1,721,129 research outputs found
Total synthesis and biological investigation of promysalin and analogues
No full textMyristic acid serves as biosynthetic precursor of a plethora of secondary metabolites. These metabolites demonstrate a wide range of antibacterial and antivirulence activity ranging from the inhibition of biofouling and biofilm formation to the disruption of quorum sensing mechanism.1 The metabolites are active against both gram positive and negative bacteria. The rapid rise of antibiotic resistant superbugs justifies the need for identifying new compounds targeting specific pathogenic bacteria. In 2011 Wen Li and coworkers isolated the myristamide metabolite promysalin from rhizosphere of rice root associated Pseudomonas putida RW10S1.2 The natural product exhibits a submicromolar activity against Pseudomonas aeruginosa (PA) and some other gram negative bacteria. The compound also promotes swarming of the producer and its surface colonization. The most recent studies have demonstrated that promysalin disperses established biofilms and inhibits pyoverdine production. The unusual bioactivity, unknown mode of action and structural uniqueness increased the interest for the compound.
Here in us report a convergent total synthesis of promysalin.3 The synthetic approach is based around a salicyldehydroproline core and a dihydroxymyristamide fragment. The key steps include a MacMillan asymmetric α-hydroxylation4 applied for the construction of the myristamide framework and one pot reduction of lactam with Superhydride and base mediated concomitant elimination of lactamol to obtain the dehydroproline fragment.5 The synthetic route can be easily adapted for the rapid generation of analogues
Sintesi e attività antitumorale di derivati poliamminici della camptotecina
No full textMolte sostanze antitumorali interagiscono con il DNA con diversi meccanismi1 compromettendone le funzioni, distruggendone la struttura fino a causare l’arresto della proliferazione cellulare o l’apoptosi. Al fine di aumentare la selettività di una sostanza citotossica sono stati fatti molti tentativi per trovare una “via specifica” attraverso cui essa possa interagire con la cellula tumorale e il suo DNA. Un’interessante soluzione proposta e documentata in letteratura2 è quella di coniugare il farmaco a poliammine. Le poliammine naturali3 sono infatti composti ubiquitari, che giocano un ruolo fondamentale sulla proliferazione e sulla differenzazione cellulare. Nelle celllule eucariotiche sono presenti sistemi specifici di trasporto attivo4 che ne permettono l’uptake e il rilascio; sembra tuttavia che questi sistemi siano particolarmente attivi nelle cellule proliferanti, come quelle tumorali, e che l’uptake delle poliammine nei tessuti tumorali sia più alto che in altri tessuti. Su questa base coniugare un citotossico a residui poliamminici potrebbe aumentarne la citotossicità e/o la selettività per la cellula tumorale.
Recentemente abbiamo riportato la sintesi e l’attività citotossica di una serie di immine5 e ossime6 della 7-formilcamptotecina. La camptotecina e i suoi analoghi sono potenti inibitori della Topoisomerasi I, un enzima nucleare che gioca un ruolo importante nella modulazione della topologia del DNA, richiesta durante alcuni processi biologici fondamentali (replicazione, trascrizione, ecc.); due suoi derivati Topotecan® ed Irinotecan® rivestono un ruolo importante nella pratica clinica.
In questo lavoro si riporta la sintesi, la valutazione della citotossicità in vitro e dell’inibizione dell’attività della Topoisomerasi I di un gruppo di derivati poliamminici della camptotecina
Approach to the total synthesis of new Pseudomonas antifungal metabolites containing a 2-pyrroline-5-carboxyl moiety
No full textRecent studies on the bio control activity of plant-associated Pseudomonas have revealed their ability to produce a series of antagonistic molecules to compete with other microorganisms, in particular phytopathogenic fungi. In 2011 Wen Li & co-workers isolated a novel type of secondary metabolites produced by Pseudomonas putida RW10S1 to promote its own swarming and biofilm formation, and to selectively inhibit many other Pseudomonas, including multidrug resistant clinical isolates of the opportunistic human pathogen Pseudomonas aeruginosa (IC50 = 1.75 μM). The amphipathic nature of these antibiotics, their role in bacterial quorum sensing and the unprecedented structural features, containing a unique 2-pyrroline-5-carboxyl moiety, enticed us to develop a synthetic sequence to this nucleus, which could be adopted for the construction of variously substituted compounds with the same skeleton.
The proposed route is centred on the use of L-pyroglutamic acid as a chiral synthon for the synthesis of 2-pyrroline-5-carboxyl moiety. Key step of the sequence is the reduction of N-protected pyroglutamate by Super-Hydride, followed by dehydratation of the resulting lactamol
Perspectives in the development of hybrid bifunctional antitumour agents
Full text linkIn spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents
First Total Synthesis of Cyrmenin B1
No full textA short and efficient synthesis of cyrmenin B1, an antifungal metabolite of myxobacteria Cystobacter armeniaca and Archangium gephyra, is described. The crucial steps of the synthesis included the formation of the dehydroalanine moiety from the corresponding serine acetate and the formation of the β-methoxyacrylate system via trimethylsilyldiazomethane methylation of the corresponding β-hydroxy enamid
2-ACRILOILFENOLI E COMPOSIZIONI ANTIMICOTICHE CHE LI CONTENGONO
No full textSi descrivono composti di formula (I)
e loro stereoisomeri, dove
R1 è idrogeno, C1-18 alchile, aloalchile, C1-C4 alcossi C1-C6 alchile, arile sostituito, eteroarile sostituito, dove il sostituente è scelto fra alogeno, nitro, ammino, OH, C1-C4 alcossi;
R2 e R3, uguali o diversi tra loro, sono idrogeno o C1-6 alchile, arile, alogeno, C1-C4 alcossi, nitro, ammino, C1-C4 alchilammino, C1-C4 alchiltio;
R4 è idrogeno, C1-18 alchile, C1-18 alchenile, C2-C18 alchinile,
C4-C18-alcadienile, fenile sostituito con alogeno, ciano, C1-4 alcossi,
C1-4 alchiltio, C1-6 alchile, aloC1-6 alchile; 2-tienile; o 3-tienile;
R5 e R6, sono idrogeno, alogeno, C1-C4 alcossi, nitro, ammino, ciano;
R7 e R8, uguali o diversi tra loro, sono idrogeno, C1-C6 alchile, arile;
R7 e R8 potendo costituire, presi assieme, un ciclo a 5, 6, 7 atomi, eventualmente sostituito con C1-C6 alchile, C1-C4 alcossi, alogeno, ammino;
R2 e R4 potendo a loro volta formare un anello carbociclico o eterociclico, eventualmente sostituito con C1-C6 alchile, C1-C4 alcossi, alogeno, nitro, ammino
Synthesis and antifungal activity of a series of 2-hydroxy-4,5-methylenedioxyarylketones analogues of kakuol
No full textNew heterocyclic scaffolds by intramolecular reactions of 4-quinolone-2-carboxamides
No full textThe quinolone moiety is an important structural unit in medicinal chemistry and many compounds with this scaffold have shown a broad range of biological properties including anticancer, antimicrobial, antiviral and antimalarial activity. In pursuance of our research on the development of new antitumor compounds, we became interested in accessing structurally diverse heterocyclic rings containingthe quinolone moiety.We have devised a reliable synthetic route to 4-quinolone-based fused systems starting from 4-quinolone-2-carboxylic acid oxoamides. The acid-catalyzed intramolecular reaction of N-unsubstituted quinolones gives structurally diverse compounds, depending on the length of the chain. Acid treatment of β-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas acid treatment of δ- and ε-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction.
As no examples of such heterocyclic structures have been reported in the literature so far, the sequence represents a versatile approach to new scaffolds andspecifically provides a method for the rapid preparation of differently substituted
derivatives. The results of a preliminary test on compound 2 (m = 1) (IC50 = 10 μM on H460 tumor cell lines) suggest that these classes of compounds could be worth of further investigation
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