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Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.

An efficient synthetic approach to synthesize N-aryl-5-aminopyrazoles from anilines via a one-pot, telescoped reaction performed in entirely aqueous conditions has been developed. This protocol provides a rapid, convenient method to prepare N-aryl-5-aminopyrazoles, useful building blocks for the synthesis of several bicyclic nitrogen heterocycles, by avoiding the isolation of the toxic intermediate arylhydrazines and the use of a metallic reductant.

Introduction: It has long been considered that the most significant risks for breast cancer are gender and age but, as many other tumors, this cancer has also been undeniably linked to gene mutations. The vast majority of breast cancers in postmenopausal women are estrogen-responsive, a hormone which is biosynthesized from blood-circulating androgens through an aromatization reaction, catalyzed by aromatase (AR). One strategy, therefore, to combat breast cancer, has been to find compounds that can inhibit the activity of aromatase to reduce estrogen levels. Areas covered: The authors provide a broad and updated overview of the general structure–activity relationships and on the latest ligand- and structure-based approaches applied to the discovery of potent, selective and safer breast cancer drugs. Specifically the authors review the most consolidated techniques, based on structure–activity relationships, pharmacophore mapping, rigid and flexible molecular docking, as well as sophisticated and reliable pr...

O-Methylcaprolactim 3 reacts in hot dimethylsulfoxide with α-amino acids 4 to give 5H-3-oxo-2,3,6,7,8,9-hexahydroimidazo[1,2-a]azepines 6 and, unexpectedly, hydroxylated derivatives 7a,c and 8c. The structures of the hydroxylated compounds have been elucidated by spectroscopic means and, when necessary, further confirmed by an independent unequivocal synthesis. The formation of 7 as well as the isomerization of 7c to 8c are discussed in detail.

A large homologous series of quaternary ammonium derivatives of perhydropyrrolo[3,4-c]pyridine 5 was synthesized and tested for in vitro antibacterial activity against different Gram-positive and Gram-negative bacteria. Coumpounds 5 proved to be always more potent than benzalkonium chloride, taken as reference. Antibacterial activity, expressed as log 1/MIC, was found linearly related to lipophilicity up to C 13 -C 14 homologs, where a break in the linear relationship was observed

A series of amidinosulfonic acids IIIa-f, analogs of taurine and homotaurine, was synthesized by reacting 2-aminoethane or 3-aminopropane sulfonic acid with lactim ethers Ia-c and then cyclized to sultams IVa-c and Vd-f. The effects of some selected amidinosulfonic acids III on membrane ionic conductances of rat skeletal muscle are described.

The in vitro antibacterial and antifungal activities of a series of pyridazinoindolonic acids II against some selected representative of Gram-positive, Gram-negative bacteria and fungi have been investigated. Some interesting observations among the structural features necessary for high antibacterial activity are presented and discussed.

A series of pyrrolo[3,2-c]pyridines, isosteres of the antithrombotic drug ticlopidine, has been synthesized and evaluated in vitro for the ability to inhibit aggregation of human platelet-rich plasma induced by adenosin 5'-diphosphate (ADP). Structure-activity relationships showed their antiplatelet effects to be related to the lipophilicity.

MDM2 and MDMX are oncogenic homologue proteins that regulate the activity and stability of p53, a tumor suppressor protein involved in more than 50% of human cancers. While the large body of experiments so far accumulated has validated MDM2 as a therapeutically important target for the development of anticancer drugs, it is only recently that MDMX has also become an attractive target for the treatment of tumor cells expressing wild type p53. The availability of structural information of the N-terminal domain of MDM2 in complex with p53-derived peptides and inhibitors, and the very recent disclosure of the crystal structure of the N-terminal domain of MDMX bound to a p53 peptide, offer an unprecedented opportunity to provide insight into the molecular basis of p53 recognition and the identification of discriminating features affecting the binding of the tumor suppressor protein at MDM2 and MDMX. By using coarse graining simulations, in this study we report the exploration of the conformational transitions featured in the pathway leading from the apo-MDM2 and apo-MDMX states to the p53-bound MDM2 and p53-bound MDMX states, respectively. The results have enabled us to identify a pool of diverse conformational states of the oncogenic proteins that affect the binding of p53 and the presence of conserved and non-conserved interactions along the conformational transition pathway that may be exploited in the design of selective and dual modulators of MDM2 and MDMX activity.

A total of 142 matrix metalloproteinase (MMP) X-ray crystallographic structures were retrieved from the Protein Data Bank (PDB) and analyzed by an automated and efficient routine, developed in-house, with a series of bioinformatic tools. Highly informative heat maps and hierarchical clusterograms provided a reliable and comprehensive representation of the relationships existing among MMPs, enlarging and complementing the current knowledge in the field. Multiple sequence and structural alignments permitted better location and display of key MMP motifs and quantification of the residue consensus at each amino acid position in the most critical binding subsites of MMPs. The MMP active site consensus sequences, the C-α root-mean-square deviation (RMSd) analysis of diverse enzymatic subsites, and the examination of the chemical nature, binding topologies, and zinc binding groups (ZBGs) of ligands extracted from crystallographic complexes provided useful insights on the structural arrangements of the most poten...

Hydrogenated γ-carbolines underwent tandem piperidine ring cleavage on treatment with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate (EP) in the presence of alcohols, producing 3-alkoxymethyl-substituted indoles in high yields. These compounds were cyclized to tetrahydroazocino[4,5-b]indoles in the presence of AlCl3. Hydrogenated β-carbolines produced tetrahydroazocino[5,4-b]indoles directly upon treatment with EP in ethanol. The resulting azocinoindole derivatives were subjected to a preliminary evaluation of their in vitro acetylcholinesterase (AChE) inhibitory activities. Most of them were found to inhibit AChE with IC50 values in the micromolar range, compound 17 being the most potent (IC50 = 8.7 μM). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A large number of pyridazino[4,3-b]indoles and indeno[1,2-c]pyridazines were synthesised and tested to evaluate their binding affinities at both central (CBR) and peripheral (PBR) benzodiazepine receptors. Relatively good PBR binding affinities were found for ligands belonging to the 3-arylmethyloxy-pyridazinoindole series, whereas only 2-aryl-indenopyridazines 7a, 8a and 10a display a weak binding affinity for CBR. To find out the main structural determinants affecting PBR affinity, a molecular modelling study based on the comparative analysis of the three-dimensional properties of four properly selected derivatives 24a, 3b, 18a and 10d, with those of highly active and selective PBR ligands, taken as reference, was performed.

SnCl2 enables a direct, high-yield conversion of 5-nitro-1,3-dialkyl-6-styryl(furyl-, thienyl-vinyl)-uracils to 8-substituted-9-deazaxanthines under very mild experimental conditions. The method has a general applicability and it is compatible with the reactivity of the most common organic functional groups. In slightly experimental different conditions, it allows a high-yield and fast (

As a further part of our chemical and biological studies in this field, we describe the multistep preparations of the properly substituted 2-(1-piperazinyl)chromone 1b , 4-(1-piperazinyl)coumarins 5c – h , their linear benzo-fused analogues 4a , b and 8a , b , bicyclic ( 15e – g ) and tricyclic ( 15h , i ) fused derivatives of 6-(1-piperazinyl)pyrimidin-4(3 H )-one, and of the 4 H -pyrido[1,2- a ]pyrimidine derivatives 9b , c . The in vitro evaluation of their inhibitory properties towards human platelet aggregation induced in platelet-rich plasma by ADP, collagen, or the Ca 2+ ionophore A23187 showed the high activity of compounds 5d – g and 15f , g , i , among which the coumarins 5g and 5d proved to be, in that order, the most effective in vitro antiplatelet agents until now synthesized by us. Thus, in order to consider also the 4-aminocoumarin structural class, we developed a new statistically significant 3-D QSAR model, more general than the one previously obtained, through a further CoMFA study based on the antiplatelet activity data and molecular steric and electrostatic potentials of both the previously studied and herein described compounds.

Some derivatives of the title heterocycles have been prepared by a «one step» synthesis from 2-hydroxy-2-acylmethylene-1,3-indandiones, tosyl chloride and isoquinoline or phthalazine. The synthesis of new indeno[2,1-b]indolizine derivatives performed by using pyridine as base is also reported

Treatment of the tetracyclic oxazinoisoquinolines (I) with sodium borohydride results in formation of the alcohols (II) or the hexahydrooxobenzoxazinoisoquinolines (IIIb).

Upon reductive cyclization cyano esters 2, 3, and 9 yielded piperidones and perhydropyrrolo[3,4-c]pyridine lactams, generally as a mixture of diasteromeric cis-trans forms. X-ray crystallographic analyses were carried out on bicyclic dilactam derivatives 6 and 10, and a cis configuration at the ring junction was determined in both cases. A series of neuropsychopharmacological tests performed on the title compounds indicated that they are generally nontoxic even at high doses (up to 1000 mg/kg ip). The cognition activating properties of lactams 4, 5, 6, and 10 were evaluated in enhancing retention for passive avoidance learning in rats without and after electroconvulsive shock (ECS); compounds 5 and 10 were found to be more potent than piracetam in the amnesia-reversal testing.