Chimica farmaceutica: farmaci sistemici: Lezioni del prof. Ettore Novellino

[English]:For thousands of years, pharmacological knowledge coming from natural remedies, has been handed down from generation to generation, without any awareness of the ways in which preparations are made to face diseases. The advent of pharmaceutical chemistry and of the modern drug industry turned that lack of awareness into a scientific knowledge that changed the destiny of the human race. The twenty-eight chapters of this book, are taken from the lectures held by Professor Ettore Novellino every year in his course “Pharmaceutical Chemistry and Toxicology 2”. The first chapters address the basic notions of drugs, homeostasis, pharmacopoeia, and receptor; then, the different pharmaceutical classes are introduced by analyzing their pharmacological and chemical aspects. In particular, the structural study of the interaction between drugs and receptors or biological enzymes gives the fundamentals to connect the chemical and stereochemical properties of a compound family, with the biological activity, a correlation better known as Quantitative Structure-Activity Relationship (QSAR). Several examples of the synthesis of some of the most historically renown drugs, provided at the end of each chapter, integrate the book./ [Italiano]: Per migliaia di anni, la conoscenza farmacologica proveniente dai rimedi naturali è stata tramandata di generazione in generazione senza alcuna consapevolezza riguardo le modalità d’azione delle preparazioni allestite per affrontare le malattie. L’avvento della chimica farmaceutica e della moderna industria del farmaco ha permesso di tradurre quell’assenza di consapevolezza in un sapere scientifico capace di rivoluzionare le sorti dell’umanità. I ventotto capitoli di questo libro sono tratti dalle lezioni che il professor Ettore Novellino tiene ogni anno per il suo corso di “Chimica farmaceutica e tossicologica 2”. Il testo prende avvio dalle nozioni basilari di farmaco, omeostasi, farmacoforo e recettore e affronta le varie classi di farmaci analizzandone gli aspetti chimici e farmacologici. In particolare, lo studio strutturale dell’interazione tra il farmaco e il recettore o l’enzima biologico, fornisce al lettore le basi per correlare le proprietà chimiche e stereochimiche di una famiglia di composti all’attività biologica, correlazione meglio conosciuta come “relazione quantitativa struttura-attività” (QSAR). Completano il libro alcuni esempi, posti in chiusura di ogni capitolo, di sintesi dei farmaci storicamente più noti

Thiazolidin-4-one formation. Mechanistic and synthetic aspects of the reaction of imines and mercaptoacetic acid under microwave and conventional heating

Microwave irradiation of a mixture of benzylidene-anilines and mercaptoacetic acid in benzene gives 1,3-thiazolidin-4- ones in very high yield (65–90%), whereas the same reaction performed through using the conventional method, at refluxtemperature, requires a much longer time and gives a much lower yield (25–69%). This difference seems to be due to someintermediates and by-products formed during the conventional reaction. On the basis of 1H NMR studies, two differentmechanisms, acting in benzene and in DMF, respectively, have been hypothesized for the thiazolidin-4-one system formation

Antitumor Agents. 5. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Dimethyl-5H-pyridophenoxazin-5-ones, Tetrahydro-5H-benzopyridophenoxazin-5-ones, and 5H-Benzopyridophenoxazin-5-ones with Potent Antiproliferative Activity

New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5Hbenzopyrido[ 2,3-j]phenoxazin-5-ones (7-9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10-12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1-6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7-9 were scarcely active, whereas the corresponding benzo derivatives 10-12 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors ð-ð stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 10-12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase

Antitumor Agents 6. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Spiro[imidazolidine-4,3′-thieno[2,3-g]quinoline]-tetraones and Spiro[thieno[2,3-g]quinoline-3,5′- [1,2,4]triazinane]-tetraones with Potent Antiproliferative Activity†

Two series of quinolinquinone derivatives, 2′H-spiro[imidazolidine-4,3′-thieno[2,3-g]quinoline]-2,4′,5,9′- tetraones (2a-n) and 2H-spiro[thieno[2,3-g]quinoline-3,5′-[1,2,4]triazinane]-3′,4,6′,9-tetraones (3a-e), were designed and synthesized using the previously described ethyl 3-amino-4,9-dioxo-2,3,4,9-tetrahydrothieno[2,3- g]quinoline-3-carboxylate (1) as a starting material. All compounds were evaluated for their antiproliferative activity against a panel of representative liquid and solid human tumor cell lines and exhibit IC50 values in the micromolar/submicromolar range. Series 2 displayed higher cytotoxicity than did series 3. The nature of the substituents on both imidazoline and triazinane N1 nitrogen markedly affected the activity profile of these series. Spectrophotometric and fluorescence measurements as well as unwinding assays performed on the most cytotoxic compounds, 2c, 2g, and 2k, showed that they are nonintercalative DNA agents and inhibit the catalytic activity of Topo II in a concentration-dependent mode. 2g was the most active Topo II inhibitor with activity levels comparable to those of VP-16

Chemical composition and biological activity of Capparis spinosa L. from Lipari Island

Several plants belonging to the genus Capparis are the focus of growing interest due to their singular nutritional and medicinal properties. In the present study, flower bud samples from C. spinosa L. (Lipari Island, Italy) were subjected to decoction, Soxhlet, and microwave extraction techniques and the individual extracts investigated to better characterize the phytochemical and antioxidant profiles of the plant. Total phenolic and flavonoid amounts, phenolic composition, radical scavenging as well as reductive and metal chelating properties were determinated by well-established chemical and analytical procedures. Furthermore, cholinesterase inhibitory effects were evaluated by Ellman's method. Fatty acid percentage and essential oil composition were also detected by GC and GC-MS techniques respectively. Rutin was found to be the major component in the studied extracts. The Soxhlet extract exhibited the strongest radical scavenging and reductive activities as compared to the other extracts, most probably due to the highest concentration of phenolics, especially rutin. The best cholinesterase inhibitory effect was observed in the microwave extract. Palmitic acid was the most abundant fatty acid in the studied oil, whereas docosane was the major volatile compound in the essential oil. Present data corroborate the multipurpose potential of C. spinosa for designing bio-based drug formulations or functional applications. (c) 2018 SAAB. Published by Elsevier B.V. All rights reserved

Urantide Conformation and Interaction with the Urotensin-II Receptor

Urotensin II (U-II) is a disulfide bridged peptide hormone identified as the ligand of a G protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have previously identified the compound termed urantide (H-Asp-c[Pen-Phe-DTrp-Orn-Tyr-Cys]-Val-OH), which is the most potent UT receptor (UTR) antagonist described to date. Urantide may have potential clinical value in the treatment of atherosclerosis. In the present study, we studied the conformational preferences of urantide in DPC micelles and developed a urantide/UTR interaction model. This model can help the design of novel peptides and small molecules as UTR antagonists

DOTA-Derivatives of Octreotide Dicarba-Analogs with High Affinity for Somatostatin sst2,5 Receptors

In vivo somatostatin receptor scintigraphy is a valuable method for the visualization of human endocrine tumors and their metastases. In fact, peptide ligands of somatostatin receptors (sst's) conjugated with chelating agents are in clinical use. We have recently developed octreotide dicarba-analogs, which show interesting binding profiles at sst's. In this context, it was mandatory to explore the possibility that our analogs could maintain their activity also upon conjugation with DOTA. In this paper, we report and discuss the synthesis, binding affinity and conformational preferences of three DOTA-conjugated dicarba-analogs of octreotide. Interestingly, two conjugated analogs exhibited nanomolar affinities on sst(2) and sst(5) somatostatin receptor subtypes

Farmaci oppioidi e Cannabis nella terapia del dolore

[English]:“Opioid and Cannabis in Pain Control” is the result of studies performed by the Pharmacy Department and the “Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione” (CIRFF) of the University of Naples, “Federico II”. This book is aimed to those who work in a pharmacy and who, scholars, teachers or students, are interested in delve into the issue. The text analyzes different topics with an interdisciplinary approach. A large part is devoted to the chemical and pharmacological aspects related to this topic. Subsequently, the text focuses the theme, still very debated, of using opioids and Cannabis in therapy through an exhaustive analysis of the entire existing legislation: from the first laws promulgated by the Kingdom of Italy until the last ministerial circulars by Italian republic. Finally yet importantly, an important part of the book focuses on medical and therapeutic interpretation with regard to the effects on pain control, where opioids and Cannabis are not only a fruitful frontier of research, but also a consolidated and effective tool to counteract some types of pain / [Italiano]: “Farmaci oppioidi e Cannabis nella terapia del dolore” rappresenta il frutto di alcuni studi, condotti per almeno tre lustri nel Dipartimento di Farmacia e nel Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione (CIRFF) della Federico II, e si rivolge sia a chi presta servizio ogni giorno in una farmacia, sia a chi, studioso, docente o studente, è interessato ad approfondire l’argomento. Il testo, utilizzando un approccio interdisciplinare, si muove su piani euristici differenti. Naturalmente, ampio spazio è stato dedicato alla parte farmaceutica, analizzando tutti gli aspetti chimici e farmacologici connessi a questo tema. Un secondo punto di rilievo riguarda la problematica normativa legata alla dibattuta questione dell’utilizzo in terapia degli oppioidi e della Cannabis. In tal senso, si è cercato di offrire una prospettiva chiara ed esauriente del complesso quadro legislativo vigente: a partire dalle prime leggi promulgate dal Regno d’Italia, fino ad arrivare alle ultime circolari ministeriali in materia, è stata rivista ed esaminata l’intera normativa sulle sostanze stupefacenti, spiegandone anche i passaggi più delicati e controversi. Infine, soprattutto per ciò che concerne le ricadute sulla terapia del dolore, una parte significativa del libro si è concentrata sull’interpretazione medica e terapeutica, dove i farmaci oppioidi e la Cannabis costituiscono non solo una feconda frontiera di ricerca, ma anche un consolidato ed efficace strumento per contrastare alcune tipologie di dolore

Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides

Nucleopeptides represent an intriguing class of nucleic acid analogues, in which nucleobases are placed in a peptide structure. The incorporation of D- and/or L-amino acids in nucleopeptide molecules allows the investigation of the role of backbone stereochemistry in determining the formation of DNA and RNA hybrids. Circular Dichroism (CD) spectroscopic studies indicated the nucleopeptide as having fully l-backbone configuration-formed stable hybrid complexes with RNA molecules. Molecular Dynamics (MD) simulations suggested a potential structure of the complex resulting from the interaction between the l-nucleopeptide and RNA strand. From this study, both the backbone (ionics and H-bonds) and nucleobases (pairing and pi-stacking) of the chiral nucleopeptide appeared to be involved in the hybrid complex formation, highlighting the key role of the backbone stereochemistry in the formation of the nucleopeptide/RNA complexes.This research was supported by Scientific Independence of Young Researchers (SIR) 2014 (RBSI142AMA) and University of Campania Luigi Vanvitelli (Valere) to S.D.M