QSAR for the cytotoxicity of 2-alkyl or 2,6-dialkyl, 4-X-phenols: the nature of the radical reaction

In a continuation of studies on the radical mediated toxicity of phenols to leukemia cells, a set of di- and tri- substituted phenols with mostly alkyl substituents in the ortho position were examined. These analogs are similar in structure to the commercial antioxidants BHA and BHT. A QSAR analysis of their growth inhibitory constants led to the formulation of this simple but unusual equation based on 18 congeners:ES-2 is the Taft steric parameter for the larger of the two ortho substituents while ER is Otsu's radical parameter, which was originally defined to correlate radical reactions.

[1]  W. Jones,et al.  A Study of Free Energy Relationships in Hindered Phenols. Linear Dependence for Solvation Effects in Ionization , 2002 .

[2]  E. Müller,et al.  III. Mitteil. über Sauerstoffradikale: Ein weiteres, stabiles Sauerstoffradikal, das 4-Methoxy-2.6-di-tert.-butyl-phenoxyl-(1) , 1955 .

[3]  T. Iyanagi,et al.  One-electron-transfer reactions in biochemical systems. II. The reaction of free radicals formed in the enzymic oxidation. , 1969, Biochimica et biophysica acta.

[4]  O. Takahashi,et al.  Dose--response study of hemorrhagic death by dietary butylated hydroxytoluene (BHT) in male rats. , 1978, Toxicology and applied pharmacology.

[5]  H. Stich,et al.  The beneficial and hazardous effects of simple phenolic compounds. , 1991, Mutation research.

[6]  E. Nera,et al.  A carcinogenesis reversibility study of the effects of butylated hydroxyanisole on the forestomach and urinary bladder in male Fischer 344 rats. , 1988, Toxicology.

[7]  S. Sakai,et al.  Factors Influencing the Antioxidant Activities of Phenols by an Ab Initio Study , 1993 .

[8]  Christopher S. Foote,et al.  CHEMISTRY OF SINGLET OXYGEN—XXVI. PHOTOOXYGENATION OF PHENOLSy † , 1978 .

[9]  T. Brinck,et al.  A Computational Analysis of Substituent Effects on the O-H Bond Dissociation Energy in Phenols: Polar Versus Radical Effects , 1997 .

[10]  T W Schultz,et al.  Development of quantitative structure-activity relationships for the toxicity of aromatic compounds to Tetrahymena pyriformis: comparative assessment of the methodologies. , 2001, Chemical research in toxicology.

[11]  J. M. Simoes,et al.  Energetics of the O–H Bond in Phenol and Substituted Phenols: A Critical Evaluation of Literature Data , 1998 .

[12]  C. Hansch,et al.  Radical toxicity of phenols: A reference point for obtaining perspective in the formulation of QSAR , 2001, Medicinal research reviews.

[13]  M. Nair,et al.  Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system. , 1998, Free radical biology & medicine.

[14]  S. Fukushima,et al.  Carcinogenicity of butylated hydroxyanisole in F344 rats. , 1983, Journal of the National Cancer Institute.

[15]  J. Fowler,et al.  Reaction of hindered phenols with diazomethane , 1968 .

[16]  Corwin Hansch,et al.  Comparative QSAR: Radical Reactions of Benzene Derivatives in Chemistry and Biology. , 1997, Chemical reviews.

[17]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[18]  H. Witschi,et al.  Enhancement of adenoma formation in mouse lung by butylated hydroxytoluene. , 1979, Toxicology and applied pharmacology.

[19]  M. Fujio,et al.  The Substituent Effect. V. NMR Chemical Shifts of Hydrogen-bonding Hydroxyl Proton of Phenols in DMSO , 1975 .

[20]  T. Ito,et al.  The Reactivities of Nuclear-Substituted Phenyl Methacrylates in Radical Copolymerization with Styrene , 1968 .

[21]  H. Egli,et al.  Die Acidität substituierter Phenole und Thiophenole , 1934 .

[22]  E. Furimsky,et al.  Arrhenius Parameters for Reaction of tert-Butylperoxy Radicals with some Hindered Phenols and Aromatic Amines , 1973 .

[23]  Xian‐Man Zhang,et al.  Assessment of the Importance of Changes in Ground-State Energies on the Bond Dissociation Enthalpies of the O-H Bonds in Phenols and the S-H Bonds in Thiophenols , 1994 .

[24]  J. Kleinjans,et al.  Butylated hydroxyanisole in perspective. , 1991, Chemico-biological interactions.

[25]  D. Stefanidis,et al.  Equilibrium and kinetic acidities of benzylic ketones. Application of the Marcus equation to the deprotonation of carbon acids , 1988 .

[26]  C. Hansch,et al.  Phenol toxicity in leukemia cells: a radical process? , 1998, Chemico-biological interactions.

[27]  G. Veith,et al.  Rules for distinguishing toxicants that cause type I and type II narcosis syndromes. , 1990, Environmental health perspectives.

[28]  Rajni Garg,et al.  Comparative QSAR: On the Toxicology of the Phenolic OH Moiety , 2001, Critical reviews in toxicology.

[29]  James S. Wright,et al.  Theoretical Calculation of Substituent Effects on the O−H Bond Strength of Phenolic Antioxidants Related to Vitamin E , 1997 .

[30]  M. Cronin,et al.  Validation of Vibrio fisheri acute toxicity data: mechanism of action-based QSARs for non-polar narcotics and polar narcotic phenols. , 1997, The Science of the total environment.

[31]  X. Creary,et al.  Methylenecyclopropane rearrangement as a probe for free radical substituent effects. .sigma..bul. Values for commonly encountered conjugating and organometallic groups , 1987 .

[32]  M. Gray,et al.  Sensitive determination of cell number using the CyQUANT cell proliferation assay. , 2001, Journal of immunological methods.