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Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2-4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.

In the last years, the introduction of side chains in different molecular compounds takes increasing importance. As recently reported in literature, heterocyclic scaffolds with poor biological activity , if properly decorated with selected side chains, can improve their anticancer activity against a large spectrum of human tumor cell lines. For example, the annelated Pyrrolo[3,4-e]Pyrimidines and Pyrrolo[3,2-e]Pyrimidines, opportunely functionalized with a large number of side chains, showed a good increase in the antitumor activity with respect to the starting core structure. New compound thus obtained showed antiproliferative activity against all the human tumor cells, generally in the low micromolar concentration range (1). Furthermore, this increase in activity is confirmed in the new linear derivatives Thieno[3,2-d][1,2,3]Triazolo [1,5- α]Pyrimidines (2) and their angular isomer Thieno[2,3-e][1,2,3]Triazolo[1,5- α]Pyrimidines (3). Another confirmation is provided by the Indolo [3,2-e][1,2,3]Triazolo [1,5- α]Pyrimidines, that resulted inactive as antitumor agent, but when a functionalization with side chains takes place, the anticancer activity has interestingly appeared (4). Here, with the aim to explore the importance of the addition of side chains on smaller molecular scaffolds, of easier synthetic access and decoration, we focused our attention on a new series of substituted “chained” pyrrole derivatives in order to evaluate their anticancer potential.

First observed in cells exposed to high temperatures, Heat shock proteins (Hsps) are nowadays considered the most important cell “chaperone” complexes over-­expressed in response to a number of cell stress stimuli.1 The chaperone activity is the main function of the eukaryotic Heat shock protein 60 kDa (Hsp60), involved in the capture and refold of unfolded or misfolded proteins. Additional roles in signal transduction,2 senescence activation3 and apoptosis4 have been ascribed to cytosolic Hsp60. During the carcinogenIc process, in vivo studies demonstrated increased levels of human Hsp60 in several organs, such as uterine exocervix,5 large bowel,6 and prostate.6 In this context, our study aims to elucidate the structural details of the interaction between Hsp60 and novel designed antagonists able to specifically block this chaperonine. A preliminary virtual screening of 24 million molecules, available in the Zinc database, was carried out on the ATP-­binding site of a bacterial Hsp60 monomer, the coordinates of which were taken from Protein Data Bank (ID: 1WE3), figure 1. Compounds with high affinity were further refined by other in silico protocols previously and successfully applied by us in the study of several biological targets.7The analysis of virtual screening results highlights the N-­{5-­[1H-­imidazol-­4-­yl-­methyl)-­ amino]-­benzofuran-­3-­yl}-­benzamides of type 1 as interesting series for the inhibition of Hsp60 ATP-­binding site. Selected compounds were prepared in excellent yields, following appropriate synthetic pathways. All compounds are currently tested in order to proof they potential anticancer activity as modulator of Hsp60 function in tumor cells.

The pyrrolo[3,2-c]quinoline scaffold has been known as a core structure of a wide number of bioactive molecules. Several derivatives of such a tricyclic angular heterocycle have shown a wide spectrum of biological activities, such as hypotensive, anti-inflammatory properties, gastric (H)ATPase inhibition effect, and remarkable antitumor activity (1). The high therapeutic potentiality of such a skeleton along with our interest in targets featuring aza-polycondensed aromatic structures, attracted us to develop an alternative synthetic strategy, in order to reach a series of pyrrolo[3,2-c]quinolines in quantitative yields (2). The reaction of 3-acetyl-1,4-dione 1 with selected amines allowed the isolation of intermediates 2. Subsequent reduction of the nitro group and condensation with substituted aldehydes drove the cyclization to pyrrolo[3,2-c]quinoline ring system 3.Substituted pyrrolo[3,2-c]quinolines 3 were preliminary evaluated for antiproliferative activity (MTS assays) against 5 human tumor cell lines (colon tumor Caco2; breast cancer MCF7; brain cancer LAN5; cervix HeLa and lung tumor H292), and human epithelial bronchial cell line 16HBE as control. Moreover, benzomethylen-dioxy derivative tested at DTP/NCI showed an appreciable and selective cell growth inhibitory effect against Leukemia SR, Melanoma MDA-MB-435, Renal Cancer UO-31 cell lines.

In recent years, besides the main field of nonsteroidal anti-inflammatory agents, the interest towards pyrazolone derivatives has been renewed because of their wide biological and pharmacological applications [1]. Currently, particular attention is focused on such a class of compounds due to the affinity with sigma receptor and their relationship with cancer [2].To these purposes we planned to design, synthesize and evaluate the antiproliferative activity (MTS assays) of a new series of 3-methyl-2-(1-R-naphthalen-2-yl)-1,2-dihydropyrazol-3-one derivatives 1 against HeLa, MCF-7, LAN-5, Caco2 in order to explore their anticancer potential. Additionally, further elaboration of the amino derivative 1 led to the tetracycle 2, possessing a reactive tetrazinone core which conferred valuable antiproliferative activity as previously reported [3]. Synthesis and biological results will be presented. [1] G. Mariappan, B.P. Saha, L. Sutharson, Anki, S. Garg, L. Pandey, D. Kumar, J. Pharm. Res., 2010, 3(12), 2856. [2] E. Aydar, C.P. Palmer, M. B. A. Djamoz, Cancer Res., 2004, 64, 5029. [3] A.M., Almerico, F. Mingoia, P. Diana, P. Barraja, A. Lauria, A. Montalbano, G Cirrincione, G. Dattolo, J. Med. Chem., 2005, 48, 2859.

Infective diseases caused by protozoarian agents are still relevant today more than ever. In fact, they represent the first cause of death all over the world with seventeen millions victims every year. The development of drug resistance and the broad diffusion of these pathologies make actual the research of new molecules able to act as selective and effective anti-infective chemotherapics.[1] Recently several polycondensed diazine derivatives, by means 1,3-dipolar cycloaddition, reactions [2, 3] were synthesized. A broad selection of these compounds chosen with a wide pattern of substitutions were submitted to biological in vitro screening against Plasmodium falciparum, Leishmania Infantum, Trypanosoma brucei e Trypanosoma cruzi, and they resulted active at micromolar level. In order to identify molecular targets able to explain the mechanism of action of these compounds, we performed Induced Fit Docking/MM-GBSA modeling studies. The obtained results give interesting indications about the probable mechanism of action of the most active compounds. [1] M. Gonzaalez, H. Cerecetto, Expert Opinion on Therapeutic Patents, 21, 2011, 699-715. [2] A. Lauria, A. Guarcello, G. Dattolo, A.M. Almerico, Tetrahedron Lett., 49, 2008, 1847-1850. [3] A. Lauria, A. Guarcello, G. Macaluso, G. Dattolo, A.M. Almerico, Tetrahedron Lett., 50, 2009, 7333-7336.

1,3-Dipolar cycloaddition reactions can be considered a powerful synthetic tool in the building of heterocyclic rings, with applications in different fields. In this review we focus on the synthesis of biologically active compounds possessing the 1,2,3-triazole core through 1,3-dipolar cycloaddition reactions. The 1,2,3-triazole skeleton can be present as a single disubstituted ring, as a linker between two molecules, or embedded in a polyheterocycle. The cycloaddition reactions are usually catalysed by copper or ruthenium. Domino reactions can be achieved through dipolarophile anion formation, generally followed by cyclisation. The variety of attainable heterocyclic structures gives an illustration of the importance of the 1,2,3-triazole core in medicinal chemistry. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

As extension of previous studies on polycyclic planar systems which synthetic approach and antiproliferative activity against leukemic cells (FLC, DRTL) were reported, now we became interested to test their antireplicative activity against human immunodeficiency virus since the incorporation of the pyrrole moiety has already led to several classes of non nucleoside reverse transcriptase inhibitors. For this purpose new and non new derivatives of the planar system pyrrolo[1,2-f]phenanthridine and their “non-rigid analogues” were chosen as model framework reaching in total to more than forty compounds variously functionalized. The need for the search of new anti-HIV agent is still pursued because of the increasing spread of the disease in spite of several prevention campaigns, and because of the rapid appearance of drug resistant viral strains which limits drug effectiveness. Among the current anti-HIV agents the reverse transcriptase inhibitors the Nevirapine and TIBO have an important clinical role. It is suggested that they interact with an allosteric site of the enzyme assuming a “butterfly conformation.” This type of conformation is proposed in our “non-rigid” analogue derivatives tested. Molecular modelling studies by using some physico-chemical descriptors (molecular volume, accessible surface area) evidenced good similarities when compared with planar derivatives and highly described substituted pyrroles and were found in good agreement with the docking studies performed by Ding et al, which proposed a receptor having a “butterfly shape region”. At the same time, the superimposition in the conformation of the minimum of energy between Nevirapine, some selected planar compounds and the corresponding non-rigid analogues showed a good geometric fit between the structures (RMS in the range 0.0270-0.0455). These data suggest that a lot of our derivatives could fit favourably in the same binding pocket. Biological screenings evidenced that only few derivatives showed a moderate selectivity against HIV-1, suggesting that even planar molecules having suitable size can inhibit virus replication probably interacting with the same receptor. Moreover, an interesting biological new data has emerged: a planar derivative showed unique properties being able not only to reduce the virus-induced cyto-pathogenecity, but also to stimulate the growth (20-35%) of the same lymphocytes. Considering that the stimulation of the lymphocytes cells can be a crucial factor in anti-AIDS therapy, this class of compounds can be considered for further developments of new candidates which join anti-AIDS and immuno-stimulant activity.

A set of variously substituted 1-arylpyrazol-3-one derivatives, including the di-ortho-aryl substituted ones, was synthesized as new potential anticancer compounds. To fulfill this aim, herein a regiospecific synthesis was proposed utilizing a new revisited one pot procedure, starting from commercial anilines and easily accessible 2,5-dimethyl-furan-3-one. In the course of the sequential ordered steps, in some cases, a nitro group displacement by chlorine took place to a minor extent. The in vitro screening against the full panel of ~60 human cancer cell lines (NCI) showed a moderate, but promising selective antiproliferative activity against the UO31 renal tumor cell line, only in compounds with the introduction on the phenyl moiety of a -CF3 or two Cl groups.

A new series of 3-benzoylamino-5-(1H-imidazol-4-yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration-dependent antiproliferative activity against HeLa and MCF-7 cancer cell lines, exhibiting GI50 values in the low micromolar range. In most cases, insertion of a methyl substituent on the imidazole moiety improved the antiproliferative activity. Therefore, methyl-imidazolyl-benzo[b]furans compounds were tested in cell cycle perturbation experiments, producing cell cycle arrest with proapoptotic effects. Their core similarity to known colchicine binding site binders led us to further study the structure features as antitubulin agents by in silico protocols. This article is protected by copyright. All rights reserved.

The X-ray emission of the young Sun was much harder and intense than today and might have played a significant role in the evolution of complex organics in protoplanetary environments. We investigate the effects of soft X-rays on tryptophan molecules in aqueous solutions at room temperature. As results of the irradiation experiments we detect several light species indicative of fragmentation, together with large molecular structures such as tryptophan dipeptide and tripeptide. Complexification is more evident in H2O solution than in D2O, probably due to isotopic effects. The abundances of peptides depend on the irradiation dose and decrease with increasing energy deposition. Radicals such as D, OD, H and OH, induced by the X-ray interaction with solvents, play a major role in determining the final products.

The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-β in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-β inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 inhibitors included in the Binding Database. In order to overcome the difficulty due to the lack of crystallographic data for IKK-β, a homology model of this protein has been built and validated. The results allowed to study in depth the structural bases for the interaction of each family of inhibitors and provided clues for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting this enzyme.

1,3-Dipolar cycloaddition reactions can be considered a powerful synthetic tool in the building of heterocyclic rings, with applications in different fields. In this review we focus on the synthesis of biologically active compounds possessing the 1,2,3-triazole core through 1,3-dipolar cycloaddition reactions. The 1,2,3-triazole skeleton can be present as a single disubstituted ring, as a linker between two molecules, or embedded in a polyheterocycle. The cycloaddition reactions are usually catalysed by copper or ruthenium. Domino reactions can be achieved through dipolarophile anion formation, generally followed by cyclisation. The variety of attainable heterocyclic structures gives an illustration of the importance of the 1,2,3-triazole core in medicinal chemistry.