabolites of DHEA, can activate androgen receptor (AR) target genes. Adiol is maintained at a high concentration in prostate cancer tissue; even after androgen deprivation therapy and its androgen activity is not inhibited by the antiandrogens currently used to treat prostate cancer patients. We have synthesized possible metabolites of DHEA and several synthetic analogues and evaluated their role in androgen receptor transactivation to identify AR modulators. Steroids with low androgenic potential in PC-3 cell lines were evaluated for anti-dihydrotestosterone (DHT) and anti-Adiol activity. We discovered three potent antiandrogens: 3beta-acetoxyandrosta-1,5-diene-17-one 17-ethylene ketal (ADEK), androsta-1,4-diene-3,17-dione 17-ethylene ketal (OAK), and 3beta-hydroxyandrosta-5,16-diene (HAD) that antagonized the effects of DHT as well as of Adiol on the growth of LNCaP cells and on the expression of prostate-specific antigen (PSA). In vivo tests of these compounds will reveal their potential as potent antiandrogens for the treatment of prostate cancer.

Six new steroid glycosides, linckosides F-K, and a related metabolite were isolated from the Okinawan blue starfish Linckia laevigata as mimics or enhancers of nerve growth factor (NGF). Their structures and stereochemistry were elucidated by spectroscopic methods and chemical derivatization. Structure-activity relationships suggest that both a carbon branch modified by a pentose at the side chain and 2'-O-methylxylopyranose at C-3 of the aglycon are important for neuritogenic activity.

A comparative study of classical and ultrasound-assisted extractions of steroids and triterpenoids from stem, leaves and flowers of Chresta exsucca, C. scapigera and C. sphaerocephala is described. The direct analysis of crude apolar and medium-polar extracts has been conducted by high-resolution gas chromatography followed by co-injections of the crude extract with certified standards on capillary columns of different polarities. The use of ultrasound decreased significantly the total time of treatment and in addition, this extraction method was more effective for the steroids and most of the triterpenes.

This paper reports on the cytotoxic effect induced by a new natural steroidal saponin, icogenin, on the myeloid leukemia cell line HL-60. Icogenin was found to be a cytotoxic compound IC(50) 2.6+/-0.9microM at 72h, with growth inhibition caused by the induction of apoptosis, as determined by microscopy of nuclear changes and the fragmentation of poly(ADP-ribose) polymerase-1.

Three new steroid glycosides, linckosides C-E, were isolated from the Okinawan starfish Linckia laevigata. Their structures and partial stereochemistry were elucidated by spectroscopic methods and chemical derivatization. These metabolites are additional members of the linckosides that were previously discovered as a novel class of neuritogenic compounds. Each of them possesses two monosaccharide units at C-3 of a polyhydroxylated steroidal aglycon and at the side chain (C-28 or C-29). Linckosides C and D are the first steroids that possess a hydroxyisopropyl substituent at C-24 of the side chain. These compounds are not only potent inducers of neurite outgrowth on PC12 cells but also significant enhancers of nerve growth factor (NGF) to induce the neurite outgrowth. The structure-activity relationships within the linckosides revealed that the presence of xylopyranose at the side chain was important rather than arabinofuranose, but that the diversity of the side chain carbon skeleton was not.

Six minor new ecdysteroid components have been isolated from Silene otites (L.) Wib. by a combination of chromatographic methods. Three of them (2-deoxy-20-hydroxyecdysone 3,22-diacetate, 5 alpha-2-deoxy-20-hydroxyecdysone 3-acetate, and 2-deoxy-20-hydroxyecdysone 3-crotonate) are new natural products.

Five new trichilin-type limonoids, named 12-deacetyltrichilin I (1), 1-acetyltrichilin H (2), 3-deacetyltrichilin H (3), 1-acetyl-3-deacetyltrichilin H (4), 1-acetyl-2-deacetyltrichilin H (5), together with four known trichilins, meliatoxin B1 (6), trichilin H (7), trichilin D (8) and 1,12-diacetyltrichilin B (9) were isolated from the extract of the root bark of Melia azedarach. The structures were elucidated by spectroscopic means and their cytotoxic activities against P388 cells in vitro were tested by means of MTT assay.

This study compares the effect of Mandevilla velutina compounds with some anti-inflammatory drugs against phospholipase A2- and phospholipase C-induced rat hindpaw oedema. Injection of phospholipase A2 (Naja naja, 2.5-20 U/paw) and phospholipase C (Clostridium perfringens, 0.03-0.05 U/paw) caused a dose-and-time-related increase in paw oedema. Compounds MV 8608 (55 mumol/kg) and MV 8612 (32 mumol/kg, i.p.) inhibited phospholipase A2-induced paw oedema without interfering with phospholipase C-induced oedema. Local injection of both M. velutina compounds also partially attenuated the oedema evoked by phospholipases A2 and C. Dexamethasone (1.3 mumol/kg, p.o.) suppressed only phospholipase A2-induced paw oedema, while indomethacin (11 mumol/kg, p.o.) attenuated only the early phase of phospholipase C-induced oedema. By contrast, phenidone (616 mumol/kg, i.p.) inhibited only phospholipase C-induced oedema, while cyproheptadine (31 mumol/kg) and pyrilamine (100 mumol/kg, p.o.) inhibited only phospholipase A2 oedema. Treatment of animals with compound 48/80 markedly suppressed phospholipase A2-induced paw oedema and to a lesser degree the oedema caused by phospholipase C. Our results indicate that there are marked differences regarding the mechanisms underlying the paw oedema responses caused by phospholipase A2 and phospholipase C. In addition, our data show that M. velutina compounds cause potent and long-lasting inhibition of the pro-inflammatory action of phospholipase A2, an effect which may account for their reported anti-inflammatory activities.

Certain synthetic and endogenous steroids are known to modulate neuronal responses to gamma-aminobutyric acid (GABA) and also change the firing frequency of certain neurons. However, there is nothing known of the effect(s) of steroids on voltage-gated calcium currents in mammalian neurons. We show here that the steroids (0.1-100 microM) allotetrahydrocorticosterone (THCC), dehydroepiandrosterone sulfate (DHEAS) and pregnanolone can rapidly and reversibly depress voltage-gated calcium currents in freshly isolated adult hippocampal CA1 pyramidal neurons. This blocking action occurs in the presence of picrotoxin (10 microM). Tail current analysis shows that THCC appears to be a ligand that selectively and reversibly depresses the omega-conotoxin (fraction GVIA) sensitive portion of the calcium current. These results demonstrate that certain steroid metabolites have a direct membrane site of action which may influence brain excitability.