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A new class of pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI50values reaching the nanomolar level, with mean graph midpoints of 0.08–0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC50values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC50values of 1.9–8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.

Background: Isoindolo[2,1-a]quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning. Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-a]quinoxalin-6-imines, by comparing them with known inhibitors. Methods: Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked. Conclusion: Our docking studies performed on Isoindolo[2,1-a]quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.

A large number of indolyl-4-azaindolyl thiazoles, nortopsentin analogues, were conveniently synthesized. The antiproliferative activity of the new derivatives was examined against four human tumor cell lines with different histologic origin. Seven derivatives consistently reduced the growth of the experimental models independently of TP53 gene status and exhibited the highest activity against the malignant peritoneal mesothelioma (STO) cell line. The most active compound of this series acts as a CDK1 inhibitor, and was found to cause cell cycle arrest at G2/M phase, to induce apoptosis by preventing the phosphorylation of survivin in Thr34; and to increase the cytotoxic activity of paclitaxel in STO cells.

Background:Manipulation and suspension of the superficial musculoaponeurotic system (SMAS) is performed by 74% of rhytidectomy surgeons. Multiple variations in suture techniques are employed in this task, but they have never been evaluated for differences in their ability to withstand stress.

Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor grooveinteracting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments.

The aim of this work was devoted to develop a method to predict ΔG values for a series of minor groove binders. Starting from a matrix of docking dataset for 10 minor groove binders (known and not) to 20 DNA fragments, with various sequences, it was possible to analyze the interaction modes and to calculate the ΔG value for new derivatives through MADoSPRO procedure. The method allowed, through the QSPR analysis, to characterize the type of interactions in such complexes, that was demonstrated to be related to quantum chemical and electrostatic descriptors, in agreement with the information available in literature on the structural requirements of specific minor groove ligands.

This paper describes the use of the multivariate statistical procedure principal component analysis as a tool to explore the inhibitory activity of classes of protease inhibitors (PIs) against HIV-1 viruses (wild type and more-frequent single mutants, V82A, V82F, and I84V) and against protease enzymes. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the 51 derivatives considered in this study. The best results were obtained in the case of the I84V mutant for which a high number of predictions was achieved. On this basis, this statistical approach is proposed as a reliable method for the prediction of the activity of PIs, for which the data against mutant strains have not been reported.

1-Methylpyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-ones 4, synthesized in good to excellent yields, were designed as novel alkylating agents because of their peculiar chemical behavior. All derivatives showed antiproliferative activity against more than 50 types of tumor cell lines with GI50 reaching sub-micromolar values. SAR studies revealed that the presence of a chlorine atom is well-tolerated in both positions 8 and 9, whereas in the case of the methyl group, switching from the 8 to the 9 position gives rise to the most active compound of the series, 4g, either for the number of cell lines inhibited and for selectivity against leukaemia and renal cancer subpanels. COMPARE and 3D-MIND computations indicate, for compounds 4, an activity profile analogous to rifamycins and cytidine analogues.

This paper describes the use of multivariate statistical procedure PCA as a tool to explore the inhibitory activity of classes of NNRTIs against HIV-1 viruses (wild type and more frequent mutants, Y181C, V106A, K103N, L100I) and against RT enzyme. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the fifty five derivatives considered in this study. The best results were obtained in the case of L100I and K103N mutants for which the higher number of assignments was found when the principal components derived from the descriptors were used. On this basis this statistical approach is proposed as a reliable method for the prediction of the activity of NNRTIs, for which the data against mutant strains have not been reported.

A study designed to compare the effects on VEGF-induced angiogenesis of a number of known anti-angiogenic agents together with some novel derivatives thereof was undertaken. Thus the isoflavone biochanin A 1, indomethacin 2, the 3-arylquinoxaline SU1433 and its derivatives 3–6, the benzoic acid derivative 7, the oxindoles SU5416 8and SU6668 11, together with their simple N-benzyl derivatives 9, 10, and 12were selected for study. Using an in vitroassay the compounds were evaluated for their ability to inhibit VEGF-induced angiogenesis in HUVECs, and the cytotoxicity of representative compounds was also studied in tumour cell lines using 24-h exposure. The results indicate that the SU compounds, SU1433, SU5416 and SU6668, are more potent inhibitors of VEGF-induced angiogenesis than indomethacin or the naturally occurring biochanin A, presumably because they inhibit VEGF receptor signalling. Blocking one of the phenolic OH groups of SU1433 reduced anti-angiogenic activity, as did blocking the NH groups of SU5416 and SU6668. Cytotoxicity studies indicate that none of the compounds examined exhibited cytotoxicity at anti-angiogenic concentrations.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Indolequinones were selected for study on the basis of the X-ray crystal structure of the human enzyme, and were designed to probe the effect of substituents particularly at N-1. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, and that groups larger than methyl at N-1 are clearly tolerated. Compounds with a leaving group at the 3-indolyl methyl position generally inactivated the enzyme. The toxicity toward human colon carcinoma cells with either no detectable activity (BE-WT) or high NQO1 activity (BE-NQ) was also studied in representative quinones. The most toxic compounds were those with a leaving group at the C-3 position; these compounds were 1.1−5.3-fold more toxic to the BE-NQ than the BE-WT cells.

2-Diazo-2H-indoles were prepared by diazotization of the corresponding 1H-indol-2-amines and subsequent neutralization. On the basis of NMR data and ab initio and semiempirical calculations, we suggest that the zwitterionic form A is the most representative structure for 2-diazo-2H-indoles. In fact, spectral data are compatible with a 1H-indole structure, and the fully optimized molecules gave distances in agreement with those reported for the anion obtained from 1H-indole. The calculated charges are compatible with a zwitterionic structure in which the negative charge is mainly located at the ring N-atom at variance with the case of diazopyrroles and 3-diazo-3H-indoles where the negative charge is essentially located on the ipso C-atom.

Derivatives of the new ring system pyrrolo3,4e1,2,3 triazolo1,5apyrimidine 6were prepared in high yields in one step by reaction of 3azidopyrrole 3and substituted acetonitriles. Compound 6brearranged, upon heating in dimethyl sulfoxide in the presence of water, to pyrrolo3,4d1,2,3triazolo1,5apyrimidine 7.

The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of 7gScheme 1(a) RR1R2H; (b) RR2H, R1Cl; (c) RR1H, R2Cl; (d) RR1H, R2Me; (e) ROMe, R1R2H (f) RCl, R1R2H; (g) RBr, R1R2H; (h) RNO2, R1R2H; (i) RNO2, R1Cl, R2H.Table 1Antiproliferative activity of indolo[3,2-c]cinnolinesIC50[μM]aCell lines7a7b7c7d7e7f7g7h7iDoxoLeukemia/lymphomaL1210121.03.5305024>1000.3ND0.23Wil2-NS4.50.51.0201018890.21.10.02CCRF-SB50.72.8213.227>1000.21.10.01Raji6.80.817>1012>10>1001.21.80.08CCRF-CEM50.51.9107.35.0540.082.20.10MOLT-43.30.41.6123.212>1000.080.20.03MT-42.20.94.7252.350>1000.30.50.09CarcinomaHT-29505.20.82.8>502.1941.94.50.05HeLa8.91.01048.133>10>1007.71.00.25ACHN>5.03.11.241.515.5>10>1003.03.00.4456374.00.32.11019>1018.90.72.70.02NeuroblastomaIMR-325.80.6NDND7.0NDNDNDND<0.01aCompound concentration required to reduce cell multiplication by 50% under conditions allowing untreated controls to undergo at least three consecutive rounds of multiplication. L1210, mouse leukemia; Wil2-NS, human splenic B-lymphoblastoid cells; CCRF-SB, human acute B-lymphoblastoic leukemia; Raij, human Burkitt lymphoma; CCRF-CEM and MOLT-4, human acute T-lymphobastic leukemia; MT-4, human CD4+T-cells containing an integrated HTLV-1 genome; HT-29, human colon adenocarcinoma; HeLa, human cervix carcinoma; ACHN, human renal adenocarcinoma; 5637, human bladder carcinoma; IMR-32, human neuroblastoma. ND: not determined.Table 3Antifungal activity of indolo[3,2-c]cinnolinesMIC [μM]aSpecies7a7b7c7d7e7f7g7h7iMiconazoleC. albicans1509.412>200>200>200>2001.6667.5C. parapsilosis1.82.3100>200>200>200>2001.6220.9C. paratropicalis371950>200>200>200>2001.6667.5C. neoformans0.80.16.2>200>200>200>2001.67.40.9T. mentagrophytes1.875NDND>200NDNDNDND0.9A. fumigatus5.04.7200>200>200>200>2003.12001.9aMinimum inhibitory concentration. ND: not determined.Table 4Antibacterial activity indolo[3,2c]cinnolinesMIC [μM]aSpecies7a7b7c7d7e7f7g7h7iStreptomycinStreptococcus0.20.10.46.23.16.2>2000.050.32.1Staphlyococcus0.10.070.46.26.26.21000.020.094.2Salmonella>200>200>200>200>200>200>2003.12008.6Shigella>200>200>200>200>200>200>2001.6662.1aMinimum inhibitory concentration., all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Cryptococcus neoformans.

Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine 5 were synthesized by diazotization of substituted 2-(2-aminophenyl)indoles followed by an intramolecular coupling reaction of the diazonium group with the indole nitrogen. To obtain the indolobenzotriazine system it was necessary to protect the 3 position of the indole nucleus to avoid cyclization into the indolo[3,2-c]cinnoline system 4. Indolobenzotriazines 5a−g were evaluated in vitro for antitumor activity against a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell lines. Some compounds inhibited the proliferation of T and B cell lines at submicromolar concentrations, whereas their activity against solid tumor cell lines was in the micromolar range. When evaluated for their antifungal potential 5a,d inhibited some of the fungi tested, although at concentrations very close to those inhibiting the proliferation of human cells. On the contrary, all indolobenzotriazines proved fairly potent and selective inhibitors of Streptococcus and Staphylococcus. In particular 5b,c,g were up to 80 times more potent than the reference drug streptomycin and inhibited the growth of the above Gram-positive bacteria at concentrations far lower than those cytotoxic for animal cells.

This paper has been written with the object of clarifying a much-misunderstood situation. While the conclusions arrived at represent the author’s own deductions from current accomplishments, they are based on known facts and data, and other authorities are quoted extensively in order to present unbiased views from engineers who have no direct interest in the production of any particular type of engine and to avoid the impression of a one-man idea. Where opportunity has permitted it, reliable data have been quoted; where not so permissible, data have been omitted; but the author will gladly corroborate any statement or quotation which is thought by others to be doubtful or not sufficiently substantiated. It is suggested that the bibliography appended to the paper be carefully consulted in order that the scope of this effort may be fully digested. In substance, the paper should be considered a compendium of practically all that has been accomplished to date in this line which is, in the author’s opinion, worthy of note.

A nucleophilic substitution reaction in the pyrrole series, achieved by a neutral nucleophile, led to the key intermediate 7which by reduction and successive diazotization afforded the new ring system pyrrolo3,2c1,2,5benzotriazocine 9in good yield.

A variety of pyrrolizinoindolones (VIII) is synthesized as demonstrated for derivative (VIIIa).

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.