Synthesis, cytotoxicity, and QSAR analysis of X-thiophenols in rapidly dividing cells.
In this study, the cytotoxicities of a series of X-thiophenols vs rapidly growing mouse leukemia cells in vitro are determined. The resulting ID(50) values are then used to formulate a quantitative structure-activity relationship, which is well-correlated by the Brown variation of the Hammett electronic parameter, sigma-plus (sigma(+) ), such that Log 1/ID(50) = -0.93 (+/-0.18) sigma(+) + 0.86 (+/-0.24) I(H) + 3.99 (+/-0.13). I(H) represents an indicator variable that calls attention to the unusual activity of halogens and pseudohalogens. In lieu of sigma(+), homolytic bond dissociation energies (BDE) are also used successfully to correlate the cellular cytotoxicities of thiophenols. The nature of substituent effects on cellular toxicity is examined, and they reveal that electron-releasing substituted thiophenols such as 4-amino thiophenol and the 4-alkoxy thiophenols are highly cytotoxic and effective at inhibiting cellular proliferation at physiological pH. On the other hand, electron-attracting substituted thiophenols such as the 4-cyano and 4-halogen analogues show a reduced ability to inhibit the cell growth of this cell line. Thus, there is a clear parallel between enhanced biological activity and electron releasing ability as measured by sigma(+) constants or BDE values. The susceptibility of the cellular interaction to electronic effects as delineated by the coefficient with the sigma(+) term (also called the Hammett rho value) is high (-0.96), suggesting that substantial energetic assistance is provided by the substituents and that a weak initiating radical reactant such as superoxide radical may be involved. Previous cytotoxicity studies of a large diverse data set of X-phenols in this cell line and embryo cells have also revealed a more pronounced dependence on sigma(+) and deltaBDE. A comparison of reaction constants obtained from thiophenoxy radical formation reactions and phenoxy radical formation reactions in organic media suggests radical-mediated involvement in cell cytotoxicity. Such cells could be more vulnerable to the effects of reactive thiyl species on their metabolism and subsequent proliferation.
Verma
Rajeshwar P
RP
Department of Chemistry, Pomona College, Claremont, California 91711, USA.
Kapur
Sanjay
S
Barberena
Omar
O
Shusterman
Alan
A
Hansch
Corwin H
CH
Selassie
Cynthia D
CD
D000818:Animals; D004583:Electrons; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D010636:Phenols; D013438:Sulfhydryl Compounds; C042983:thiophenol