PubMed Health⌕ Search

Biomedical subjects

C Hansch

Publications and source records attributed to C Hansch.

At least 19 recordsLinked to original sources
PubMed2003

IARC carcinogens reported in cigarette mainstream smoke and their calculated log P values.

Cigarette smoke is a complex aerosol of minute liquid droplets (termed the particulate phase) suspended within a mixture of gases (CO(2), CO, NO(x), etc.) and semi-volatile compounds. The International Agency for Research on Cancer (IARC) has classified a number of the chemical constituents reported in cigarette mainstream smoke (MS) as carcinogens. Previously, we published a series of historical reviews reporting that 11 IARC Group 1 (known human), nine Group 2A (probable human) and 48 Group 2B (possible human) carcinogens have been observed in MS. Here, we expand the list of IARC classified carcinogens from 68 to 81 compounds (11 Group 1, 14 Group 2A and 56 Group 2B) reported in MS. A number of the IARC compounds reported in MS are found in the vapor phase including three Group 1, eight Group 2A and 18 Group 2B constituents. Several IARC MS compounds are found in both the vapor and particulate phases including two in Group 1, one in Group 2A and one in Group 2B. Forty-eight IARC MS carcinogens are found in the particulate phase only. Lipophilicity, as determined by the base 10 logarithm of the calculated octanol-water partition coefficient and denoted as Clog P, is reported for each of the 71 non-metallic MS IARC carcinogens. Clog P correlates with a number of biological activities including in vitro mutagenicity and carcinogenicity in rodents, and in the absence of any additional toxicological or epidemiological data, a high log P compound is more likely to be carcinogenic than a low log P compound.

Animals↗
PubMed2001

Radical toxicity of phenols: a reference point for obtaining perspective in the formulation of QSAR.

In this report we discuss some of the surprising ways phenols interact in vivo and how some of their toxic activity can be understood in terms of QSAR and in fact can be related via electronic terms to be similar to processes of simple chemical reactions. A simple two-term QSAR is found to be a good predictor of estrogenic toxicity. However, it is also shown that even the simplest of phenols can yield quite unexpected results than can be elucidated via QSAR. We still have a long way to go before we can predict under what conditions a phenol will produce toxic effects such as cancer and how much phytophenols one can consume before reaping a toxic reaction.

Free Radicals↗
PubMed2001

Mechanism of toxicity of esters of caffeic and dihydrocaffeic acids.

Ten esters each of caffeic acid and dihydrocaffeic acid have recently been synthesized. Cytotoxicity evaluations of these esters versus L1210 leukemia and MCF-7 breast cancer cells in culture have led to the delineation of substantially different QSAR for each series. The L1210 QSAR for dihydrocaffeic acid esters resembles the QSAR obtained for simple phenols and estrogenic phenols. However, the QSAR pertaining to the caffeic acid esters differs considerably from its sister QSAR. This difference may be attributed to the presence of the olefinic linkage in the side chain. The octyl ester of caffeic acid is nearly ten times as toxic to the leukemia cells than the widely studied phenethyl ester, CAPE.

Animals↗
PubMed2001

Searching for allosteric effects via QSARs.

A study of our database of 7,000 QSARs involving chemical-biological interaction uncovered 11 examples where the QSARs all contain inverted parabolas based on molecular refractivity. That is, biological activity first decreases with increase in MR and then increases. Two of the examples are for enzymes: cyclooxygenase and trypsin. The others are for various receptors. The results seem to be best rationalized by the larger compounds inducing a change in a receptor unit that allows for a new mode of interaction.

Allosteric Regulation↗
PubMed2001

QSAR of anticancer compounds. Bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides).

QSAR have been developed for the anticancer activity (growth inhibition) of various tumor cells by bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides). Of the seven QSAR, positive hydrophobic interactions are found in only two examples: bis(naphthalimides) versus human colon cancer cells. This is consistent with other QSAR of anticancer compounds where hydrophobic interactions are found to be unimportant.

1-Naphthylamine↗
PubMed2001

Comparative QSAR studies on bibenzimidazoles and terbenzimidazoles inhibiting topoisomerase I.

Terbenzimidazoles that inhibit topoisomerase are of interest as anticancer drugs. We have reviewed the literature and have developed 13 quantitative structure-activity relationships (QSARs) on cleaving DNA or inhibiting the growth of tumor cell cultures. The results are correlated with octanol/water partition coefficients or molecular refractivity. Suggestions have been made for the development of improved derivatives.

Animals↗
PubMed2001

QSAR of the inhibition of angiogenesis by TNP-470 and ovalicin analogues: another example of an allosteric interaction.

QSAR have been formulated for variations of TNP-470 and Ovalicin on various cell lines. In the examples of mouse lymphocyte cells and bovine endothelial cells the results suggest an allosteric interaction. These results are compared with the binding of nitrobenzene to hemoglobin in rats in vivo. Such a reaction does not occur with methionine aminopeptidase.

Aminopeptidases↗
PubMed2001

Possible allosteric effects in anticancer compounds.

We have found in this report, and an earlier one, that in a variety of instances an inverted parabolic relationship between biological activity and CMR or logP is observed. That is, activity first decreases as CMR or logP increases and then turns about and increases. This could be attributed to the ligands causing a change in the receptor structure. The present report considers QSAR for a variety of resistant and sensitive cancer cells.

Antineoplastic Agents↗
PubMed2001

Comparative QSAR: on the toxicology of the phenolic OH moiety.

In this report we consider the effect of substituents on phenol toxicity and show how the parameters used in Quantitative Structure-Activity Relationships (QSAR) can be used to draw mechanistic inferences of value in understanding the reasons behind the various types of toxicity. In particular, we are interested in gaining clearer insight into mechanisms via the Hammett-type parameters sigma, sigma(-), sigma(+) and octanol/water parti tion coefficients. Particular attention is given to the role of radical reactions and their role in attacking DNA to cause cancer or estrogenic toxicity.

Animals↗
PubMed2000

Comparative QSAR evidence for a free-radical mechanism of phenol-induced toxicity.

Phenol and 14 substituted-phenols were tested for their ability to impair epithelial cell membrane integrity in WB rat liver cells as determined by an increase in lactate dehydrogenase release. Two quantitative structure-activity relationship (QSAR) regression equations were developed which showed that separate mechanisms of phenolic cytotoxicity are important - nonspecific toxicity due to hydrophobicity and formation of phenoxyl radicals. The equations most predictive of phenol toxicity are denoted as log1/C=-0. 98sigma(+)+0.77logP+0.23 or log1/C=-0.11BDE+0.76logP+0.21, respectively, where C is the minimum concentration of substituted-phenol required for a toxic response. P is the octanol-water partition coefficient, sigma(+) is the electronic Hammett parameter and BDE is the OH homolytic bond dissociation energy. In the literature, phenol toxicity correlated to sigma(+) is rare, but there is strong evidence that phenols possessing electron-releasing groups may be converted to toxic phenoxyl radicals. A common feature in a variety of cells is generation of elevated amounts of reactive oxygen species (ROS) associated with a rapid growth rate. The slightly elevated cancer risk associated with the use of Premarin may be due to phenoxyl-type radicals derived from one or more of its components.

Animals↗
PubMed2000

Toxicology of benzyl alcohols: a QSAR analysis.

There is an evidence that benzyl alcohols may exhibit toxicity via a radical mechanism. To test this possibility, we studied the toxicity of para substituted benzyl alcohols on rapidly dividing cancer cells (L1210 leukemia). This system has previously found utility in studying the apparent radical toxicity of a variety of phenols. However, no evidence could be found for an electronic effect and the cellular toxicity was associated primarily with hydrophobicity. Comparison of this quantitative structure-activity relationships (QSAR) with others for the reactions of benzyl alcohols in diverse systems provides insight into mechanisms of action. A QSAR for the interaction of benzyl alcohols with protozoa yields an equation that is dependent on both hydrophobicity and acidity of the OH group versus a mixture of bacteria and fungi, the critical dependence on hydrophobicity prevails with a small dependence on a resonance-stabilized, radical mediated electronic effect. The chloramphenicols provide an instructive example, where the radical mediated electronic effect overshadows the hydrophobic contribution to bacterial toxicity. These various QSAR for benzyl alcohols indicate that mechanisms of growth inhibition in vitro vary depending on cell/organism type, the strength of the bond and lability of the hydrogen, and the strength of the initiating radical reagent.

Animals↗
PubMed2000

The relative toxicity of compounds in mainstream cigarette smoke condensate.

Many different in vivo and in vitro tests are currently used to assess the toxicity of chemicals and complex mixtures such as cigarette smoke condensate. In vivo tests include assays in rodents to determine carcinogenicity, tumorigenicity and reproductive effects In vitro tests of mutagenicity are conducted with both bacterial and mammalian cell systems. A first step towards lowering the toxicity of cigarette smoke condensate is the identification of the relevant compound However, changing the concentration of a given smoke component may not linearly alter the biological activity of the complex mixture due to interactive effects. The "effective toxicity" of a chemical constituent is a function of the concentration, the metabolic fate, the potency in in vivo and in vitro assays, and the ability to reach the target tissues. The logarithm of the octanol-water partition coefficient (log P) is an important parameter since it affects metabolism, biological transport properties and intrinsic toxicity. Using concentration data from the International Agency for Cancer Research (IARC), biological activity data from the Registry of Toxic Effects of Chemical Substances (RTECS) database and measured and calculated log P values, we have rank ordered some of the important compounds in cigarette smoke condensate by their measured or potential toxicity. Condensates from different cigarette brands, tar categories and styles vary in their concentrations of these compounds. Chemicals of greater commercial or scientific interest may be toxicity tested more extensively, thereby increasing the probability of positive test results and highlighting the need for consideration of structure-activity relationships.

Acetaldehyde↗
PubMed2000

Comparative QSAR studies on substituted bis-(acridines) and bis-(phenazines)-carboxamides: a new class of anticancer agents.

Quantitative structure-activity relationships have been formulated for two sets of DNA binding topoisomerase agents (bis-acridines and bis-phenazines) acting on murine P388 leukemia cells, murine Lewis lung carcinoma (LL(C)) cells and human Jurkat leukemia wild-type (JL(C)) cells. For the acridines, all three QSARs (1-3) show only a (small negative) hydrophobic effect. In sharp contrast, the phenazines in all three studies (4-6) show a strong hydrophobic effect, with the optimum ClogP being near 7.3 for all examples. This suggests that, despite the structural similarity of the compounds, different modes of enzyme and/or DNA binding may be involved.

Acridines↗