59 research outputs found
Chemo-enzymatic approach to the synthesis of the antithrombotic clopidogrel
No full textA (S)-2-chlorophenylglycine moiety is well recognized in the structure of (S)-clopidogrel, a known antithrombotic drug. We prepared this chiral building block optically pure through an enzyme-catalyzed resolution of (R,S)-N-Boc-2-chlorophenylglycine methylester, the best results being obtained by means of an immobilized subtilisin, the cross-linked enzyme aggregate (Alcalase-CLEA®). The high value of enantiomeric excess of the obtained synthon kept unaltered in the course of clopidogrel synthesis and the process simplicity make this pathway suitable also for large scale preparations
Lipase-catalyzed preparation of corticosteroid 17alpha-esters endowed with antiandrogenic activity
No full textSeveral 17alpha-monoesters of cortexolone and its delta 9-derivative are endowed with antiandrogenic activity. Their synthesis can be accomplished by means of a lipase-catalyzed chemoselective alcoholysis of the corresponding 17alpha,21-diesters
Evaluation, synthesis and characterization of tacrolimus impurities
No full textTacrolimus is an immunosuppressant macrolactam of fermentative origin. By means of HPLC, LC-MS and NMR analyses, coupled with the reference standard synthesis, the main impurities of tacrolimus bulk drug samples were identified and their chemical-physical properties reported. Known ascomycin and tautomers I and II were detected. The correct relative retention time HPLC value of 39,40-dihydro tacrolimus was established. The not described 23,24-anhydro derivative was detected and completely characterized. A full characterization of ascomycin and 39,40-dihydro tacrolimus was also reported
Diastereoselective Synthesis of an Argatroban Intermediate, Ethyl (2R,4R)-4-methylpipecolate, by means of a Mandyphos/Rhodium Complex-catalyzed Hydrogenation
No full textThe synthetic antithrombotic argatroban is a dipeptide between the nonproteogenic (2R,4R)-4-methyl-2-piperidine carboxylic acid and L-arginine, in turn bonded to a methyltetrahydroquinoline sulfonyl group. An extensive screening of transition metal-based complexes with different ligands was performed in order to identify the best catalyst for the diastereoselective hydrogenation of the suitable 4,5-dehydropiperidine aimed towards the synthesis of the (2R,4R)-4-methyl piperidine moiety
Biological activity of constituents of Salvia chamaedryoides
No full textSalvia chamaedryoides Cav. (Lamiaceae) is a Mexican species [1] recently introduced in the Ligurian agricultural market as an ornamental plant, and for extractive purposes [2]. The dichloromethane extract of the aerial parts was investigated for its antimicrobial and hypoglycaemic properties with the aid of bioassay-‐oriented fractionation. Six new clerodane diterpenes
along with six known compounds were isolated, and their structures established by extensive 1D and 2D NMR, and HRESI-‐TOFMS. For determination of the absolute configuration acetonide derivatives were prepared, and analyzed by comparison
of experimental and calculated ECD spectra. The antimicrobial activity was analyzed on several Gram positive (Staphylococcus
aureus, S. epidermidis, Enterococcus faecium, E. faecalis, Streptococcus pyogenes, S. agalactiae) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Moraxella catarrhalis) bacteria, including multidrug resistant strains. The total extract displayed the strongest activity (MIC 2-‐4 μg/mL), while almost all semi-‐purified fractions and one pure compound (MIC 32-‐128 were active on both staphylococci and enterococci. The potential hypoglycaemic properties
were evaluated by measuring the inhibitory properties of extract, fractions, and pure compounds against α-‐amylase and α-‐glucosidase. Some of the isolated compounds showed a moderate inhibitory activity against α-‐amylase, while the highest activity was found against α-‐glucosidase. Three compounds showed IC50 values ranging from 0.20 to 0.29 mM and were
stronger inhibitors than the positive control acarbose (IC50=0.45mM). Our results indicate that S. chamaedryoides can be
considered as a plant with activity against important Gram positive human pathogens, and may also be helpful to control
postprandial hyperglycemia. Keywords:
Salvia
chamaedryoides,
antimicrobial
activity,
hypoglycaemic
activity
References
[1]
Epling
C.
A
Revision
of
Salvia,
subgenus
Calosphace.
Repertorium
Specierum
Novarum
Regni
Vegetabilis.,
ed.
Fedde,
F.
Vol.
110,
Verlag
des
Repertoriums,
Dahlem
dei
Berlin.
Berkley,
California:
University
of
California
Press;
1939-‐1940:
154
[2]
Cervelli
C.
Salvie.
Caratteristiche,
usi
e
coltivazione.
San
Remo:
Edizioni
Ace2;
2011:
4
Antibacterial and Hypoglycemic Diterpenoids from Salvia chamaedryoides
No full textA surface extract of the aerial parts of Salvia chamaedryoides afforded 13 diterpenes (1-13), with seven compounds (1, 3, 4, 7-9, 12) described for the first time. The structures of the new compounds were established using 1D and 2D NMR spectroscopic methods, HRESIMS, and ECD data. The potential hypoglycemic effects of the crude extract, fractions, and pure compounds from S. chamaedryoides were investigated by inhibition of α-glucosidase and α-amylase enzymes. The extract and its fractions showed a moderate dose-dependent inhibition; the pure compounds exhibited differential inhibitory activity against these two enzymes. Molecular modeling studies were also performed to suggest the interaction mode of compound 3 in the α-glucosidase enzyme active site. The antimicrobial activity of the purified compounds was investigated against 26 clinical pathogens. No activity was detected for the Gram-negative species tested nor on Candida albicans and C. glabrata, while variable susceptibilities were observed using Gram-positive staphylococcal and enterococcal species
Modulation of ion channels by natural products - identification of hERG channel inhibitors and GABAA receptor ligands from plant extracts
No full textIon channels are expressed in virtually all cell types in the human body and are involved in various physiological processes. Hence, it is not surprising that ion channels play an important role in modern drug discovery. Lead compounds are nowadays routinely tested against a panel of ion channels to evaluate selectivity and potential off-target activities.
The human ether-à-go-go-related gene (hERG) channel, a voltage-gated potassium channel, is the currently most critical antitarget with respect to cardiac safety. Inhibition of the hERG channel can prolong the QT interval on the electrocardiogram (ECG) and, as a consequence, lead to life-threatening arrhythmia. Considering the daily intake of plant-derived foods and herbal products, surprisingly few natural products have been tested for hERG blocking properties. In the course of an interdisciplinary hERG project, a selection of widely used herbal drugs and dietary plants was screened by means of a two-microelectrode voltage-clamp assay with Xenopus oocytes. Moderate hERG block was observed for the traditional Chinese herbal drug Coptidis rhizoma and black pepper fruits, and successfully tracked by HPLC-based activity profiling to dihydroberberine and piperine, respectively. The hERG blocking activity of cinnamon, guarana, and nutmeg, in contrast, was attributed to tannins. Our screening data suggest that major European medicinal plants and frequently consumed food plants are associated with a low risk for hERG inhibition. However, the case of Coptidis rhizoma pointed towards a need for a more thorough assessment of herbal drugs of the traditional Chinese medicine (TCM). Subsequent screening of a plant-derived alkaloid library led to the identification of several potent hERG blockers. Further investigations are certainly warranted to assess the cardiac safety profile of these alkaloids.
Dehydroevodiamine (DHE), a major bioactive constituent of the traditional Chinese herbal drug Evodiae fructus, has been previously shown to inhibit several cardiac ion currents in vitro. For further evaluation of its in vivo pharmacological and toxicological properties, gram amounts of DHE were needed. Since DHE is not commercially available, we developed an efficient method for its gram-scale isolation from a crude Evodia extract. Our approach is based on a combination of cation-exchange chromatography and preparative RP-HPLC. Moreover, the DHE content in commercially available Evodia products was assessed by HPLC-PDA analysis. A daily intake of up to mg amounts of DHE was calculated from recommended doses of these products. We also devised a procedure for the production of DHE-depleted Evodia products, should DHE indeed turn out to be toxicologically relevant.
The gamma-aminobutyric acid type A (GABAA) receptor, a ligand-gated chloride channel, mediates fast inhibitory neurotransmission in the central nervous system (CNS), and is thus a clinically important drug target. In the search for positive α1β2γ2S GABAA receptor modulators of plant origin, we investigated an extract of Curcuma kwangsiensis rhizomes. HPLC-based activity profiling was used in combination with a two-microelectrode voltage-clamp assay on Xenopus oocytes to identify the active constituents. Targeted isolation afforded a series of 11 structurally related labdane diterpenoids, including four new natural products. Structure elucidation was achieved by comprehensive analysis of HR-ESI-TOF-MS and NMR data. The absolute configuration of the compounds was assigned by electronic circular dichroism (ECD). The highest GABAA receptor modulating activity was observed for zerumin A.
From a more general perspective, this study demonstrates that HPLC-based activity profiling is an effective strategy to characterize bioactive compounds in crude natural extracts
Sopravvivenze. Due contesti superstiti della Napoli medievale.
No full textLʼintervento presenta per la prima volta in unʼoccasione pubblica la riscoperta di due spazi di Età medievale
miracolosamente scampati alle trasformazioni subite dalla città di Napoli negli ultimi sei secoli: la chiesa della famiglia
Orimina a Via dei Tribunali e una ʻnuovaʼ Cappella Minutolo nei pressi del Duomo. Entrambi i contesti, tuttavia, hanno
pagato un alto prezzo per la loro sopravvivenza. Nel primo caso, dopo un abbandono durato oltre cinquantʼanni il luogo
di culto ha riaperto in veste di pizzeria; nel secondo, lo spazio è stato murato tra la cripta della più nota cappella Minutolo
nel Duomo e il palazzo adiacente, un tempo residenza di quello stesso prestigioso casato
- …
