Search PubMed⌕ Search

Biomedical subjects

C Hansch

Publications and source records attributed to C Hansch.

At least 109 records · Page 6Linked to original sources
PubMed1981

A comparison of mutagenic and carcinogenic activities of aniline mustards.

A set of 15 derivatives of aniline mustard (I) was tested to give a quantitative measure of mutagenicity in Salmonella typhimurium TA-1535 and TA-100 and also carcinogenicity as lung tumors in strain-A mice. The structural variation in the set was chosen to minimize collinearity between hydrophobic, electronic, and molar refractive properties. By these measures, there was not a direct relationship between mutagenicity and carcinogenicity; in fact, since the 4-OPh analogue ranked highest in mutagenicity and among the lowest in carcinogenicity, while the reverse was noted for the 3,5-(NHCONH2)2 analogue, an inverse relationship was marginally significant. S-9 activation was required in the Ames test using TA-100, and the dose-response curve, prior to toxicity, appeared biphasic.

Adenoma↗
PubMed1981

Comparison of the inhibition of methotrexate-sensitive and -resistant Lactobacillus casei cell cultures with purified Lactobacillus casei dihydrofolate reductase by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazines. Use of quantitative structure-activity relationships in making inferences about the mechanism of resistance and the structure of the enzyme is situ compared with the enzyme in vitro.

The inhibitory action of a set of 4,5-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazines on Lactobacillus casei dihydrofolate reductase is compared with their action on methotrexate-resistant and methotrexate-sensitive cell cultures by means of quantitative structure-selectivity analysis. The analysis uncovers major differences in the steric and hydrophobic interactions of the substituents X with the three different systems. Correlation analysis is used to define the hydrophobic binding site for 3-X in the isolated enzyme. This is shown to be similar to that of the sensitive cells but different from that in the resistant cells, which have a larger hydrophobic binding site. When X has the general structure 3-CH2ZC6H4-Y (Z = O or NH), it is shown that Y does not interact with the isolated enzyme, but in the living cells, Y interacts with a molecular barrier in a way that can be quantitatively related to the molar refractivity of X. The methotrexate-resistant cells are resistant to highly hydrophilic inhibitors such as methotrexate but are not able to resist hydrophobic inhibitors. The results with the inhibition of L. casei dihydrofolate reductase are compared with the inhibition of enzyme from bovine liver.

Drug Resistance↗
PubMed1980

Mutagenicity of substituted (o-phenylenediamine)platinum dichloride in the Ames test. A quantitative structure-activity analysis.

A set of 13 substituted (o-phenylenediamine)platinum dichlorides has been studied in the Ames test using Salmonella typhimurium (TA-92). These cis-platinum compounds are mutagenic without activation by microsomes. The following correlation equation shows that the most important determinant of mutagenicity by substituents (X) is electron withdrawal via through resonance: log 1/C = 2.23 sigma sigma minus + 5.78. C in this expression is the molar concentration of compound producing 30 mutations/10(8) bacteria initially delivered above background mutation, and sigma minus is the Hammett constant obtained from substituted anilines.

Animals↗
PubMed1980

Antitumor structure-activity relations. Nitrosoureas vs. L-1210 leukemia.

A quantitative structure-activity relationship (QSAR) for 90 nitrosoureas acting against L-1210 leukemia in mice has been formulated. This QSAR is compared with one correlating the LD10 of 96 nitrosoureas. The results indicate that neutral nitrosoureas with octanol/water partition coefficients in the range of -1.5 to -2.5 might have better therapeutic indices than those currently in use.

Animals↗
PubMed1980

Confidence interval estimators for parameters associated with quantitative structure-activity relationships.

Use of the "jackknife" as a statistical tool for construction of both point and confidence interval estimators for parameters which are functions of regression coefficients and/or iteratively estimated parameters is described. Examples are presented demonstrating its utility in constructing estimators for log P0 and pi 0 using the parabolic and bilinear quantitative structure-activity relationship (QSAR) models relating nonlinear dependence of activity on hydrophobicity and for log [1/Ki(app)] assuming competitive enzyme inhibition.

Chemical Phenomena↗
PubMed1980

Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted-benzyl)-2,4-diaminopyrimidines.

A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of purified E. coli dihydrofolate reductase by 23 5-(substituted benzyl)-2,4-diaminopyrimidines: log 1/C = 1.14MR'3,4,5 + 5.73; r = 0.887; s = 0.285. In this expression, MR'3,4,5 refers to the sum of MR values for X in the 3, 4 and 5 positions of the phenyl moiety. MR' signifies that the effective value of MR is limited to 0.79. Comparison of the QSAR for E. coli enzyme inhibition with that previously obtained for bovine enzyme offers the first general explanation for the great selectivity of the important antibacterial agent trimethoprim. Such QSSR promise to be of value in devising more selective drugs.

Animals↗
PubMed1980

Inhibition of dihydrofolate reductase. 3. 4.6-Diamino-1,2-dihydro-2,2-dimethyl-1-(2-substituted-phenyl)-s-triazine inhibition of bovine liver and mouse tumor enzymes.

Inhibition of dihydrofolate reductase from bovine liver and murine L5178YR-C3 tumor cells has been examined for a series of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2-X-phenyl)-s-triazines. For both enzymes all 2-X substituents cause a decrease in inhibitory activity relative to X = H, with the notable exception of X = SH which is 7.4-12 times as active as X = H. Although there is a high correlation between the activities of these compounds vs. these two enzymes, significant deviations from this correlation for three of the triazines (X = CF3, CH2CN, and Cl) suggest that (a) there may exist significant differences in the two enzymes and their interactions with these triazines and (b) exploitation of such differences might allow for the selective inhibition of enzyme from tumor cells.

Animals↗
PubMed1980

The quantitative structure-selectivity relationship of anthracycline antitumor activity and cardiac toxicity.

Quantitative structure-activity relationships (QSAR) are developed for both the antitumor activity (B-16 melanoma) and cardiotoxicity of a set of anthracycline derivatives, for the purposes of finding exploitable differences between the two which would lead to improvements in the therapeutic indices of these compounds. It was found that most structural features which lead to improvement in antitumor activity, such as increases in drug hydrophilicity, also lead to increases in cardiotoxicity. However, demethoxylation and demethoxylation at the 4-position of these molecules appears to have much greater effect on cardiotoxicity than on antitumor activity. If these effects are brought about by alterations in the oxidation-reduction potential of the quinone structure, as is suggested, then it may be possible to make analogs with a better therapeutic index by the introduction of small hydrophilic electron-releasing groups in the A-ring of these adriamycin derivatives that are conjugated with the carbonyl functions.

Animals↗
PubMed1979

Quantitative structure-activity relationships in 1-aryl-2-(alkylamino)ethanol antimalarials.

A quantitative structure-activity relationship has been formulated for 646 antimalarials acting against P. berghei in mice. The equation developed has 14 terms, 9 of which are indicator variables. The correlation coefficient for the QSAR is 0.898 and the standard deviation is 0.309. The antimalarials are all arylcarbinols of the type X-ArCHOHCH2NR1R2. Sixty different aryl structures, including a variety of heterocyles, are contained in the study. The most important determinate of activity is found to be the electron-withdrawing ability of the substituents X; the hydrophobic character of X and R plays less important roles. Suggestions for more potent analogues are made and the lack of activity of about 100 additional analogues is also considered.

Animals↗
PubMed1979

Ames test of 1-(X-phenyl)-3,3-dialkyltriazenes. A quantitative structure-activity study.

The mutagenicity of 1-(X-phenyl)-3,3-dialkyltriazenes was tested in the Ames test using Salmonella typhimurium TA92. The following quantitative structure-activity relationship (QSAR) was formulated: log 1/C = 1.09 log P -1.63 sigma+ + 5.58. In this expression, C is the molar concentration of triazene producing 30 mutations/10(8) bacteria above background. This equation is based on 17 congeners and has a correlation coefficient of 0.974. The QSAR for mutagenicity is compared with QSAR for antileukemia action and toxicity (LD50) in mice. The mutagenicity of aflatoxin B (log 1/C = 9.5) and DTIC (log 1/C = 3.0) have also been determined.

Animals↗
PubMed1979

Quantitative structure-activity relationship of 5-(X-benzyl)-2,4-diaminopyrimidines inhibiting bovine liver dihydrofolate reductase.

The inhibitory effect for a set of 23 5-(X-benzyl)-2,4-diaminopyrimidines acting on bovine liver dihydrofolate reductase (DHFR) had led to the following quantitative structure-activity relationship (QSAR): log 1/C = 0.62pi3 + 0.33epsilon sigma + 4.99, where r = 0.931 and s = 0.146. C in this expression is the molar concentration of inhibitor producing 50% inhibition, pi3 is the hydrophobic parameter for substituents on the 3 position of the phenyl moiety, and epsilon sigma is the the sum of the Hammett sigma constants for the 3, 4, and 5 substituents of the phenyl ring.

Animals↗