Quantitative structure-activity relationship Hansch analysis

Hansch and Verma contribute to the quantitative structure-activity relationship (QSAR) analysis of heterocyclic topoisomerase I and II inhibitors. These inhibitors, known to inhibit either enzyme, act as antitumor agents and are currently used in chemotherapy and in clinical trials. 

Quantitative structure-activity relationships, HANSCH S CORRELATION ANALYSIS QUANTASOME QUANTUM... 

For further reading on the strategy and tactics of perfecting a lead by quantitative structure—activity relationships (correlation analysis) ofdrugs, see Topliss (1983), Hahn (1975), and Martin (1978, 1979). For more information on the physicochemical properties of drugs and how to estimate them, see Hansch and Leo (1979), Yalkowsky, Sinkula and Valvoni (1980), and Lyman, Rechl and Rosenblatt (1982). 

Hansch, C. et al. (1986) A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase. J. Med. Chem., 29 (5), 615-620. 

Hansch analysis Hansch analysis is a common quantitative structure-activity relationship approach in which a Hansch equation predicting biological activity is constructed. The equation arises from a multiple linear regression analysis of both observed biological activities and various molecular property parameters (Hammett, Hansch, and Taft parameters). 

Debnath, A.K., Hansch, C., Kim, K.H., and Martin, Y.C., Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA), J. Med. Chem., 36, 1009-1116, 1993. 

These efforts were guided by the study of quantitative structure-activity relationships (QSAR) following the Hansch approach. In this method linear free-energy related and other electronic, hydrophobic, and steric substituent constants are used for a quantitative analysis of the possible ways in which substituents may modulate bioactivity in a congeneric series. In the QSAR studies of benzoylphenyl ureas the electronic Hammett a-constants and the hydro-phobic Hansch n-constants were used. To measure the steric influences, steric substituent constants of a new type (B1,B2,B3,B4, and L) were applied which had recently been introduced by us and which give improved correlations in comparison with the steric Es constants used in the literature hitherto (21, 22). The constants B- toBj are measures of the widths of substituents in four rectangular directions. The L-constant accounts for the length of a substituent ... 

The epoch of QSAR (Quantitative Structure-Activity Relationships) studies began in 1963-1964 with two seminal approaches the a-p-7i analysis of Hansch and Fujita " and the Free-Wilson method. The former approach involves three types of descriptors related to electronic, steric and hydrophobic characteristics of substituents, whereas the latter considers the substituents themselves as descriptors. Both approaches are confined to strictly congeneric series of compounds. The Free Wilson method additionally requires all types of substituents to be suflficiently present in the training set. A combination of these two approaches has led to QSAR models involving indicator variables, which indicate the presence of some structural fragments in molecules. 

Kubinyi, H. (1976a). Quantitative Structure-Activity Relationships. 2. A Mixed Approach, Based on Hansch and Free-Wilson Analysis. J.Med.Chem., 19,587-600. 

Kubinyi H. Quantitative structure-activity relationships 1. The modified free-Wilson approach. 2. A mixed approach, based on Hansch and Free-Wilson analysis. J Med Chem 1976 19 587-600. 

Classical Quantitative Structure-Activity Relationship Techniques The early QSAR models for calcium channel ligands were based on classical Hansch analysis and elucidated the structural requirements for the binding of molecules to their receptors [111-115], It was found that various steric (Bl, L), electronic (a), and hydrophobic (n) parameters or their combination correlated well with the potency of various DHPs [111]. QSAR analysis of another set of DHPs revealed good correlations between electronic properties (F-constants) of the phenyl ring substituents and binding affinities or functional potency [112] lipophilicity as well as ortho- and meta-substituents inductivity... 

Hemmateenejad B, Akhond M, Miri R, Shamsipur M. Quantitative structure-activity relationship study of recently synthesized 1,4-dihydropyridine calcium channel antagonists. In Application of the Hansch analysis method. Weinheim Arch Pharm, 2002. p. 472-80. 

Roy, N.K., Nidiry E.S.J., Vasu, K., Bedi, S., Lalljee, B. and Singh, B. (1996) Quantitative structure-activity relationship studies of 0,0-bisaryl alkyl phosphonate fimgicides by Hansch approach and principal component analysis. J. Agr. Food Chem., 44, 3971-3976. 

Quantitative structure-activity relationships have been determined for some of the 1,4-dihydropyridines. Hansch analysis reveals significant correlations between negative inotropy and (a) minimum width (i.e., or/Ao-substituted phenyl derivatives), (b) van der Waals s volume (ester-substituted derivatives) and (c) lipophilicity (ester derivatives) [76]. 

Hansch C, Hatheway GJ, Quinn FR, Greenberg N. Antitumor l-(X-aryl)-3,3-dialkyltriazenes 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure-activity relationships of l-(X-phenyl)-3,3-dialkyltriazenes in mice. J Med Chem 1978 21 574-577. 

Hansch C, Li RL, Blaney JM, Langridge R. Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines quantitative structure-activity relationships, x-ray crystallography, and computer graphics in structure-activity analysis. J Med Chem 1982 25 777-784. 

BR is the relative biologic activity under investigation, for example the molar EDr>o or the percent response at a given dose. Log P is the logarithm of the octanol-water partition coefficient, a is the approprite Hammett signa constant (electronic in nature), and Es is the Taft steric parameter. With the important demonstration by Hansch that the partition coefficient is often an additive constitutive property, all of the physical parameers may be obtained from the literature. A second important contribution by Hansch is the recognition that the use of statistical techniques is essential to the analysis of quantitative structure-activity relationships. To develop an equation such as that above, one feeds the... 

The interactions of drugs with their biological counterparts are determined by intermolecular forces, i.e. by hydrophobic, polar, electrostatic, and steric interactions. Quantitative structure-activity relationships (QSAR) derive models which describe the structural dependence of biological activities either by physicochemical parameters (Hansch analysis), by indicator variables encoding different structural features (Free Wilson analysis), or by three-dimensional molecular property profiles of the compounds (comparative molecular field analysis, CoMFA). 

Due to the relationship between biological activity and the free energies of binding (or partitioning) also the terms extrathermodynaraic relationships or linear free energy-related approach are used for quantitative structure-activity relationships, especially Hansch analysis. 

Due to the relationships between Hansch analysis and the Free Wilson model, indicator variables (chapter 3.8) have relatively early been included in Hansch analyses (e.g. [21, 427, 428]). Both models can be combined to a mixed approach, in a linear (eq. 78) and a nonlinear form (eq. 79), which offers the advantages of both, Hansch analysis and Free Wilson analysis, and widens their applicability in quantitative structure-activity relationships [22]. 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

C. Hansch, T. Klein, J. McClarin, R. Langridge, and N. W. Cornell, ]. Med. Chem., 29, 615 (1986). A Quantitative Structure-Activity Relationship and Molecular Graphics Analysis of Hydrophobic Effects in the Interactions of Inhibitors of Alcohol Dehydrogenase. 

Hansch, C. and Fujita, T. (1964) p-o-7i Analysis. A method for correlation of biological activity and chemical structure. J. Am. Chem. Soc. 86,1616. Maddalena, D. J. (1996) Applications of artificial neural networks to quantitative structure-activity relationships. Expert Opin. Ther. Pat. 6,239-251. 

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