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M Cotta-Ramusino

Publications and source records attributed to M Cotta-Ramusino.

8 recordsLinked to original sources
PubMed2000

Deriving a quantitative chirality measure from molecular similarity indices.

A versatile new method has been developed as a continuous symmetry measure for chiral compounds. The application of principal component analysis (PCA) to the complete N x N pairwise similarity matrices (electrostatic potential and shape indices) of a series of dihydropyridine calcium channel antagonists allowed to single out a chirality component and to compute a chirality score in terms of the between-enantiomers difference on the component value. The possibility to have chirality defined continuously at the series level could be of importance in eudismic analyses where the relative potency of two enantiomers is studied as well as in QSAR studies dealing with chiral molecules in order to improve the power of the generated models.

Calcium Channel Blockers↗
PubMed1998

QSAR models for discriminating between mutagenic and nonmutagenic aromatic and heteroaromatic amines.

In a previous article, we demonstrated that the structure-activity relationship model for the mutagenic potency of aromatic amines is different from that for discriminating between mutagens and nonmutagens. In this work, we present further analyses on the molecular determinants of the mutagenicity of aromatic amines. Based on the use of various methodological approaches, our results indicate that mutagenic activity is influenced by different molecular characteristics in different subclasses of aromatic amines. Thus, the general lesson of this article is that 1) in genetic toxicology, it is necessary to separately investigate the structure-activity relationships for discrimination between positive and negative chemicals, and the structure-activity relationships for the potency of the positive chemicals; 2) in structure-activity studies, it is necessary to investigate the degree of homogeneity (congenericity) of apparently similar chemicals in order to assess and describe the various mechanisms of action that may be elicited by the chemicals.

Amines↗
PubMed1995

Toxicology of halogenated aliphatic hydrocarbons: structural and molecular determinants for the disturbance of chromosome segregation and the induction of lipid peroxidation.

The induction of mitotic chromosome malsegregation, mitotic arrest and lethality by a set of 55 halogenated hydrocarbons was investigated. To this aim, genetic assays in the mould Aspergillus nidulans, able to provide precise quantitative information on the end-points studied, were used throughout the work. The experimental data obtained were used to develop QSAR models for the induction of aneuploidy, which pointed to a major role of electrophilicity as molecular determinant for the aneugenic potential of the halogenated hydrocarbons investigated. Within the hypothesis of a link between the electrophilicity of haloalkanes and their propensity to undergo a reductive biotransformation, with production of free radical species, a subset of 27 compounds was also tested for the ability to induce lipid peroxidation in rat liver microsomes in vitro. The results obtained indicate a partial coincidence between the abilities to initiate lipid peroxidation and to disturb chromosome segregation at mitosis. The data base obtained was also used to investigate the relationship between chemical structure and peroxidative potential. The analysis indicated that electronic and structural parameters related to the ease of homolitic cleavage of the carbon-halogen bond play a pivotal role as determinants for the peroxidative character of haloalkanes.

Aneuploidy↗
PubMed1995

Molecular similarity matrices and quantitative structure-activity relationships: a case study with methodological implications.

Recently, statistical analysis of molecular similarity matrices has been applied to the quantitative structure-activity relationship (QSAR) analysis of a number of molecular series. This paper addresses a number of methodological issues relative to the similarity matrices. A series of halogenated aliphatic hydrocarbons, for which the mutation (aneuploidy) induction ability had previously been determined, was used as test bench. The chemical information carried by the similarity matrices was shown to overlap to a considerable extent the information carried by the classical descriptors (physical chemical and quantum mechanical parameters). A good QSAR was obtained on the basis of the similarity matrices, in analogy with that obtained with the classical descriptors; however, the similarity matrices neither complemented the classical descriptors nor were able to improve on their performance. The effect of the compound's spatial orientation on the similarity values was also investigated.

Aneuploidy↗
PubMed1993

Quantitative structure-activity relationship models correctly predict the toxic and aneuploidizing properties of six halogenated methanes in Aspergillus nidulans.

In a previous study, the relationships between the chemical structure and the ability of 35 chlorinated aliphatic hydrocarbons to induce aneuploidy and toxicity in Aspergillus nidulans were analyzed. Quantitative structure-activity relationships (QSAR) were defined for each of the biological activities under study: ARR (the dose able to block mitotic growth), D37 (the dose with 37% of survival) and LEC (the lowest efficient concentration in aneuploidy induction). In this study, these QSAR equations were used to predict the toxic and genetic activity of a further six chemicals, not included in the previous data base: bromotrichloromethane, bromoform, bromochloromethane, bromodichloromethane, dibromochloromethane and dibromochlorofluoromethane. Their ARR, D37 and LEC values were measured, and were in agreement with the predicted values, with correlation coefficients around 0.99. Furthermore, the QSAR model, which had previously been developed to discriminate between aneugenic and inactive halogenated hydrocarbons, correctly predicted the aneugenic activity of five out of six methanes. These correct predictions confirmed the validity of our QSAR model, according to which the induction of aneuploidy in A. nidulans depends on both the electrophilic and steric properties of the chemicals, whereas toxicity mainly depends on steric factors.

Aneuploidy↗
PubMed1992

Electrophilicity as measured by Ke: molecular determinants, relationship with other physical-chemical and quantum mechanical parameters, and ability to predict rodent carcinogenicity.

This paper analyzes electrophilicity data as measured by the Ke system for 205 chemicals including both rodent carcinogens and non-carcinogens. Multivariate statistical methods were used. The analysis identified atoms and substructures contributing to electrophilicity, and permitted to establish a theoretical method by which the Ke value (electrophilicity) of chemicals can be easily estimated. In a subset of chemicals, the Ke parameter was compared with other physical-chemical and quantum mechanical properties: Ke appeared to be mostly correlated with the energy of the lowest unoccupied molecular orbital and with the absolute electronegativity. The role of Ke in structure-activity studies was also investigated; in particular, a comparative analysis of the performance of Ke, Salmonella typhimurium and Ashby's structural alerts in predicting carcinogenicity was carried out. The Ke system performed better than the other systems. However, because of the many different mechanisms underlying carcinogenesis, the Ke system cannot predict the potential carcinogenicity of all kinds of chemicals. It is concluded that the main role of Ke in risk assessment consists in producing a probabilistic estimate of the rodent carcinogenicity of the chemicals: e.g. a chemical with Ke higher than 3.0 x 10(12) M-1S-1 has nearly 80% probability of being a carcinogen. Such a probability estimate can be used to rank the chemicals in a priority scale for subsequent and more detailed studies, either theoretical or experimental. In view of this, the role of our method for estimating Ke is particularly important: it gives rapidly and at no cost a chemical classification for risk assessment and priority setting.

Animals↗
PubMed1991

Relationship between chlorofluorocarbon chemical structure and their Salmonella mutagenicity.

This paper is a quantitative analysis of the relationship between the chemical structure and the Salmonella mutagenicity of a number of chlorofluorocarbons (CFC). The molecules were characterized by both molecular orbital and physical chemical parameters. The results of the analysis indicated that the CFC mutagenicity is correlated with two parameters: the free energy of binding to biological receptors, and the energy of the highest occupied molecular orbital (HOMO). Since these are the same factors that would favor the cytochrome P-450-catalyzed metabolism, it would appear that the CFC mutagenicity is determined more by the rate of initial activation than by the rate of DNA attack.

Biotransformation↗