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Giovanni Appendino

Publications and source records attributed to Giovanni Appendino.

At least 37 records · Page 2Linked to original sources
PubMed2005

Advances in the universal NMR database approach. 2'-substituted taxanes as probes for an improved protocol of diastereomeric differentiation.

[structure: see text] The configuration of the alpha-substituted alpha-hydroxy-beta-aminoester moiety in a series of 2'-substituted taxanes was analyzed according to the recently proposed Universal NMR Database (UDB) approach. A critical analysis of the results showed that modifications regarding chemical shift adjustment (so as to render the shifts virtually connectivity independent) were necessary to get consistent stereoassignments in this set of compounds. On this basis, a modified UDB-based strategy, especially tailored to the configurational assignment of densely substituted diastereomeric fragments, is proposed.

Databases, Factual↗
PubMed2005

SERCA-inhibiting activity of C-19 terpenolides from Thapsia garganica and their possible biogenesis.

An investigation of Thapsia garganica afforded a series of tetracyclic C-19 dilactones, whose production was dependent on the time and location of the collection. These unusual tetrahomosesquiterpenoids are presumably biosynthesized via a carbon dioxide-triggered electrophilic polyolefin cyclization. Despite the structural differences with thapsigargin, these compounds showed SERCA-inhibiting properties.

Animals↗
PubMed2005

Cytotoxic germacrane sesquiterpenes from the aerial parts of Santolina insularis.

Chemical investigation of Santolina insularis afforded 11 germacrane sesquiterpenes (1-11), four of which (2, 3, 10, and 11) are new. The stereostructures of these compounds have been established by a combination of spectroscopic techniques (mainly NMR), chemical transformations, and application of the modified Mosher method. Compounds 8 and 10 showed a potent and selective cytotoxic activity against the human colon carcinoma cell line.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Protective effect of capsinoid on lipid peroxidation in rat tissues induced by Fe-NTA.

The activity of a single IP administration (15 or 30 mg/Kg body weight) of vanillyl nonanoate, a simplified analog of capsiate, on ferric nitrilotriacetate (Fe-NTA)-mediated oxidative damage was investigated. A sub-lethal dose of Fe-NTA (15 mg Fe/Kg body weight) was administered IP to rats; animals were sacrificed, and kidney and plasma were collected 1 h after injection. In response to the Fe-NTA administration, a reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol was observed, accompanied by a rise in the concentrations of malondialdehyde (MDA), conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in plasma and kidney 1 h after administration. A pre-treatment with synthetic capsiate (SCPT) showed remarkable protective effect on the reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol, and the cellular antioxidant vitamin E, inhibiting the increase of MDA, conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in the plasma and kidney. The protective effect of SCPT and two analogues (vanillyl alcohol and vanillin) during the linoleic acid and cholesterol oxidation was investigated in in vitro systems, providing evidence of definite structure-activity relationships.

Analysis of Variance↗
PubMed2004

Modulation of chemoselectivity by protein additives. Remarkable effects in the oxidation of hyperforin.

Protein additives have a dramatic effect on the H(2)O(2) oxidation of hyperforin, either protecting the enolized phloroglucinol core from oxidation (human albumin) or promoting (HRP and ovalbumin) reaction pathways derived from the intermediacy of the enollactone 4, a minor component of the oxidation mixture in the absence of protein additives. To rationalize the exquisite specificity of several steps and their mechanistic oddity, an organocatalytic effect is postulated. The use of protein additives allows a straightforward and multigram preparation of the enollactone 6, an interesting multifunctionalized scaffold for bioactivity induction and/or modulation.

Bridged Bicyclo Compounds↗
PubMed2004

Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential.

Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin. We have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compound named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC(50) = 6 versus 0.7 nM), but more versatile in terms of structural modifications because of the presence of an additional functional group. Acetylation and phenylacetylation of rinvanil re-established and dramatically enhanced, respectively, its potency at hTRPV1. With a two-digit picomolar EC(50) (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC(50), 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, respectively, whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidation) of the double bond were tolerated. Finally, iodination of the aromatic hydroxyl caused a dramatic switch in functional activity, generating compounds that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compound was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.

Amidohydrolases↗
PubMed2004

Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line.

We have investigated the ionophoretic and apoptotic properties of the daucane sesquiterpene ferutinin and three related compounds, ferutidin, 2-alpha-hydroxyferutidin and teferin, all isolated from various species of plants from the genus Ferula. Ferutinin induced a biphasic elevation of intracellular Ca2+ in the leukemia T-cell line, Jurkat. First, a rapid calcium peak was observed and inhibited by BAPTA-AM. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through L-type calcium channels and sensitive to inhibition by EGTA. Moreover, ferutinin-induced apoptosis in Jurkat cells, and this event was preceded, in a cyclosporine-A sensitive manner, by a loss of mitochondrial transmembrane potential (DeltaPsim) and by an increase in intracellular reactive oxygen species. Ferutinin-induced DNA fragmentation was mediated by a caspase-3-dependent pathway, and was initiated independently of any specific phase of the cell cycle. The evaluation of ferutinin analogs in calcium mobilization and apoptosis assays showed strict structure-activity relationships, with p-hydroxylation of the benzoyl moiety being requested for activity.

Apoptosis↗
PubMed2004

Hyperforin inhibits cancer invasion and metastasis.

Hyperforin (Hyp), the major lipophilic constituent of St. John's wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 micromol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 micromol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 > 100 micromol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 micromol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA-without reaching tumor-cytotoxic blood levels-remarkably reduced inflammatory infiltration, neovascularization, lung weight (-48%), and size of experimental metastases with C-26 (-38%) and number of lung metastases with B16-LU8 (-22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.

Adenocarcinoma↗
PubMed2004

Imperatorin inhibits HIV-1 replication through an Sp1-dependent pathway.

Coumarins and structurally related compounds have been recently shown to present anti-human immunodeficiency virus, type 1 (HIV-1) activity. Among them, the dietary furanocoumarin imperatorin is present in citrus fruits, in culinary herbs, and in some medicinal plants. In this study we report that imperatorin inhibits either vesicular stomatitis virus-pseudotyped or gp160-enveloped recombinant HIV-1 infection in several T cell lines and in HeLa cells. These recombinant viruses express luciferase as a marker of viral replication. Imperatorin did not inhibit the reverse transcription nor the integration steps in the viral cell cycle. Using several 5' long terminal repeat-HIV-1 constructs where critical response elements were either deleted or mutated, we found that the transcription factor Sp1 is critical for the inhibitory activity of imperatorin induced by both phorbol 12-myristate 13-acetate and HIV-1 Tat. Moreover in transient transfections imperatorin specifically inhibited phorbol 12-myristate 13-acetate-induced transcriptional activity of the Gal4-Sp1 fusion protein. Since Sp1 is also implicated in cell cycle progression we further studied the effect of imperatorin on cyclin D1 gene transcription and protein expression and in HeLa cell cycle progression. We found that imperatorin strongly inhibited cyclin D1 expression and arrested the cells at the G(1) phase of the cell cycle. These results highlight the potential of Sp1 transcription factor as a target for natural anti-HIV-1 compounds such as furanocoumarins that might have a potential therapeutic role in the management of AIDS.

Base Sequence↗
PubMed2004

Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kappa B, NFAT, and activator protein 1 signaling pathways.

Endogenous N-acyl dopamines such as N-arachidonoyldopamine (NADA) and N-oleoyldopamine have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. As endocannabinoids show immunomodulatory activity, and T cells play a key role in the onset of several diseases that affect the CNS, we have evaluated the immunosuppressive activity of NADA and N-oleoyldopamine in human T cells, discovering that both compounds are potent inhibitors of early and late events in TCR-mediated T cell activation. Moreover, we found that NADA specifically inhibited both IL-2 and TNF-alpha gene transcription in stimulated Jurkat T cells. To further characterize the inhibitory mechanisms of NADA at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-kappaB, NF-AT, and AP-1 transcription factors in Jurkat cells. We found that NADA inhibited NF-kappaB-dependent transcriptional activity without affecting either degradation of the cytoplasmic NF-kappaB inhibitory protein, IkappaBalpha, or DNA binding activity. However, phosphorylation of the p65/RelA subunit was clearly inhibited by NADA in stimulated cells. In addition, NADA inhibited both binding to DNA and the transcriptional activity of NF-AT and AP-1, as expected from the inhibition of NF-AT1 dephosphorylation and c-Jun N-terminal kinase activation in stimulated T cells. Finally, overexpression of a constitutively active form of calcineurin demonstrated that this phosphatase may represent one of the main targets of NADA. These findings provide new mechanistic insights into the anti-inflammatory activities of NADA and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.

Adult↗
PubMed2004

A structure-activity relationship study on N-arachidonoyl-amino acids as possible endogenous inhibitors of fatty acid amide hydrolase.

N-arachidonoyl-glycine (NAGly) has been recently identified in rodent tissues and found to exhibit analgesic activity in vivo. NAGly is a potent inhibitor of the fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for the degradation of the endocannabinoid N-arachidonoyl-ethanolamine (anandamide), and was shown recently to elevate the blood levels of the this analgesic compound. We have synthesized several N-arachidonoyl-amino acids of potential natural occurrence, as well as the D- and L-isomers of N-arachidonoyl-alanine, and have tested their activity on FAAH preparations from mouse, rat, and human cell lines, and from mouse or rat brain. The results indicate that the relative potency and enantioselectivity of N-arachidonoyl-amino acids as FAAH inhibitors depend on the animal species. Thus, whilst NAGly is the most potent compound on the rat and mouse enzymes, N-arachidonoyl-isoleucine is active only on human FAAH and N-arachidonoyl-alanine enantiomers show a varying degree of potency. Taken together, these data support the view that an enhancement of endogenous anandamide levels underlies in part the analgesic effects of NAGly in rodents.

Alanine↗
PubMed2004

Synthesis and biological evaluation of paclitaxel-thiocolchicine hybrids.

The bifunctional taxoid-colchicinoid hybrids 6-8 were synthesized and evaluated in assays of cytotoxicity and tubulin assembly/disassembly. All compounds showed a high degree of cytotoxicity, but, while 6 and 7 behaved as bifunctional tubulin binders not unlike an equimolecular mixture of taxol and thiocolchicine, 8 was surprisingly devoid of tubulin activity, acting on a distinct and yet to identify molecular target.

Animals↗
PubMed2004

Polyoxygenated eudesmanes and trans-chrysanthemanes from the aerial parts of Santolina insularis.

The eudesmane sesquiterpenoids 1-3 and the trans-chrysanthemyl monoterpenoid 4 have been isolated from the aerial parts of Santolina insularis, a bush endemic to Sardinia. The absolute stereostructures of these novel compounds and of two known but incompletely characterized chrysanthemanes (5, 6) were established by spectroscopic techniques and by application of the modified Mosher method. The presence of the p-menthane aldehyde eucamalol (7) gives credit to the widespread use of S. insularis to fend off mosquitoes.

Animals↗
PubMed2004

Structure-activity relationships of ring C-secotaxoids. 1. Acylative modifications.

The acylative modification of IDN 5390 (3a), a 7,8-secotaxoid under preclinical development, was investigated. A modest decrease of potency was observed upon acylation of the primary and the enolic hydroxyls, suggesting that, just like in paclitaxel, the hydroxyl groups in the upper right-hand sector are not critical for cytotoxicity. The activity of these analogues, and especially of the chemically robust carbonates 3c and 3d, makes it unlikely that the activity of IDN 5390 is due to in vivo oxidation to a fledgling 7-aldehyde and re-aldolization to the corresponding taxane derivative.

Acylation↗
PubMed2004

Coumarins from Opopanax chironium. New dihydrofuranocoumarins and differential induction of apoptosis by imperatorin and heraclenin.

Opopanax chironium is a rich source of furano- and dihydrofuranocoumarins, whose accumulation in all plant parts and especially the roots is presumably responsible for the poisonous properties of the species. The presence of two distinct chemotypes was evidenced, with the one from Sicily affording the new dihydrofuranocoumarins 5d and 5e, while extracts from the Sardinian chemotype showed powerful apoptotic activity, which was traced to the prenylated furanocoumarins heraclenin (2a) and imperatorin (2b). Despite a close structural similarity, compounds 2a and 2b induced apoptosis in Jurkat leukemia cells in mechanistically different ways.

Antineoplastic Agents↗
PubMed2004

Antimycobacterial coumarins from the sardinian giant fennel (Ferula communis).

The structure of a new prenylated coumarin (E-omega-benzoyloxyferulenol, 1b) from the Sardinian giant fennel (Ferula communis) has been confirmed by synthesis. The parent compound ferulenol (1a) showed sub-micromolar antimycobacterial activity, which was partly retained in 1b and in the simplified synthetic analogue 3, but diminished in its omega-hydroxy and omega-acetoxy derivatives (1c and 1d, respectively). The outstanding activity of 1a, its low toxicity, and the evidence for definite structure-activity relationships make this prenylated 4-hydroxycoumarin an interesting antibacterial chemotype worth further investigation.

Anti-Bacterial Agents↗
PubMed2004

Structure--activity relationships of the estrogenic sesquiterpene ester ferutinin. Modification of the terpenoid core.

Esterification of p-hydroxybenzoic acid, a very weak estrogenic compound, with the daucane alcohol jaeschkeanadiol (1b) leads to a spectacular magnification of the estrogenic activity. To identify the structural elements responsible for this effect, the terpenoid core of jaeschkeanadiol p-hydroxybenzoate (ferutinin, 1a) was modified, capitalizing on the presence of two functionalities, the monoacylated, hydrogen-bonded 1,3-diol system and the double bond. The hydrogen bonding, while possibly useful, was not critical for activity, while hydrogenation and cyclopropanation of the double bond were tolerated. Conversely, oxidative modifications of the double bond that placed a hydroxyl on the alpha-face of the molecule proved detrimental. Taken together, these observations identified the substitution at C-8/C-9 as critical for activity.

Benzoates↗