Synthesis and antiproliferative activity of substituted 3[2-(1H-indol-3-yl)- 1,3-thiazol-4-yl]-1H-pyrrolo[3,2-b]pyridines, marine alkaloid nortopsentin analogues.

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 Thr(34) and to increase the cytotoxic activity of paclitaxel in STO cells.

Diagnosis of broken-bars fault in induction machines using higher order spectral analysis.

Detection and identification of induction machine faults through the stator current signal using higher order spectra analysis is presented. This technique is known as motor current signature analysis (MCSA). This paper proposes two higher order spectra techniques, namely the power spectrum and the slices of bi-spectrum used for the analysis of induction machine stator current leading to the detection of electrical failures within the rotor cage. The method has been tested by using both healthy and broken rotor bars cases for an 18.5 kW-220 V/380 V-50 Hz-2 pair of poles induction motor under different load conditions. Experimental signals have been analyzed highlighting that bi-spectrum results show their superiority in the accurate detection of rotor broken bars. Even when the induction machine is rotating at a low level of shaft load (no-load condition), the rotor fault detection is efficient. We will also demonstrate through the analysis and experimental verification, that our proposed proposed-method has better detection performance in terms of receiver operation characteristics (ROC) curves and precision-recall graph.

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy.

The SWI/SNF chromatin-remodeling complex serves as a master switch that directs and limits the execution of specific cellular programs, such as differentiation and growth control. SWI/SNF function requires one of two paralogous ATPase subunits, Brahma (BRM) or BRM-related gene 1 (BRG1), which we previously found are lost together in cancer cell lines and primary lung cancers. Although BRG1 has been found to be mutated in cancer cell lines, the mechanisms underlying BRM silencing are not known. To address this question, we sequenced BRM in 10 BRM/BRG1-deficient cancer cell lines and found that BRM was devoid of abrogating mutations. Moreover, histone deacetylase (HDAC) inhibitors restored BRM expression in each of these BRG1/BRM-deficient cancer cell lines, indicating that epigenetic silencing is a major mechanism underlying the loss of BRM expression. Despite their ability to restore BRM expression, these HDAC inhibitors also blocked BRM function when present. However, after their removal, we observed that BRM expression remained elevated for several days, and during this period, BRM activity was detected. We also found that the suppression of BRM occurs in a broad range of human tumor types and that loss of one or both BRM alleles potentiated tumor development in mice. Thus, BRG1 and BRM are silenced by different mechanisms, and it may be possible to clinically target and reexpress BRM in a number of tumor types, potentially impacting tumor development.

The MCA EXIN neuron for the minor component analysis.

The minor component analysis (MCA) deals with the recovery of the eigenvector associated to the smallest eigenvalue of the autocorrelation matrix of the input data and is a very important tool for signal processing and data analysis. It is almost exclusively solved by linear neurons. This paper presents a linear neuron endowed with a novel learning law, called MCA EXINn and analyzes its features. The neural literature about MCA is very poor, in the sense that both a little theoretical basis is given (almost always focusing on the ODE asymptotic approximation) and only experiments on toy problems (at most four-dimensional problems) are presented, without any numerical analysis. This work addresses these problems and lays sound theoretical foundations for the neural MCA theory. In particular, it classifies the MCA neurons according to the Riemannian metric and justifies, from the analysis of the degeneracy of the error cost; the different behavior in approaching convergence. The cost landscape is studied and used as a basis for the analysis of the asymptotic behavior. All the phases of the dynamics of the MCA algorithms are investigated in detail and, together with the numerical analysis, lead to the identification of three possible kinds of divergence, here called sudden, dynamic, and numerical. The importance of the choice of low initial conditions is also explained. A lot of importance is given to the experimental part, where simulations on high-dimensional problems are,presented and analyzed. The orthogonal regression or total least squares (TLS) technique is also presented, together with a real-world application on the identification of the parameters of an electrical machine. It can be concluded that MCA EXIN is the best MCA neuron in terms of stability (no finite time divergence), speed, and accuracy.

Pyrrolo[2,1-d][1,2,3,5]tetrazinones deaza analogues of temozolomide with potent antitumor activity.

The title compounds, that hold the deaza skeleton of temozolomide, exhibited potent in vitro antiproliferative activity. An evaluation of such a biological activity indicates that the mode of action of these compounds differs from that of temozolomide and is also mechanistically unrelated to that of any known antitumor drug.

Synthesis and antiproliferative activity of 2-triazenothiophenes.

A series of 2-triazenothiophene derivatives was prepared and tested to evaluate their biological activity. Two compounds 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. Compound 3c inhibited DNA, RNA and protein synthesis, and was also effective against KB cells resistant to etoposide and vincristine. The compounds were inactive against fungi and bacteria.

Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine with potent antitumor and antimicrobial activity.

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.

Against the convergence of the minor component analysis neurons.

We investigate the dynamical behavior of some linear neurons devised for the minor component analysis. Contrary to their convergence theorems, our analysis reveals the existence of a divergence in a finite time.

Glycosidopyrroles. Part 3. Effect of the benzocondensation on acyclic derivatives: 1-(2-hydroxyethoxy) methylindoles as potential antiviral agents.

The new of 1-(2-hydroxyethoxy)methylindole derivatives 3a-i were prepared in good yields. None of them showed any significant anti-HIV activity and therefore the benzocondensation between the 2 and 3 positions of the pyrrole ring definitely reduced the weak activity found in the analogues 1a-c.

2-Diazopyrroles: synthesis and antileukemic activity.

The title compounds were synthesised in preparative yields by diazotization of the corresponding 2-aminopyrroles. In preliminary screening tests as antileukemic agents they showed modest activity against the murine and human leukemic cell lines FLC and K562S and their multidrug-resistant daunorubicin selected sublines.

Determination of copper and zinc levels in human hair: influence of sex, age, and hair pigmentation.

The Cu and Zn levels of both 607 men (1-85 y old) and 649 women (1-92 y old) were determined by atomic absorption spectrometry. Sex does not influence Cu (14.89 + or - 0.89 mu g/g and 15.26 + or - 0.79 mu g/g hair for males and females, respectively) and Zn contents (200.97 + or - 9.68 mu g/g for men and 209.81 + or - 9.49 mu g/g hair for women). Age influences Cu and Zn concentrations, but only significantly in females: Cu levels decrease over 60 y of age; whereas Zn levels increase significantly from age groups 2-5 to 20-40 years. Hair color influences Cu concentrations in both males and females. In males, white hair contains less Cu than black hair; in females, white hair's Cu levels are significantly lower than those of dark blond, red, light brown, and brown hair. There are no significant differences in Zn concentrations with respect to different hair colors, in either males or females.

3-Diazopyrroles. Part 6. Mutagenic activity of 3-diazopyrroles in Streptomyces coelicolor A3(2) during various phases of growth.

3-Diazopyrroles, a class of compounds particularly interesting from a chemical and biological point of view, were assayed for their ability to induce gene mutations employing back mutation (his+ reversion) test in the philamentous bacterium Streptomyces coelicolor at various time during life cycle. Our results suggest that in evaluating the mutagenicity and toxicity of chemicals in Streptomyces system it is important to consider factors such as growth phase. Furthermore in this series of diazopyrroles a relationship between toxicity, mutagenicity and chemical structure was found. The observed mutagenic activity can be the molecular basis for the appearance of antitumor activity.

Polycondensed nitrogen heterocycles. Part 27. Indolo[3,2-c]cinnoline. Synthesis and antileukemic activity.

Indolo[3,2-c]cinnolines of type 5, variously substituted either in the indole and in the cinnoline moieties, were prepared in good overall yields, by intramolecular cyclization of indolo derivatives 4. Compounds 5a-d showed a good cytotoxic activity against FLC and K562 leukemic cell lines, both sensitive and multi-drug resistant.

Azolophenanthridines as antineoplastic agents.

Pyrrolo-, pyrazolo- and triazolo-phenanthridines were synthetized by using a Pschorrtype cyclization reaction or an intramolecular cyclization of arylnitrenium ions. By using these synthetic methods several azolo-phenanthridines, variously functionalized either in the azolo ring and in the phenanthridine moiety, were prepared. The title compounds, tested against murine leukemia cell lines, sensible and multidrug resistant, showed moderate activity with IC50 in the range 5-50 microM.

3-Triazenopyrroles: synthesis and antineoplastic activity.

Some 3-triazenopyrroles were prepared by coupling 3-diazopyrroles and secondary amines. In preliminary in vitro screening tests derivatives 3 showed to be cytotoxic and exhibited mutagenic effects.

3-Diazopyrroles. Part 5 (1). Antibacterial activity of 3-diazo-2-phenylpyrroles.

3-Diazo-2-phenylpyrroles 3a-g showed antimicrobial activity against Gram-positive bacteria, whereas against Gram-negative strains the inhibitory activity is limited to derivatives 3a and 3c. The substituents at 4 and 5 positions strongly influence the inhibitory activity, but the presence of the diazo group is crucial for appearance of activity.