Cellular apoptosis and cytotoxicity of phenolic compounds: a quantitative structure-activity relationship study

In this comprehensive study on the caspase-mediated apoptosis-inducing effect of 51 substituted phenols in a murine leukemia cell line (L1210), we determined the concentrations needed to induce caspase activity by 50% (I50) and utilized these data to develop the following quantitative structure-activity relationship (QSAR) model: log 1/I50 = 1.06 B5(2) + 0.33 B5(3) - 0.18pi(2,4) - 0.92. B5(3) and B5(2) represent steric terms, while pi(2,4) represents the hydrophobic character of the substituents on the ring. The strong dependence of caspase-mediated apoptosis on mostly steric parameters suggests that the process is a receptor-mediated interaction with caspases or mitochondrial proteins being the likely targets. Conversely, cytotoxicity studies of 65 electron-releasing phenols in the L1210 cell line led to the development of the following equation: log 1/ID50 = -1.39sigma+ - 0.28 B5(2,6) + 0.16 log P - 0.58I(2) - 1.04I(1) + 3.90. The low coefficient with log P may pertain to cellular transport that may be enhanced by a modest increase in overall hydrophobicity, while the presence of sigma+ is consistent with the suggestion that radical stabilization is of prime importance in the case of electron-releasing substituents. On the other hand, the QSAR for the interactions of 27 electron-attracting phenols in L1210 cells, log 1/ID50 = 0.56 log P - 0.30 B5(2) + 2.79, suggests that hydrophobicity, as represented by log P is of critical importance. Similar cytotoxicity patterns are observed in other mammalian cell lines such as HL-60, MCF-7, CCRF-CEM, and CEM/VLB. The significant differences between the cytotoxicity and apoptosis QSAR for electron-releasing phenols suggest that cytotoxicity involves minimal apoptosis in most of these substituted monophenols.     

QSAR of the inhibition of glyoxalase by S-substituted glutathiones

A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of glyoxalase I from yeast by 37 S-substituted glutathiones: log 1/C = 1.23 pi' + 1.20 MR4 - 0.67 I1 - 0.14 pi'2 + 1.85 C in this expression is the molar concentration of inhibitor producing 50% inhibition, pi' is the usual hydrophobic parameter modified for certain substituents, MR4 is the molar refractivity of certain p-phenyl substituents, and I1 is an indicator variable for those congeners with an acetylated alpha-amino group. This equation should be of help in the design of more effective inhibitors which may be of value in cancer chemotherapy.     

Human and rat liver phenol sulfotransferase: structure-activity relationships for phenolic substrates

Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of many phenolic drugs. Human liver contains thermostable (TS) and thermolabile forms of PST. Ion exchange chromatography shows that two isozymes of TS PST (peaks I and II) are present in human liver preparations. Rat liver contains four forms of PST that can be separated by ion exchange chromatography. Quantitative structure-activity relationship (QSAR) analysis was used to study phenolic substrates for both human and rat liver PST. Thirty-six substituted phenols were tested as substrates for partially purified human liver TS PST peak I. QSAR analysis resulted in derivation of the following equation: log 1/Km = 0.92 (+/- 0.18)log P - 1.48 (+/- 0.38)MR'4 - 0.64 (+/- 0.41)MR3 + 1.04 (+/- 0.63)MR2 + 0.67(+/- 0.44) sigma- + 4.03 (+/- 0.42). In this equation Km is the Michaelis constant, P is the octanol-water partition coefficient, MR is the molar refractivity of substituents at the 2-, 3-, and 4-positions, and sigma- is the Hammett constant. Values of log 1/Km calculated with this equation were highly correlated with log 1/Km values (r = 0.950) that were observed experimentally. Nine phenols were also tested as substrates for partially purified human liver TS PST peak II. Log 1/Km values for these compounds were significantly correlated for the two isozymes of TS PST (r = 0.992, p less than 0.001). QSAR analysis was also used to derive equations that described the behavior of phenolic substrates for rat liver PST forms I and II. These equations differed substantially from the equation derived for compounds tested with human liver TS PST peak I. Therefore, the characteristics of the active sites of human liver TS PST peak I and rat liver PST forms I and II appear to differ. Application of these equations may make it possible to predict Km values of phenolic substrates for human liver TS PST and for rat liver PST forms I and II.     

Structure-activity relationship of the ficin hydrolysis of phenyl hippurates. Comparison with papain, actinidin, and bromelain

A study of the hydrolysis of 30 substituted-phenyl hippurates by the enzyme ficin has been made. From the results the following quantitative structure--activity relationship (QSAR) has been derived: log 1/Km = 0.79 pi'3 + 0.58 sigma + 0.28 MR4,5 + 3.70. In this expression Km is the Michaelis constant, pi'3 refers to the more hydrophobic of the two meta substituents, and MR4,5 is the molar refractivity of substituents in the 4- and 5-positions of the phenyl ring. This QSAR is compared with those from papain, actinidin, bromelain B, and bromelain D.     

Actinidin hydrolysis of substituted-phenyl hippurates: a quantitative structure-activity relationship and graphics comparison with hydrolysis by papain

The hydrolysis of 29 phenyl hippurates (XPhOCOCH2NHC(=O)C6H5) by the cysteine protease actinidin has been studied and a quantitative structure-activity relationship (QSAR) has been formulated: log 1/Km = 0.74 sigma + 0.50 pi'3 + 0.24MR4 + 2.90. In this expression Km is the Michaelis constant, sigma is the Hammett constant, pi'3 is the hydrophobic parameter for the more hydrophobic of the two meta substituents, and MR4 is the molar refractivity of para substituents. The QSAR for actinidin is compared with a similar one obtained for another cysteine plant protease papain. A color stereo computer graphics model constructed from the X-ray crystallographic coordinates of actinidin is compared with those of our previously reported models for papain.     

A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase

An analysis of the inhibition constants of pyrazoles, phenylacetamides, formylbenzylamines, and acetamides acting on liver alcohol dehydrogenase (ADH) yields quantitative structure-activity relationships (QSAR) having a linear dependency on octanol-water partition coefficients (log P). The average coefficient and standard deviation with the log P term for six different QSAR is 0.96 (+/- 0.14). This suggests complete desolvation of the substituents (directly comparable to partitioning into octanol) on binding to the enzyme. Study of a molecular graphics model of ADH constructed from the X-ray crystallographic coordinates shows that the substituents are engulfed in a long hydrophobic channel which is so narrow that water of solvation must be removed from them in the binding process.     

Crystallography, quantitative structure-activity relationships, and molecular graphics in a comparative analysis of the inhibition of dihydrofolate reductase from chicken liver and Lactobacillus casei by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazine s

The inhibition of dihydrofolate reductase from chicken liver and from Lactobacillus casei has been studied with 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines. It was found that for the chicken enzyme, inhibitor potency for 101 triazines was correlated by the following equation: log 1/Kiapp = 0.85 sigma tau' - 1.04 log (beta X 10 sigma tau' + 1) + 0.57 sigma + 6.36. The parameter tau' indicates that for certain substituents, tau = 0. In the case of the L. casei DHFR results, meta and para derivatives could not be included in the same equation. For 38 meta-substituted compounds, it was found that log 1/Kiapp = 0.38 tau'3-0.91 log (beta X 10 tau'3 + 1) + 0.71I + 4.60 and for 32 para-substituted phenyltriazines log 1/Kiapp = 0.44 tau'4-0.65 log (beta tau'4 + 1') - 0.90 upsilon + 0.69I + 4.67. In the L. casei equation, I is an indicator variable for substituents of the type CH2ZC6H4-Y and ZCH2C6H4-Y, where Z = O, NH, S, or Se. The parameter upsilon is Charton's steric parameter, which is similar to Taft's Es. The mathematical models obtained from correlation analysis are compared with stereo color graphics models.     

Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.     

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.     

Interaction of povidone with aromatic compounds. VI: Use of partition coefficients (log Kd) to correlate with log P values and apparent Kd values to express the binding as a function of pH and pKa

The binding of neutral aromatic compounds onto povidone was studied. It was found that the binding depends on the lipophilic character of the compound and that a linear free relationship exists between the logarithm of the partition coefficients of the macromolecular pseudo-two-phase-aqueous phase, and the log partition coefficient of n-octanol-water (log P). For the ionized ligand molecules it was shown that the binding could be expressed in terms of the acid dissociation constant of the solute, Ka, and in terms of two partition coefficients, K1 = HAPVP/HAwater and K2 = APVP/Awater for the nondissociated and dissociated forms, respectively, resulting in the apparent partition coefficient Kdapp = (HAPVP + APVP)/(HAwater + Awater). An expression was derived, permitting one to determine K1 and K2 from measurable quantities. The apparent partition coefficients (Kdapp) were independent of both drug and povidone concentrations, indicating that the modes of povidone compound interactions were essentially invariant over the ranges of systematic variables studied. The method provides a simple means of evaluating ligand-macromolecule interaction as a function of pH of the solvent and pKa of the ligand.     

Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the schiff base applicability domain for skin sensitization

Several recent (1999 onward) publications on skin sensitization to aldehydes and ketones, which can sensitize by covalent binding to skin protein via Schiff base formation, present QSARs based on the Taft sigma parameter to model reactivity and log P to model hydrophobicity. Here, all of the data are reanalyzed together in a stepwise self-consistent way using the parameters log P (octanol/water) and Sigmasigma, the latter being the sum of Taft sigma values for the two groups R and R' in RCOR'. A QSAR is derived: pEC3 = 1.12(+/-0.07) Sigmasigma + 0.42(+/-0.04) log P - 0.62(+/-0.13); n = 16 R(2) = 0.952 R(2)(adj) = 0.945 s = 0.12 F = 129.6, based on mouse local lymph node assay (LLNA) data for 11 aliphatic aldehydes, 1 alpha-ketoester and 4 alpha,beta-diketones. In developing this QSAR, an initial regression equation for a training set of 10 aldehydes was found to predict a test set consisting of the other 6 compounds. The QSAR is found to be well predictive for LLNA data on a series of alpha,gamma-diketones and also correctly predicts the nonsensitizing properties of simple dialkylketones. It is shown to meet all of the criteria of the OECD principles for applicability within regulatory practice. In view of the structural diversity within the sets of compounds considered here, the present findings confirm the view that within the mechanistic applicability domain the differences in sensitization potential are dependent solely on differences in chemical reactivity and partitioning.     

Review in quantitative structure activity relationships on lipoxygenase inhibitors

This paper reviews and evaluates all the published QSAR treatments of LOX inhibitors. This reveals that in almost all cases, the clog P parameter plays an important part in the QSAR relationships. In some cases the steric factors (B(1), B(5) and L) as well as the overall molar refractivity (CMR) or the substitutents molar refractivity (MR) are important. Electronic effects except for the Hammet's constant alpha, are comparatively unimportant. The study shows that log P as calculated from the Clog P program is suitable for this form of QSAR study. Log Po of 2.77-3.76 was found to be ideal, for the biological response.     

Structure-activity relationship of aniline mustards acting against B-16 melanoma in mice

A set of 23 aniline mustards [X-C6H4N(CH2CH2Cl)2] have been tested for their activity against B-16 melanoma in mice. The following quantitative structure-activity relationship (QSAR) correlates the data well: log 1/C = -2.06 sigma - 0.15 pi - 0.13 pi2 + 4.13 (r = 0.936). When this equation is compared with those formulated for aniline mustards acting against leukemia, it is found that log P0 (ideal lipophilicity) is higher for solid tumors. The QSAR brings out the unique activity of phenylalanine aniline mustard.     

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.     

QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides

Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.     

In vitro neurotoxicity study with dorsal root ganglia for acrylamide and its derivatives

Acrylamide and 6 derivatives inhibited neurite growth from rat dorsal root ganglion in culture. The half-maximum inhibition concentration (I50) varied among test compounds, ranging from 0.8 mM for acrylamide and N-hydroxymethylacrylamide to 30 mM for methacrylamide. The value correlated well with the acute oral LD50 for rats, the linear regression equation being I50 = 2.74LD50-6.52 (r = 0.897, P less than 0.05), but did not correlate with in vivo neurotoxicity for mice. Log (1/I50) was a linear function of the rate constant with glutathione (K), i.e. log (1/I50) = 0.828logK + 0.056 (r = 0.938, P less than 0.05).