Giuseppe Musumarra

A bioinformatic approach to the identification of candidate genes for the development of new cancer diagnostics.

Abstract A multivariate analysis of the National Cancer Institute gene expression database is reported here. The soft independent modelling of a class analogy approach achieved cell line classification according to histological origin. With the PCA method, based on the expression of 9605 genes and ESTs, classification of colon, leukaemia, renal, melanoma and CNS cells could be performed, but not of lung, breast and ovarian cells. Another multivariate procedure, called partial least squares discriminant analysis (PLS-DA), provides bioinformatic clues for the selection of a limited number of gene transcripts most effective in discriminating different tumoral histotypes. Among them it is possible to identify candidates in the development of new diagnostic tests for cancer detection and unknown genes deserving high priority in further studies. In particular, melan-A, acid phosphatase 5, dopachrome tautomerase, S100-β and acid ceramidase were found to be among the most important genes for melanoma. The potential of the present bioinformatic approach is exemplified by its ability to identify differentiation and diagnostic markers already in use in clinical settings, such as protein S-100, a prognostic parameter in patients with metastatic melanoma and a screening marker for melanoma metastasis.

Design and synthesis of trans 2-(furan-2-yl)vinyl heteroaromatic iodides with antitumour activity

A new molecular modelling approach based on physico-chemical and pharmacokinetic properties, called Volsurf plus, was used to design new heterocyclic compounds with antiproliferative activity. The synthesis and in vitro antitumour tests on a breast carcinoma cell line (MCF7) confirmed VOLSURF predicted activity values.

Photophysics and photochemistry of 2,6-distyrylpyridine and some heteroanalogues

The photophysical and photochemical properties of some symmetric (E,E)-2,6-di(arylvinyl) derivatives of pyridine, where the side aryl groups were phenyl, pyridyl, furanyl, thienyl and thiazolyl were investigated. The conformational equilibria between the two more abundant rotamers and their role in the kinetic competition between the radiative and reactive (E,E→E,Z) relaxation channels of their lowest excited singlet state are described and compared with those of the parent hydrocarbon, 1,3-distyrylbenzene. The effect of intramolecular hydrogen bonds between the nitrogen atom and the ethenic hydrogens on the nature and properties of the S1 state is discussed.

New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens.

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.

Application of principal components analysis to the evaluation and selection of eluent systems for the thin-layer chromatography of basic and neutral drugs

Abstract The R F values of 55 drugs in 40 eluent mixtures are reported. Principal component analysis of these data provides a four-significant-components model, which explains 92% of the total variance. This analysis, showing that the eluent mixtures cluster into different groups according to their information content, provides a reliable criterion for the choice of optimal eluents. Four eluent mixtures of [ethyl acetate—methanol—30% ammonia (85:10:5), cyclohexane—toluene—diethylamine (65:25:10), ethyl acetate—chloroform (50:50) and acetone with the plate dipped in potassium hydroxide solution), chosen on the basis of the above criterion and of the R F reproducibility, provide a two significant principal components model that can be used for the identification of unknown samples.

Shortcuts in genome-scale cancer pharmacology research from multivariate analysis of the National Cancer Institute gene expression database

Application of a soft multivariate statistical procedure, called PLS, partial least squares modelling in latent variables or projections to latent structures, allows extensive exploitation of the enormous amount of information embedded in the National Cancer Institute gene expression and antitumour screen databases. Interpretation of the statistical results provides new significant biological insights such as classification of human tumour cell lines based on their gene expression patterns, evaluation of the influence of gene transcripts on drug efficacy and assessment of their selectivity for classes of compounds which act by the same mechanism, and identification of uncharacterized gene expression targets involved in cancer chemotherapy. Among them, the transcripts GC11121, GC17689, and GC18564 (unknown gene products extremely selective for RNA/DNA antimetabolites) are indicated by the present work as deserving high priority in future molecular studies.

Design, synthesis and biological evaluation of trans 2-(thiophen-2-yl)vinyl heteroaromatic iodides

A modeling approach based on physico-chemical and pharmacokinetic properties, called Volsurf+, was used to design new trans 2-(thiophen-2-yl)vinyl heteroaromatic iodides with antiproliferative activity. The synthesis and in vitro antitumor tests on two cell lines (MCF-7 and LNCap) confirmed Volsurf predicted activity values. An Almond model, derived to have an overall structural insight on the above compounds, supported the validity of Volsurf and provided guidelines for the synthesis of new compounds.

In vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines and pyridiniums.

The in vitro antitumor activities of 2,6-di-[2-(heteroaryl)vinyl]pyridines versus the standard National Cancer Institute 60 cell lines panel and of 2,6-di-[2-(heteroaryl)vinyl] pyridinium cations versus MCF7 (human mammary carcinoma) and LNCap (prostate carcinoma) cell lines are reported. Antiproliferative effects in both series are particularly evident for MCF7 mammary adenocarcinoma cells. Multivariate analysis of DNA microarray data for responsive tumor cell lines suggest a mechanistic pathway involving polyamine biosynthesis and prolactin signal transduction.

Reactions of aromatic sulphonyl chlorides with anilines : Studies of solvent effects by the approach of multiparameter empirical correlations

Abstract The reaction kinetics of 5-substituted 2-thiophenesulphonyl chlorides with anilines were studied in fourteen pure solvents (protic and aprotic) and in mixed solvents at 25°. The approach of multiparameter equations to describe solvent effects according to the Palm-Koppel and Krygowski-Fawcett models was unsuccessful. Instead satisfactory single parameter linear correlations, one for protic solvents with positive slope and another for aprotic solvents with negative slope, were found by using the dielectric constant ϵ. An S A N mechanism for these reactions was proposed, bond-making being the rate-determining step for protic solvents and bond-breaking for aprotic ones. The analysis of some data for the reactions of benzenesulphonyl chloride showed that the mechanism is analogous also for this substrate and the rate-determining step is depending on both solvent and nucleophile. Hammett ρ-values for the reactions of substituted 2-thiophenesulphonyl chlorides with aniline are in accord with the proposed mechanism. ϱ-Values for the reactions of 2-thiophenesulphonyl chloride with substituted anilines are related to the solvent effects by equation ϱ = − 15.7 f(ϵ) + 0.113E + 3.94. The solvent effects on these values can be interpreted by the effect of the dielectric constant and the influence of H-bonding. Mixed solvents are characterized by the presence of a maximum rate.

A multivariate insight into the in vitro antitumour screen database of the National Cancer Institute: classification of compounds, similarities among cell lines and the influence of molecular targets.

A multivariate insight into the in vitro antitumour screen database of the NCI by means of the SIMCA package allows to propose hypotheses on the mechanism of action of novel anticancer compounds. As an example, the application of multivariate analysis to the NCI standard database provided clues to the classification of drugs whose mechanism is either unknown or controversial. Moreover, the influence of intrinsic biochemical cell line properties (molecular targets) on the sensitivity to drug treatment could be evaluated simultaneously for classes of compounds which act by the same mechanism. Interestingly, the present approach can also provide a correlation between the molecular targets and the therapeutical fingerprint of novel active compounds thus suggesting specific biochemical studies for the investigation of new mechanisms of drug action and resistance. The statistical approach reported here represents a valuable tool for handling the enormous data sets deriving from recent genome-wide investigations of gene expression in the NCI cell lines.