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At least 19 recordsLinked to original sources
PubMedDate not supplied

Secosteroids of marine origin.

This review describes the isolation from marine organisms of all secosteroids reported in the literature from 1972 to 2004. Secosteroids are highly oxidized metabolites with bond cleavage in the rings of the steroid tetracyclic nucleus. All secosteroids are grouped in accordance with their ring joined to side chain as 5,6-, 9,11-, 9,10- 8,9-, 8,14- and 13,17-secosteroids and the structures and the synthetic works, where available, are reported. Furthermore, this review gives details on the biological activities of the isolated secosteroids (e.g. antiproliferative, antifouling, antiinflammatory, antimicrobial, ichthyotoxic and antiviral).

Animals↗
PubMed1994

1,25(OH)2 vitamin D3 activates PKC-alpha in Caco-2 cells: a mechanism to limit secosteroid-induced rise in [Ca2+]i.

Our laboratory recently reported that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] rapidly increases the breakdown of membrane phosphoinositides, raises intracellular calcium concentration ([Ca2+]i), and translocates protein kinase C (PKC) from the cytosolic to the particulate fraction of Caco-2 cells. In the present experiments, we found that Caco-2 cells contained predominantly the alpha- and zeta-isoforms of PKC, with minimally detectable amounts of PKC-beta and -epsilon by Western blotting. 1,25(OH)2D3 and the PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) each caused time-dependent translocations of PKC-alpha, but not PKC-zeta. TPA treatment of these cells for 24 h induced a significant concentration-dependent downregulation of PKC-alpha, but not PKC-zeta. Since PKC inhibits phospholipase C-induced mobilization of Ca2+ in other cells, we examined the effects of staurosporine and H-7, PKC inhibitors, and TPA on 1,25(OH)2D3-stimulated increase in [Ca2+]i. As previously demonstrated by our laboratory, 1,25(OH)2D3 caused a biphasic increase in [Ca2+]i, with an initial elevation (transient phase) followed by a sustained increase (plateau phase). We previously demonstrated that the transient phase is mediated, at least in part, by an increase in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] stimulated by the secosteroid. Acute pretreatment with staurosporine or H-7 caused a significant stimulation, whereas acute TPA pretreatment caused a significant inhibition of the 1,25(OH)2D3-induced increase in the transient phase of [Ca2+]i. Preincubation of Caco-2 cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxy-methyl ester (BAPTA-AM) abolished both the rise in [Ca2+]i and the increase in particulate-associated PKC-alpha stimulated by 1,25(OH)2D3. Moreover, downregulation of PKC-alpha by chronic TPA treatment significantly augmented the transient phase of the 1,25(OH)2D3-stimulated rise in [Ca2+]i but had no effect on the 1,25(OH)2D3-induced change in Ins(1,4,5)P3 concentration. Furthermore, in these PKC-alpha downregulated cells staurosporine no longer increased the secosteroid-stimulated transient rise in [Ca2+]i. These results indicate that 1,25(OH)2D3, which increases [Ca2+]i and diacylglycerol, activates PKC-alpha, but not PKC-zeta. The alpha-isoform, in turn, limits the secosteroid-stimulated rise in [Ca2+]i, at a step distal to Ins(1,4,5)P3 accumulation in Caco-2 cells.

Calcitriol↗
PubMed2005

Mechanisms of the anti-inflammatory effects of the natural secosteroids physalins in a model of intestinal ischaemia and reperfusion injury.

Reperfusion of an ischaemic tissue is associated with an intense inflammatory response and inflammation-mediated tissue injury. Physalins, a group of substances with secosteroidal chemical structure, are found in Physalis angulata stems and leaves. Here, we assessed the effects of physalins on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in mice and compared with the effects of dexamethasone. Following I/R injury, dexamethasone (10 mg kg(-1)) or physalin B or F markedly prevented neutrophil influx, the increase in vascular permeability in the intestine and the lungs. Maximal inhibition occurred at 20 mg kg(-1). Moreover, there was prevention of haemorrhage in the intestine of reperfused animals. Dexamethasone or physalins effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-alpha. Interestingly, treatment with the compounds was associated with enhancement of IL-10. The anti-inflammatory effects of dexamethasone or physalins were reversed by pretreatment with the corticoid receptor antagonist RU486 (25 mg kg(-1)). The drug compounds suppressed steady-state concentrations of corticosterone, but did not alter the reperfusion-associated increase in levels of corticosterone. The IL-10-enhancing effects of the drugs were not altered by RU486. In conclusion, the in vivo anti-inflammatory actions of physalins, natural steroidal compounds, appear to be mostly due to the activation of glucocorticoid receptors. Compounds derived from these natural secosteroids may represent novel therapeutic options for the treatment of inflammatory diseases.

Animals↗
PubMed1992

Kinetic mechanism of reduction of testosterone by hepatic 5 beta-reductase of chicken and inhibition of the reductase activity by a secosteroid, an azasteroid and glycyrrhetinic acid.

The present studies on initial velocity of testosterone reduction by hepatic 5 beta-reductase (4-en-3-oxosteroid 5 beta-reductase) of chicken and mode of inhibition of the 5 beta-reduction by 5 beta-dihydrotestosterone and NADP+ indicated that the reduction of testosterone occurred after the 5 beta-reductase bound firstly to NADPH and then to testosterone, forming a ternary complex. After 5 beta-reduction, 5 beta-dihydrotestosterone and then NADP+ were liberated from the complex, following a mechanism of "ordered Bi-Bi". Effect of (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione (a steroidal 5 alpha-reductase-inhibitor or Secosteroid), diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (the other steroidal 5 alpha-reductase-inhibitor or 4-MA), and glycyrrhetinic acid (3 beta-hydroxy-11-oxoolean-12-en-30-oic acid, a 5 beta-reductase-inhibitor) was examined upon the 5 beta-reductase activity by double reciprocal plots. The mode of inhibition against testosterone by 4-MA and glycyrrhetinic acid was found to be competitive, while that by Secosteroid was non-competitive.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1994

Secosteroid mechanism-based inactivators and site-directed mutagenesis as probes for steroid hormone recognition by 3 alpha-hydroxysteroid dehydrogenase.

Rat liver 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD, EC 1.1.1.50) inactivates circulating androgens, progestins, and glucocorticoids. 3 alpha-HSD is a member of the aldo-keto reductase superfamily, and the X-ray structure of the apoenzyme shows the presence of an (alpha/beta)8 barrel [Hoog, S. S., Pawlowski, J. E., Alzari, P. M., Penning, T. M., & Lewis, M. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 2517-2521]. As yet, a three-dimensional structure of the ternary complex E.NADPH.steroid is unavailable. To identify regions of the enzyme involved in steroid hormone recognition, we have employed mechanism-based inactivators and site-directed mutagenesis. (3 RS)-1,10-Seco-5 alpha-estr-1-yne-3,17 beta-diol (1) and (17 RS)- 17-hydroxy-14,15-secoandrost-4-en-15-yn-3-one (3) are secosteroids which contain latent Michael acceptors (alpha,beta-unsaturated alcohols) at opposite ends of the steroid nucleus (at the C-3 and C-17 positions, respectively). It was found that compounds 1 and 3 inactivated 3 alpha-HSD only in the presence of NAD+. The requirement for cofactor implies that 1 and 3 are oxidized to the corresponding alpha,beta-unsaturated ketones for inactivation to occur. Chemically prepared 17 beta-hydroxy-1,10-seco-5 alpha-estr-1-yn-3-one (2) and 14,15-secoandrost-4-en-15-yne-3,17-dione (4), the presumed products of 1 and 3 oxidation, behaved as stoichiometric inactivators of 3 alpha-HSD. In the presence and absence of NAD+, 2 and 4 inactivated > 50% of the enzyme in 10 s or less.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

Diterpenoids, norditerpenoids, and secosteroids from the Formosan soft coral Cespitularia hypotentaculata.

Four new cespitularane diterpenes, cesputularins I-L (1-4), two new norverticillane norditerpenes, cespitularins M and N (5 and 6), two new verticillane diterpenes, cespitularins O and P (7 and 8), a new norditerpene, cespitularin Q (9) (having a novel carbon skeleton), a new xenicane diterpene, cespitolide (10), and two new secosteroids, 3beta,11-dihydroxy-5beta,6beta-epoxy-9,11-secocholestan-9-one (11) and 3beta,11-dihydroxy-5beta,6beta-epoxy-9,11-secogorgostan-9-one (12), were isolated from the methylene chloride solubles of the Formosan soft coral Cespitularia hypotentaculata Roxas. The structures were elucidated by extensive spectroscopic analysis, and their cytotoxicity against selected cancer cells was measured in vitro.

Animals↗
PubMed1995

New secosteroids from an undescribed gorgonian of the genus Muricella.

Three new 9,10-secosteroids, calicoferols C-E [2-4] have been isolated from an undescribed gorgonian of the genus Muricella, and their structures determined by a combination of spectroscopic methods. Calicoferol D [3] exhibited potent antiviral activity and brine-shrimp lethality.

Animals↗
PubMed1998

New secosteroids from a gorgonian of the genus Muricella.

Calicoferols F-I (2-5), four new 9,10-secosteroids, have been isolated from a gorgonian of the genus Muricella collected from Jaeju Island, Korea. The structures of these compounds have been determined by combined spectroscopic methods. Calicoferols exhibited significant cytotoxicity and inhibitory activity against PLA2.

Animals↗
PubMed1997

Retinoids and secosteroids induce gene expression in human colorectal carcinoma-derived cells but the macroscopic-scale effects remain unpredictable.

Expression of a number of retinoid-responsive genes (hRAR alpha, CRABP I, CRABP II, MK cytokine) and secosteroid-responsive genes (hVD3R, Calbindin) was studied in in vitro model of human colorectal carcinoma by Relative RT-PCR. MK cytokine mRNA has been identified in human colonocytes for the first time. Proliferation of SW480 cells was inhibited by 5 microM all-trans retinoic acid and 5 microM 1 alpha, 25-dihydroxycholecalciferol; however, SW620 cells were not inhibited by all-trans retinoic acid. Unexpectedly, SW620 cells were stimulated by nanomolar concentrations of 1 alpha, 25-dihydroxycholecalciferol. In the latter case, no induction of gene expression was seen. Gene expression was induced in both cell types, whether there was a responsive element in the promotor region or not, suggesting that signal transduction to cellular nucleus did occur. Also, the Scatchard analysis for hVD3R receptor protein confirmed that the amount of the protein was modified under the treatment with both hormones; however, non-linear relationship between the amount of the mRNA and the protein was observed. In general, the genes responded differently to the treatment than it had been predicted. While this variability could be ascribed to the genetic instability, we hypothesize that instability in the cellular network of genes, mRNAs, and proteins is responsible for the observed effects. Due to the complexity, a microscopic-scale phenomenon such as gene expression cannot determine a macroscopic-scale process such as proliferation. This study provides a molecular background for retinoid/secosteroid chemoprevention of colorectal carcinoma; however, these hormones should be applied early to control premalignant lesions rather than advanced carcinomas.

Carcinoma↗
PubMed1999

Activation of a beta-adrenergic-sensitive signal transduction pathway by the secosteroid hormone 1,25-(OH)2-vitamin D3 in chick heart.

In recent studies we have established that 1 alpha, 25-dihydroxy-vitamin D3[1,25(OH)2D3] rapidly stimulates dihydropyridine-sensitive calcium channel-mediated Ca2+influx in chick cardiac muscle by a non-genomic action which is accompanied by PKA-dependent phosphorylation of a 45 kDa microsomal membrane protein. To investigate the signal transduction pathway activated by 1,25(OH)2D3 in heart, we have compared the effects of the secosteroid hormone with those of the beta-adrenergic agonist isoproterenol (IPT) by employing cultured chick embryonic cardiac cells (myocytes) and thin-slice preparations of differentiated adult heart muscle. The increases in 45Ca2+ uptake and intracellular calcium ([Ca2+]i), cyclic AMP accumulation and changes in microsomal protein phosphorylation evoked by 1,25(OH)2D3 could be reproduced by IPT. When combined treatments with the sterol and the beta-adrenergic agonist were performed, no additive stimulation of these parameters was observed, suggesting that a common signal transduction pathway mediates the effects of 1,25(OH)2D3 and IPT. The participation of a guanine nucleotide binding protein (G protein) in the 1, 25(OH)2D3-induced changes in heart was investigated. AlF4(-), an activator of G proteins, and cholera and pertussis toxins, like 1, 25(OH)2D3 increased 45Ca2+ uptake by myocytes. AlF4(-) did not further stimulate the effects of 1,25(OH)2D3 thereby showing that a G protein is involved in the hormone action. Moreover, 1,25(OH)2D3 potentiated pertussis toxin but was unable to modify choleric toxin-dependent myocyte Ca2+ influx. Altogether, these results provide evidence indicating that the non-genomic action of 1,25(OH)2D3 on cardiac muscle calcium influx involves modulation of the beta-adrenergic-sensitive adenylyl cyclase/cAMP/PKA pathway coupled to a Gs protein.

Adrenergic beta-Agonists↗
PubMed1978

Inhibition of testosterone 5 alpha-reductase by and antiandrogenicity of allenic 3-keto-5,10-secosteroids.

(4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione(II), A 3-keto-5,10-secosteroid which is an irreversible inhibitor of delta 5-3-ketosteroid isomerase was tested for its possible antiandrogenicity in the hamster flank organ test. The organs of female animals topically treated with 4 microgram of testosterone propionate (TP) for 4 weeks enlarged in size and showed pigmentation resembling adult males. When compound II was applied concomitantly with TP, androgenic stimulation was completely blocked and the flank organs remained small like those of female animals. These results suggest that compound II may be a useful anti-androgen when applied topically. It may well act mainly by inhibition of the formation of 5alphs-reduced metabolites was markedly inhibited.

5-alpha Reductase Inhibitors↗
PubMed1979

Selective inhibition by secosteroids of 5 alpha-reductase activity in human sex skin fibroblasts.

The effects of 5,10-secoestra-4,5-diene-3,10,17-trione (Compound I) and 5,10-seco-19-norpregna-4,5-diene,3,10,20-trione (Compound II) on the 5 alpha-reductase activity and on the androgen receptors of normal human sex skin fibroblasts were investigated. The Vmax and Km of the transformation of testosterone to 5 alpha-reduced products was 387 pg/microgram DNA/30 min and 234 X 10(-9)M, respectively. When the inhibitors were introduced in the assay, the 5 alpha-reductase activity was markedly reduced, Compound I being a less potent inhibitor than Compound II. At 15 min, the inhibition was greater than at 30 and 60 min. The Ki for Compound I was 1.60 x 10(-6)M with a Vmax of 83 to 553 pg/microgram DNA/30 min. For Compound II, the Ki was 0.53 x 10(-6)M with a Vmax of 70 to 340 pg/microgram DNA/30 min. The inhibition was of the noncompetitive type. Studies with androgen receptors showed that Compound I had a lower affinity for the receptors than Compound II. The ID50 for 3H-DHT and 3H-T for Compound I were 42.9 x 10(-7)M and 8.6 x 10(-7)M, respectively, whereas for Compound II, they were 10.6 x 10(-7)M and 4.8 x 10(-7)M.

5-alpha Reductase Inhibitors↗
PubMed1983

Studies in antifertility agents--Part XLI : Secosteroids--X : Syntheses of various stereoisomers of (+/-) 2,6 beta -diethyl-7 alpha -ethynyl-3-(p-hydroxyphenyl)-trans-bicyclo[4.3.0]nonan-7 beta-ol.

The syntheses of (+/-) 2 alpha,6 beta -diethyl-7 alpha -ethynyl-3 alpha-(p-hydroxyphenyl)-trans- bicyclo[4.3.0]nonan-7 beta-ol (8), (+/-)2 beta,6 beta-diethyl-7 alpha-ethynyl-3 beta-(p-methoxy-phenyl)-trans-bicyclo[4.3.0]nonan-7 beta-ol 12 and (+/-) 2 alpha,6 beta-diethyl-7 alpha-ethynyl-3 beta-(p-hydroxyphenyl)- trans-bicyclo[4.3.0]nonan-7 beta-ol (18) and their derivatives, which are essentially B-seco-steroids having cis-anti-trans, cis-syn-trans and trans-anti-trans geometries have been carried out. A study of their antiimplantation activities (AI) and receptor binding affinities (RBA) show that trans-anti-trans compounds are biologically most potent, followed by the corresponding cis-anti-trans and cis-syn-trans compounds. The most potent compound 18 is active at 1 mg/kg in rats. Introduction of 7 alpha-ethynyl group increases their AI activity; however, no significant effect on their RBA is observed.

Animals↗
PubMedDate not supplied

Synthesis and biological activities of a new series of secosteroids: vitamin D phosphonate hybrids.

By a structural combination of phosphonate and bisphosphonate moieties with the vitamin D skeleton a series of new vitamin D analogs was synthesized. Derivatives with 24beta-hydroxy- or 24-keto groups exerted considerable vitamin D activities in vitro while the hypercalcemic potentials were significantly reduced as compared to 1alpha,25-dihydroxyvitamin D(3) (calcitriol). Whereas the 24-hydroxy analogs did not influence bone formation in vivo in dosages below the hypercalcemic threshold, the 24-ketones were found to induce synthesis of new bone matrix in non-hypercalcemic doses. Vitamin D bisphosphonate hybrids, on the other hand, which did not elicit substantial vitamin D activities in vitro and tend to decrease serum calcium levels in vivo clearly induced osteoid formation in rats, indicating a mechanism of action different to calcitriol.

Animals↗