Synthesis, σ1, σ2-receptors binding affinity and antiproliferative action of new C1-substituted adamantanes.

The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ(1), σ(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain.

Glaucasides A-C, three saikosaponins from Atriplex glauca L. var. ifiniensis (Caball) Maire.

From the roots of Atriplex glauca L. var. ifiniensis (Caball) Maire (syn. of Atriplex parvifolia Lowe var. genuina Maire), three new saikosaponins designated as glaucasides A-C (1-3) were isolated together with the known 3-O-ß-D-glucopyranosyl-(1 → 2)-ß-D-galactopyranosyl-saikogenin F (4). The structures of the new compounds were elucidated by extensive analysis of one-dimensional and two-dimensional NMR spectroscopy, FABMS, HR-ESIMS and chemical evidence as 13ß,28-epoxy-16ß,21ß-dihydroxyolean-11-en-3ß-yl O-ß-D-[2-O-sulfate]-glucopyranosyl-(1 → 2)-α-L-arabinopyranoside (1), 13ß,28-epoxy-16ß,21ß-dihydroxyolean-11-en-3ß-yl O-ß-D-[2-O-sulfate]-glucopyranosyl-(1 → 2)-α-L-arabinopyranosyl 21-O-{4-(secbutylamido)-butanoyl ester} (2) and 3-O-ß-D-glucopyranosyl-(1 → 2)-ß-D-galactopyranosyl saikogenin G (3). The cytotoxic activities of these compounds were evaluated against the HT-29 and HCT 116 human colon cancer cell lines.

Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids.

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein-coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42-p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs.

Steroidal saponins from Chlorophytum orchidastrum.

Six new spirostane-type saponins (1-6), named orchidastrosides A-F, and chloromaloside D were isolated from an ethanol extract of the roots of Chlorophytum orchidastrum. The saponins have neotigogenin or neogitogenin as the aglycon and oligosaccharidic chains possessing seven to nine sugar units. Their structures were elucidated mainly by 2D NMR spectroscopic analyses (COSY, TOCSY, NOESY, HSQC, and HMBC) and FABMS and HRESIMS. Compounds 1-6 were tested for cytotoxicity against two human colon cancer cell lines, HCT 116 and HT-29.

Steroidal saponins from two species of Dracaena.

Four new steroidal saponins (1-4) were isolated from the stem and bark of two species of Dracaena: deistelianosides A and B (1 and 2) from D. deisteliana and arboreasaponins A and B (3 and 4) from D. arborea. Six known saponins and one known sapogenin were also isolated. The structures of 1-4 were established as diosgenin 3-O-[3-O-sulfate-alpha-l-rhamnopyranosyl-(1-->4)]-beta-d-glucopyranoside (1), 1-O-beta-d-xylopyranosyl-(1-->2)-[alpha-l-rhamnopyranosyl-(1-->3)]-beta-d-fucopyranosyl(23S,24S)-spirosta-5,25(27)-diene-1beta,3beta,23alpha,24alpha-tetrol 24-O-alpha-l-arabinopyranoside (2), pennogenin-3-O-alpha-l-rhamnopyranosyl-(1-->2)-[alpha-l-rhamnopyranosyl-(1-->3)]-[6-O-acetyl]-beta-d-glucopyranoside (3), and 24alpha-hydroxypennogenin 3-O-alpha-l-rhamnopyranosyl-(1-->2)-[alpha-l-rhamnopyranosyl-(1-->3)]-beta-d-glucopyranoside (4) using extensive 1D and 2D NMR spectroscopic analyses and mass spectrometry. Cytotoxic activity of several of these compounds was evaluated against the HT-29 and HCT 116 human colon cancer cell lines.

Triterpene saponins from Cyclamen trocopteranthum.

Two new triterpene saponins ( 1- 2) together with three known saponins, deglucocyclamin I ( 3), cyclamin ( 4), and mirabilin ( 5), were isolated from the tubers of Cyclamen trocopteranthum. They were elucidated as 3 beta- O-{4- O-[3-hydroxyl-3-methylglutaryl]- beta-D-xylopyranosyl-(1 --> 2)- beta-D-glucopyranosyl-(1 --> 4)-[ beta-D-glucopyranosyl-(1 --> 2)]- alpha-L-arabinopyranosyl}-16 alpha-hydroxy-13 beta,28-epoxy-oleanan-30-al ( 1) and 3 beta- O-{4- O-[3-hydroxyl-3-methylglutaryl]- beta-D-xylopyranosyl-(1 --> 2)-[ beta-D-glucopyranosyl-(1 --> 6)]- beta-D-glucopyranosyl-(1 --> 4)-[ beta-D-glucopyranosyl-(1 --> 2)]- alpha-L-arabinopyranosyl}-16 alpha-hydroxy-20,30-lactone-olean-12-ene ( 2). Their structures were characterized mainly by a combination of 1D- and 2D-NMR techniques ( (1)H- (1)H COSY, TOCSY, NOESY, HSQC, and HMBC) and mass spectroscopy. Saponins 1, 3, and 4 showed a weak cytotoxic activity when tested against HT-29 and HCT 116 tumor colon cancer cells.

Structure elucidation of new oleanane-type glycosides from three species of Acanthophyllum.

From the roots of three species of Acanthophyllum (Caryophyllaceae), two new gypsogenic acid glycosides, 1 and 2, were isolated, 1 from A. sordidum and A. lilacinum, 2 from A. elatius and A. lilacinum, together with three known saponins, glandulosides B and C, and SAPO50. The structures of 1 and 2 were established mainly by 2D NMR techniques as 23-O-beta-D-galactopyranosylgypsogenic acid-28-O-beta-D-glucopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->6)]-beta-D-galactopyranoside (1) and gypsogenic acid-28-O-beta-D-glucopyranosyl-(1-->3)-[beta-D-glucopyranosyl-(1-->6)]-beta-D-galactopyranoside (2). The cytotoxicity of several of these saponins was evaluated against two human colon cancer cell lines (HT-29 and HCT 116).

Two new sesquiterpene derivatives from the Tunisian endemic Ferula tunetana Pom.

A new sesquiterpene ester, tunetanin A (1), a new sesquiterpene coumarin, tunetacoumarin A (2), together with eight known compounds, i.e., coladin (3), coladonin (4), isosmarcandin (5), 13-hydroxyfeselol (6), umbelliprenin (7) propiophenone (8), beta-sitosterol (9), and stigmasterol (10), were isolated from the roots of Ferula tunetana. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D- and 2D-NMR experiments and MS analysis, as well as by comparison with published data. The cytotoxicity of compounds 1-7 towards two human colon cancer cell lines, HT-29 and HCT 116, was evaluated. Compounds 3, 4, and 6 showed weak cytotoxic activities.

Arboreasides A-E, triterpene saponins from the bark of Cussonia arborea.

Five new triterpene saponins, arboreasides A-E (1-5), and two known saponins, ciwujianoside C(3) and 23-hydroxyursolic acid 28-O-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester, were isolated from the bark of Cussonia arborea. The structures were established using extensive 1D and 2D NMR spectroscopic analyses and mass spectrometry.

Cytotoxic spirostane-type saponins from the roots of Chlorophytum borivilianum.

Four new spirostane-type saponins named borivilianosides E-H (1-4) were isolated from an ethanol extract of the roots of Chlorophytum borivilianum together with two known steroid saponins (5 and 6). The structures of 1-4 were elucidated using mainly 2D NMR spectroscopic techniques and mass spectrometry. The cytotoxicity of borivilianosides F (2), G (3), and H (4) and three known compounds was evaluated using two human colon cancer cell lines (HT-29 and HCT 116).

Cytotoxic acacic acid glycosides from the roots of Albizia coriaria.

Two new oleanane-type saponins, coriariosides A (1) and B (2), along with a known saponin, gummiferaoside C (3), were isolated from the roots of Albizia coriaria. Their structures were established by extensive analysis of 1D and 2D NMR experiments (COSY, ROESY, TOCSY, HSQC, and HMBC) and mass spectrometry. Compounds 1 and 3 when tested for cytotoxicity against two colorectal human cancer cells showed activity against the HCT 116 (IC50 4.2 microM for 1 and 2.7 microM for 3) and HT-29 (IC50 6.7 microM for 1 and 7.9 microM for 3) cell lines.

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide.

Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.

Steroidal saponins from Dioscorea preussii.

Three new steroidal saponins, named diospreussinosides A-C (1-3), along with two known ones (4, 5) were isolated from rhizomes of Dioscorea preussii. Their structures were elucidated mainly by 1D and 2D NMR spectroscopic analysis and mass spectrometry as (25S)-17α,25-dihydroxyspirost-5-en-3ß-yl-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranoside (1), (25S)-17α,25-dihydroxyspirost-5-en-3ß-yl-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside (2), and (24S,25R)-17α,24,25-trihydroxyspirost-5-en-3ß-yl-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside (3). The spirostane-type skeleton of compound 3 possessing an unusual dihydroxylation pattern on the F-ring is reported for the first time. Cytotoxicity of compounds 2-5 was evaluated against two human colon carcinoma cell lines (HT-29 and HCT 116).

Structure and cytotoxicity of steroidal glycosides from Allium schoenoprasum.

A phytochemical analysis of the whole plant of Allium schoenoprasum, has led to the isolation of four spirostane-type glycosides (1-4), and four known steroidal saponins. Their structures were elucidated mainly by 2D NMR spectroscopic analysis and mass spectrometry as (20S,25S)-spirost-5-en-3ß,12ß,21-triol 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside (1), (20S,25S)-spirost-5-en-3ß,11α,21-triol 3-O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside (2), laxogenin 3-O-α-L-rhamnopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→4)]-ß-D-glucopyranoside (3), and (25R)-5α-spirostan-3ß,11α-diol 3-O-ß-D-glucopyranosyl-(1→3)-[ß-D-glucopyranosyl-(1→4)]-ß-D-galactopyranoside (4). Four of the isolated compounds were tested for cytotoxic activity against the HCT 116 and HT-29 human colon cancer cell lines.

Triterpenoid saponins from Hydrocotyle bonariensis Lam.

Phytochemical investigation of the under-ground parts of Hydrocotyle bonariensis led to the isolation of five oleanane-type triterpenoid saponins, 3-O-{ß-D-glucopyranosyl-(1 → 2)-[α-L-arabinopyranosyl-(1 → 3)]-ß-D-glucuronopyranosyl}-21-O-(2-methylbutyroyl)-22-O-acetyl-R(1)-barrigenol, 3-O-{ß-D-glucopyranosyl-(1 → 2)-[α-L-arabinopyranosyl-(1 → 3)]-ß-D-glucuronopyranosyl}-21-O-(2-methylbutyroyl)-28-O-acetyl-R(1)-barrigenol, 3-O-{ß-D-glucopyranosyl-(1 → 2)-[α-L-arabinopyranosyl-(1 → 3)]-ß-D-glucuronopyranosyl}-21-O-acetyl-R(1)-barrigenol, 3-O-{ß-D-glucopyranosyl-(1 → 2)-[α-L-arabinopyranosyl-(1 → 3)]-ß-D-glucuronopyranosyl}-R(1)-barrigenol, and 3-O-{ß-D-glucopyranosyl-(1 → 2)-[α-L-arabinopyranosyl-(1 → 3)]-ß-D-glucuronopyranosyl}-22-O-(2-methylbutyroyl)-A(1)-barrigenol, together with the known saniculoside-R1. Their structures were established by 2D NMR techniques and mass spectrometry. Six compounds were evaluated against two human colon cancer cell lines, HCT 116 and HT-29. Two compounds showed weak cytotoxicity with IC(50) 24.1 and 24.0, 83.0 and 83.6 µM against HT-29 and HCT 116, respectively.

Solanum incanum and S. heteracanthum as sources of biologically active steroid glycosides: confirmation of their synonymy.

A new spirostanol saponin (1), along with four known saponins, dioscin (2), protodioscin (3), methyl-protodioscin (4), and indioside D (5), and one known steroid glycoalkaloid solamargine (6) were isolated from the two synonymous species, Solanum incanum and S. heteracanthum. The structure of the new saponin was established as (23S,25R)-spirost-5-en-3ß,23-diol 3-O-{ß-D-xylopyranosyl-(1→2)-O-α-L-rhamnopyranosyl-(1→4)-[O-α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside}, by using a combination of 1D and 2D NMR techniques including (1)H, (13)C, COSY, TOCSY, NOESY, HSQC and HMBC experiments and by mass spectrometry. The compounds 1, 3, 4 and 5 were evaluated for cytotoxicity against five cancer cell lines and for antioxidant and cytoprotective activity.

New adamantane phenylalkylamines with σ-receptor binding affinity and anticancer activity, associated with putative antagonism of neuropathic pain.

The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.

Unusual oleanane-type saponins from Arenaria montana.

Three oleanane-type saponins, 3-O-ß-d-glucopyranosylechinocystic acid 28-O-ß-d-xylopyranosyl-(1→4)-[α-l-rhamnopyranosyl-(1→2)]-α-l-rhamnopyranosyl ester (1), 3-O-ß-d-glucopyranosylechinocystic acid 28-O-α-l-arabinopyranosyl-(1→3)-ß-d-xylopyranosyl-(1→4)-[α-l-rhamnopyranosyl-(1→2)]-α-l-rhamnopyranosyl ester (2), 3-O-ß-d-glucopyranosylcaulophyllogenin 28-O-ß-d-apiofuranosyl-(1→3)-ß-d-xylopyranosyl-(1→4)-[ß-d-apiofuranosyl-(1→3)]-α-l-rhamnopyranosyl-(1→2)-α-l-rhamnopyranosyl ester (3) were isolated from the whole plant of Arenaria montana. Their unusual structures for the Caryophyllaceae family were established mainly by 2D NMR techniques and mass spectrometry.

Triterpene saponins from Cyclamen persicum.

A new triterpene saponin 3-O-beta-D-glucopyranosyl-(1 --> 4)-alpha-L-arabinopyranosyl-16alpha-hydroxy-13beta,28-epoxy-oleanan-30-al (1), along with four known triterpene glycosides (2-5) were isolated from Cyclamen persicum. Their structures were characterized by a combination of 1D- and 2D-NMR (1H-1H COSY, TOCSY, NOESY, HSQC, and HMBC) and MS spectrocopic data. The cytotoxicity of compounds 2 and 4 was evaluated using two human colon cancer cell lines HT-29 and HCT 116.

Acylated triterpene saponins from the roots of Securidaca longepedunculata.

Four triterpene saponins, 3-O-beta-D-glucopyranosylpresenegenin 28-O-beta-D-apiofuranosyl-(1-->3)-beta-d-xylopyranosyl-(1-->4)-[beta-D-apiofuranosyl-(1-->3)]-alpha-L-rhamnopyranosyl-(1-->2)-{4-O-[(E)-3,4,5-trimethoxycinnamoyl]}-beta-D-fucopyranosyl ester, 3-O-beta-D-glucopyranosylpresenegenin 28-O-beta-D-apiofuranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-[beta-D-apiofuranosyl-(1-->3)]-alpha-L-rhamnopyranosyl-(1-->2)-[(6-O-acetyl)-beta-D-glucopyranosyl-(1-->3)]-{4-O-[(E)-3,4,5-trimethoxycinnamoyl]}-beta-D-fucopyranosyl ester, 3-O-beta-D-glucopyranosylpresenegenin 28-O-beta-D-apiofuranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-[beta-D-apiofuranosyl-(1-->3)]-alpha-L-rhamnopyranosyl-(1-->2)-[beta-D-galactopyranosyl-(1-->3)]-{4-O-[(E)-3,4,5-trimethoxycinnamoyl]}-beta-D-fucopyranosyl ester, and 3-O-beta-D-glucopyranosylpresenegenin 28-O-beta-D-apiofuranosyl-(1-->3)-[alpha-L-arabinopyranosyl-(1-->4)]-beta-D-xylopyranosyl-(1-->4)-[beta-D-apiofuranosyl-(1-->3)]-alpha-L-rhamnopyranosyl-(1-->2)-{4-O-[(E)-3,4,5-trimethoxycinnamoyl]}-beta-D-fucopyranosyl ester, were isolated from the roots of Securidaca longepedunculata, together with three known compounds. Their structures were established mainly by 2D NMR techniques and mass spectrometry.