1,721,182 research outputs found
Capitolo 2. Proprietà chimico-fisiche e attività biologica
No full textTra gli obiettivi che hanno ispirato quest’opera c’è soprattutto quello di fornire un testo valido dal punto di vista didattico che riesca a soddisfare gli argomenti dei programmi, anzi, se possibile, che ne favorisca una maggiore omogeneità, e che risulti una guida affidabile per gli studenti. Punto di forza di questo libro è il fatto che gli autori sono docenti che insegnano Chimica Farmaceutica nella quasi totalità degli atenei italiani. Tratti distintivi sono, inoltre, la trattazione dei concetti generali più importanti nella ricerca e nello sviluppo dei farmaci e la descrizione dettagliata delle caratteristiche dei farmaci più utilizzati nelle principali patologie.
Farmacia e Chimica e Tecnologie Farmaceutiche sono due Corsi di studio con finalità differenti ma con molte materie in comune, declinate però in modo diverso; tra queste vi è la Chimica Farmaceutica. Accanto al corpo centrale del libro, sufficientemente completo e non dispersivo che trasmette i concetti fondamentali comuni a entrambi, sono possibili approfondimenti e percorsi didattici differenti. Questo è possibile grazie all’ausilio di un gran numero di schede, utili a soddisfare le specificità dei due differenti Corsi di studio.
Per rispettare questi obiettivi si è anche fatto un uso sistematico e mirato di schede pubblicate sul sito dedicato (oltre 200 schede on line): approfondimenti, sintesi e metabolismi. Per consentire una migliore fruizione dei contenuti on line è disponibile una versione e-book dell’opera, con la quale sarà più facile navigare tra testo e schede collegate.
Come ulteriore supporto allo studio e alla preparazione dell’esame, sono disponibili on line oltre 500 test di autovalutazione interattivi, direttamente inerenti i capitoli del libro, e altri 250 su argomenti più generali di Chimica Farmaceutica
The use of stilbene scaffold in medicinal chemistry and multi-target drug design
No full textThe stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent. Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields. In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes
Diaryl Urea: A Privileged Structure in Anticancer Agents
No full textAbstract: The diaryl urea is an important fragment/pharmacophore in constructing anticancer
molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a
favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor.
Many novel compounds have been synthesized and evaluated for their antitumor activity
with the successful development of sorafenib. Moreover, this structure is used to link
alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several
kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors:
it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone
amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh)
ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we
provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative
antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors
and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the
search to find new and more potent compounds
Diaryl urea:A privileged structure in anticancer agents
No full textThe diaryl urea is an important fragment/pharmacophore in constructing anticancer molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor. Many novel compounds have been synthesized and evaluated for their antitumor activity with the successful development of sorafenib. Moreover, this structure is used to link alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors: it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh) ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the search to find new and more potent compounds.</p
Multi-kinase inhibitors
No full textThe limitations of many mono-kinase inhibitors can be overcome by agents with multi-target action. An important advantage of targeting more than one kinase, is an increase in potency, due to the synergistic effect. Moreover, this approach can reduce the possibility of developing drug resistance. Several multitarget agents have been designed as single kinase inhibitors and found to be multi-target inhibitors because of the structural homology among the ATP-binding site of kinases. In other cases, these inhibitors have been obtained by optimization of potent individual inhibitors or by combination of selective ligands. Also some irreversible inhibitors act on different kinases and covalently modify the cysteine residues located near the ATP-binding pocket. In this review the most recent examples of multi-kinase inhibitors are reported, focusing on chemical structures, structure-activity relationship (SAR) and biological activity. These inhibitors, suitably substituted, could be used in designing other multitarget agents. Virtual molecular docking would suggest potential targets of molecules, moreover combining pharmacophore combination and screening methods could probably help in the discovery of more potent multikinase inhibitors.</p
Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells
Full text linkThe inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues. In cancer cells, lactate was recently found to directly increase migration ability; moreover, when released in the microenvironment, it can facilitate matrix remodeling. In this paper, we illustrate that treatment of human colon adenocarcinoma cells with TNF-α and IL-17, two pro-inflammatory cytokines, modifies LDH activity, causing a shift toward the A isoform which results in increased lactate production. At the same time, the two cytokines appeared to induce features of epithelial-mesenchymal transition in the treated cells, such as reduction of E-cadherin levels and increased secretion of metalloproteinases. Noteworthy, oxamate and galloflavin, two inhibitors of LDH activity which reduce lactate production in cells, were found to relieve the inflammation-induced effects. These results suggest LDH-A and/or lactate as common elements at the cross-road between cancer cell metabolism, tumor progression and inflammation. At present, LDH inhibitors suitable for clinical use are actively searched as possible anti-proliferative agents; our data lead to hypothesize for these compounds a wider potential in anticancer treatment
Synthesis, antibacterial activity and structure-activity relationships of N-substituted 4-diazopyrazole-5-carboxamides. 2
No full textA series of 4-diazopyrazole-5-carboxamides were synthesized and their antibacterial activity against a no. of Gram-neg. and Gram-pos. strains was tested. Some of the compds. were quite active and the whole set was allowed to further study the SAR of the class. Substituents in position 5 affect Gram-neg. and Gram-pos. activities via bulk and electronic properties resp.; position 3 mostly affects the Gram-neg. activity, while the presence of the charged diazo group in position 4 is crucial for both antibacterial activities
New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives
Full text linkIn recent years, synthetic lethality has been recognized as a solid paradigm
for anticancer therapies. The discovery of a growing number of synthetic lethal targets
has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADP-
ribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular,
molecular targets within DNA damage response have provided a source of inhibitors that
have rapidly reached clinical trials. This Perspective focuses on the most recent progress
in synthetic lethal targets and their inhibitors, within and beyond the DNA damage
response, describing their design and associated therapeutic strategies. We will conclude
by discussing the current challenges and new opportunities for this promising field of
research, to stimulate discussion in the medicinal chemistry community, allowing the
investigation of synthetic lethality to reach its full potentia
Synthesis and calcium antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(nitrogenous heteroaryl)-3,5-pyridine dicarboxylates.
No full textA new series of 4-(nitrogenous heteroaryl)-1,4-dihydropyridine (I, R1 = e.g., indol-2-yl, quinolin-4-yl, quinoxalin-5-yl, R1 = Me or Et) antagonists were synthesized and screened for inotropic, chronotropic and calcium antagonist properties, in order to evaluate the effect on pharmacol. activity of replacement of the 4-aryl group of nifedipine-like drugs by heterocyclic moieties, such as quinoline, indole, carbazole and pyrazole. The most potent bradycardic compds. of the series elicited weak calcium antagonist activity and were stronger neg. inotropic
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