Corwin Hansch

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.

The expanding role of quantitative structure-activity relationships (QSAR) in toxicology

Quantitative structure-activity relationships (QSAR) have found wide use in correlating the bioactivity of all kinds of organic compounds with all kinds of biological entities. So many QSAR have been published that it is time for a new phase of study, that of comparative QSAR. From our current database of about 6000 QSAR illustrative examples are discussed.

TOWARD A QUANTITATIVE COMPARATIVE TOXICOLOGY OF ORGANIC COMPOUNDS

Correlation equations between logP (P = octanol water partition coefficient) and the biological activity of alcohols has been derived for 101 examples on all sorts of systems, from simple proteins to whole animals. This provides an overview of the toxic nature of hydrophobic compounds which can be used as a basis for comparison of more complex chemicals. About 100 examples of the hydrophobic effects of chemicals, other than alcohols, to various living systems or their parts are presented for comparison. It is clear that hydrophobic xenobiotics are toxic to almost every form of life, including humans (or parts there of).

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.

Camptothecins: a SAR/QSAR study.

Camptothecin (CPT, I), a unique pentacyclic quinoline alkaloid originally isolated from a native tree of Tibet and China called Camptotheca acuminata in latin and Xi Shu in Chinese, is one of the prominent lead compounds in anticancer drug development.1-3 It has been identified from the early assessments that the importance of 20S chiral carbon of CPT for their activity and also pointed out a dynamic equilibrium between the close-ring lactone and open-ring carboxylic acid forms at physiological pH. Due to the extremely poor solubility of CPT in water, clinical trials were initiated using its water-soluble sodium salt (II; Figure 1). The results were disappointing: biological activity was weak relative to xenograph models and unexpected side effects including hemorrhagic cystitis and myelotoxicity, which resulted in suspension of the trials.4,5 Later on, it was established that the R-hydroxy lactone ring moiety must be intact for antitumor activity and that this ring was being opened in the preparation of the sodium salt.6 In a conformational analysis, torsional parameters for the MM3(96) force field were obtained by Carrigan et al.7 for the R-hydroxy lactone and CPT using ab initio calculations on representative compounds containing the critical dihedral angles. MM3(96) predicts two distinct “boat-like” conformations for the R-hydroxy lactone moiety. The low-energy lactone conformation predicted by MM3(96) is in good agreement with X-ray crystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piperidinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT-like R-hydroxy lactone. Nearly 20 years later, the discovery that the primary cellular target of CPT is DNA topoisomerase I (topo I) was the breakthrough that renewed interest in this agent and led to synthesizing more water-soluble analogues.8-10 Two of them, topotecan (Hycamptin, III) for the clinical treatment of the ovarian and small-cell lung cancers,11-14 and irinotecan (Camptosar or CPT-11, IV)15,16 for the metastatic colorectal cancers have already gained approval by the Food and Drug Administration (FDA) of the U.S.A.17,18 Irinotecan is a prodrug that is converted into their active metabolic form 10-hydroxy-7-ethylcamptothecin (SN-38, V; Figure 2). These two drugs (topotecan and irinotecan) and other derivatives of CPT have become a part of the multimillion dollar industry that is dedicated to finding better chemotherapeutic agents with excellent antitumor activity and less normal tissue toxicity. To achieve this goal, it is necessary to understand the details about the mechanisms of action, the targets of these drugs, and the cellular response to the drugs. Human topoisomerase I (topo I) relaxes superhelical tension associated with DNA replication, transcription and recombination by reversibly nicking one strand of duplex DNA and forming a covalent 3′-phosphotyrosine linkage. This enzyme is the sole target of the CPT family of anticancer compounds, which acts by stabilizing the covalent protein-DNA complex and enhancing apoptosis through blocking the advancement of replication forks. Once the CPT molecule has intercalated into the topo I-DNA cleavable complex, the collision between the complex and the replication fork during S-phase is thought to result in DNA double strand breaks (DSBs) that eventually lead to cell death.18,19 It has also been suggested that topo I cleaves DNA at multiple sites. The highest efficient sites exhibit significant sequence homology. Approximately 90% of topo I site have a tyrosine residue at position-1. However, sites of cleavage stabilized by CPT exhibit a strong preference for guanine at +1 position, while thymidine remains the preferred nucleobase at the -1 position.20 The exact mechanism by which CPT stabilizes the DNAtopo I covalent binary complex is not fully understood because the drug acts as an uncompetitive inhibitor and binds only the transient binary complex.21 Enzymology studies have revealed that CPT does not interact with topo I alone, nor does it bind to DNA.22 Although it has been reported that topotecan, which should be protonated at physiological pH, does bind to DNA at high concentration.23 Despite the * Phone: (909) 607-4249. Fax: (909) 607-7726. E-mail: rverma@ pomona.edu. Chem. Rev. 2009, 109, 213–235 213

The use of substituent constants in the study of structure-activity relationships in cholinesterase inhibitors

Abstract A quantitative analysis of the structure-activity relationship in cholinesterase inhibitors was made. From the results of Metcalf and Fukuto four different classes of inhibitors are considered: methylcarbamates, diethylphenylphosphates, alkylphosphonic acid esters, 2,4,5- trichloro -N- alkylphosphoramidates . It is shown by means of substituent constants and regression analysis that the effects of substituent groups can be factored into three groups: electronic, steric, hydrophobic. The results indicate that the phosphate esters react by a mechanism different from that of the carbamates. New examples of the value of Tafts steric constant, E S , for biological reactions are discussed.

On the Role of Polarizability in Chemical−Biological Interactions

This report considers the importance of electronic effects in their role in the QSAR of chemical-biological interactions. The problem of accounting for polarizability effects in ligand-substrate interactions is discussed in terms of molecular polarizability (MR) and NVE (number of valence electrons) using additive values for valence electrons. The two approaches give essentially the same result in examples of frog nerve toxicity and examples of nerve toxicity with rabbits and cockroaches. The point is made that no matter how one approaches QSAR, electronic interactions must be considered if we are to begin to develop a science of chemical-biological interactions.

Structure-activity correlations in the metabolism of drugs☆

Abstract Substituent constants and regression analysis have been employed in the study of metabolism of organic compounds. Most of the variation in the structure-activity relationship appears to be associated with relative lipophilic character of the derivatives as defined by octanol-water partition coefficients. The ideal lipophilic character for amines undergoing metabolism by crude monoamine oxidase is defined by log P 0 = 2. This same constant also applies to the formation of glucuronides by alcohols and benzoic acids and hippuric acid formation by benzoic acids.

Quantitative Structure-Activity Relationships of Cytochrome P-450

(1993). Quantitative Structure-Activity Relationships of Cytochrome P-450. Drug Metabolism Reviews: Vol. 25, No. 1-2, pp. 1-48.

Role of hydrophobic effects in mechanistic QSAR

To extend the successful application of Hammett equations, previously used to predict equilibrium and rates of physico-chemical reactions with electronic and steric parameters, to the realm of biology and biochemistry, a parameter that measures hydrophobicity is required. The partition coefficient of a solute between octanol and water, expressed in log terms to put it on the same free-energy basis as the classic Hammett parameters, has been shown to be widely applicable. It is directly involved in passive transport through membranes, in binding to proteins, and in specific binding at active sites in enzymes. Methods of calculating logP(octanol) that reflect the solvation forces involved, can be useful in elucidating unusual solute conformations that may be preferred in a non-polar environment.