Advertisement

Pharmaceutical Research

, Volume 22, Issue 6, pp 875–882 | Cite as

log P Estimation of 1,2-Dithiole-3-thiones and 1,2-Dithiole-3-ones: A Comparison of Experimental and Calculative Approaches

  • Sylvain Gargadennec
  • Gwenola Burgot
  • Jean-Louis Burgot
  • Raimund Mannhold
  • Roelof F. Rekker
Research Paper

Purpose

To estimate experimental log P values of formerly described 5-formyl- and 5-acyl-dithiole-3-thiones (DTT) and -dithiole-3-ones (DTO) and to check the validity of five log P calculation programs via experimental log P for a database of 68 DTT and DTO.

Methods

Experimental log P values were measured by means of octanol/water partitioning; for determining solute concentrations in water, RP-HPLC with spectrophotometric detection was used. For calculating log P, the fragmental methods ACD/log P, CLOGP, and KOWWIN, the atom-based approach XLOGP, and the whole-molecule approach QLOGP were applied.

Results

Quality of calculations significantly differs depending on the subset under consideration. For database compounds 0148, comprising alkyl and aryl substitution in 4- and 5-position, the fragmental methods ACD/log P, CLOGP, and KOWWIN perform significantly better than the atom-based approach XLOGP and the whole-molecule method QLOGP. For database compounds 4968, comprising formyl and acyl substitution in 4- and 5-position, superiority of the whole-molecule method QLOGP over the substructure-based approaches is observed. The strong underestimation of log P for compounds 4968 probably indicates hidden physicochemical phenomena resulting from the juxtaposition of the acyl and dithiole moieties.

Conclusions

All calculation methods included in this study need a thorough refinement to adequately cope with particular solvation behavior suspected to prevail in formyl- or acyl-DTT and DTO, which represent a chemical class of high pharmacological interest.

Key words

1,2-dithiole-3-ones 1,2-dithiole-3-thiones log P calculation octanol/water partitioning 

Notes

Acknowledgments

We thank Dr. Claude Ostermann (Altana Pharma, Konstanz, Germany) for providing us with CLOGP and ACD/log P calculations and Dr. Peter Buchwald (IVAX Research, Miami, FL, USA) for performing QLOGP calculations.

References

  1. 1.
    Sporn, M. B., Suh, N. 2002Opinion: chemoprevention: an essential approach to controlling cancerNat. Rev. Cancer2537543PubMedGoogle Scholar
  2. 2.
    Leroy, J. P., Barreau, M., Cotrel, C., Teanmart, C., Nesser, M., Benazet, F. 1978Laboratory studies of 35972 RP (Oltipraz) a new schistosomicidal compound, Proceedings of the 10th International Congress of ChemotherapyCurr. Chemother.1148151Google Scholar
  3. 3.
    Nho, C. W., O’Dwyer, P. J. 2004NF-κB activation by the chemopreventive dithiolethione oltipraz is exerted through stimulation of MEKK3 signalingJ. Biol. Chem.2792601926027PubMedGoogle Scholar
  4. 4.
    Ansher, S. S., Dolan, P., Bueding, E. 1983Chemoprotective effects of two dithiolethiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicityHepatology3932935PubMedGoogle Scholar
  5. 5.
    Wattenberg, L. W., Bueding, E. 1986Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustardCarcinogenesis713791381PubMedGoogle Scholar
  6. 6.
    Halpern, B. N., Gaudin, O. 1950Etude expérimentale de l’action stimulante du trithioparamethyoxyphenylpropene sur la cellule hépatiqueArch. Int. Pharmacodyn. Ther.834979PubMedGoogle Scholar
  7. 7.
    Lelord, G., Mercat, C., Fuseiller, C. 1969Interêt du trithioparamethoxyphenylpropene (Sulfarlem) dans la prévention des complications salivaires des traitements psychotropesGaz. Med. Fr.7622572261Google Scholar
  8. 8.
    Lam, S., Aulay, C., Riche, J. C., Dyachkova, Y., Coldman, A., Guillaud, M., Hawk, E., Christen, M. O., Gadzar, A. 2002A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasiaJ. Natl. Conc. Inst.9410011009Google Scholar
  9. 9.
    M. O. Christen, B. Laroche, and J. Maugard. Proceedings of the biennal meeting of the Society of Free Radical Research International, 11th. Editor: Pasquier Catherine, Paris, France, July 16–20 (2002).Google Scholar
  10. 10.
    Roebuck, B. D., Curphey, J. J., Li, Y., Baumgartner, K. J., Bodreddigary, S., Yan, J., Gange, S. J., Kensler, T. W., Sutter, T. R. 2003Evaluation of the cancer chemopreventive potency of dithiolethione analogs of oltiprazCarcinogenesis2419191928PubMedGoogle Scholar
  11. 11.
    J. D.Bourzat, C. Cotrel, D. Farge, J. M. Paris, and G.Touraud. Fr.Demande FR2,541,575; C.A. 102,32257e 1985.Google Scholar
  12. 12.
    Bona, M., Boudeville, P., Zekri, O., Christen, M. O., Burgot, J. L. 1995Water/n-octanol partition coefficients of 1,2-dithiole-3-thionesJ. Pharm. Sci.8411071112PubMedGoogle Scholar
  13. 13.
    Boudeville, P., Bona, M., Burgot, J. L. 1996Correlations between n-octanol/water partition coefficients and RP-HPLC capacity factors of 1,2-dithiole-3-thiones and 1,2-dithiole-3-onesJ. Pharm. Sci.85990998PubMedGoogle Scholar
  14. 14.
    Bona, M., Christen, M. O., Burgot, J. L. 1995On the lipophilicity of the dithiolethione nucleusChem. Pharm. Bull.4318941896Google Scholar
  15. 15.
    Pedersen, C. Th. 19951,2-dithiole-3-thiones and 1,2-dithiole-3-onesSulfur Rep.16173221Google Scholar
  16. 16.
    Abazid, M., Bertrand, H. O., Christen, M. O., Burgot, J. L. 1994A general synthesis of new dithiolethione derivatives: 5-(1-hydroxyimino alkyl)-1,2-dithiole-3-thiones and 5-acyl-1,2-dithiole-3-thionesPhosphorus, Sulphur and Silicon88195206Google Scholar
  17. 17.
    M. Abazid. In “Fonctionnalisation de 1,2- dithiole-3-thiones et synthèse de nouvelles 1,2-dithiole-3-thiones.” Thèse d’Université, RennesI, 1990.Google Scholar
  18. 18.
    Gargadennec, S., Legouin, B., Burgot, J. L. 2003Synthesis of 5-formyl and 5-acyl-1,2-dithiole-3-onesPhosphorus, Sulfur and Silicon17817211726Google Scholar
  19. 19.
    M. O. Christen and J. L. Burgot. PCT Int. Appl. WO9219, 613; C.A.118,124522w (1993).Google Scholar
  20. 20.
    Mannhold, R., Dross, K. 1996Calculation procedures for molecular lipophilicity: a comparative studyQuant. Struct.-Act. Relat.15403409Google Scholar
  21. 21.
    Mannhold, R., Waterbeemd, H. 2001Substructure and whole molecule approaches for calculating log PJ. Comp.-Aid. Mol. Design15337354Google Scholar
  22. 22.
    Petrauskas, A. A., Kolovanov, E. A. 2000ACD/LogP method descriptionPerspect. Drug Discov. Des.1999116Google Scholar
  23. 23.
    A. A. Petrauskas and E. A. Kolovanov. ACD Approaches For PHYS-Chem Data Prediction. 13th Eur. Symp. Quant. Struct.Act. Relat., abstr. book P. 4, Düsseldorf (2000).Google Scholar
  24. 24.
    Leo, A. J. 1987Some advantages of calculating octanol-water partition coefficientsJ. Pharm. Sci.76166168PubMedGoogle Scholar
  25. 25.
    Leo, A. J. 1991Hydrophobic parameter: measurement and calculationMethods Enzymol.202544591PubMedGoogle Scholar
  26. 26.
    Leo, A. J. 1993Calculating logPoct from structureChem. Rev.9312811306Google Scholar
  27. 27.
    Hansch, C.Leo, A. J.Hoekman, D. eds. 1995Exploring QSAR; Hydrophobic, Electronic and Steric ConstantsACS Professional Reference BookWashington, DCGoogle Scholar
  28. 28.
    Meylan, W. M., Howard, P. H. 1995Atom/fragment contribution method for estimating octanol-water partition coefficientsJ. Pharm. Sci.848392PubMedGoogle Scholar
  29. 29.
    Wang, R., Fu, Y., Lai, L. 1999A new atom-additive method for calculating partition coefficientsJ. Chem. Inf. Comp. Sci.39868873Google Scholar
  30. 30.
    Wang, R., Gao, Y., Lai, L. 2000Calculating partition coefficient by atom-additive methodPerspect. Drug Discov. Des.194766Google Scholar
  31. 31.
    Bodor, N., Buchwald, P. 1997Molecular size based approach to estimate partition properties for organic solutesJ. Phys. Chem. B10134043412Google Scholar
  32. 32.
    Rekker, R. F. 1977The Hydrophobic Fragmental ConstantElsevier Scientific Publication CompanyAmsterdam1015Google Scholar
  33. 33.
    Burgot, G., Burgot, J. L. 1984Determination simultanée de l’enthalpie, de l’enthalpie libre via le coefficient de partage et de l’entropie de transfert eau / n-octanol de l’éphedrine par titrimétrie thermométriqueThermochim. Acta.81147156Google Scholar
  34. 34.
    Chollet-Krugler, M., Legouin, B., Gargadennec, S., Burgot, G., Burgot, J. L. 2004Thermodynamic investigation of the water/n-octanol partition coefficient value of a 5-formyl-1,2-dithiole-3-thioneThermochim. Acta.424143147Google Scholar
  35. 35.
    N. Lozac’h and J. Vialle. The Chemistry of Organic Sulfur Compounds, Pergamon Press, Oxford, 1966, 2, pp. 257–285.Google Scholar
  36. 36.
    Chollet-Krugler, M., Botrel, A., Charbit, J. J., Barbe, J., Burgot, J.-L. 2000Efficiency of the MNDO-PM3 method to describe the geometric and electronic structure of 1,2-dithiole-3-thiones and 1,2-dithiole-3-onesPhosphorus, Sulfur and Silicon1662744Google Scholar
  37. 37.
    Noto, R., D’Anna, F., Gruttadourie, M., Meo, P., Spinelli, D. 2001Protonation equilibria of some ortho-substituted and annelated aryl and thiophen-2-yl and -3-yl ketonesJ. Chem. Soc. Perkin Trans.220432046Google Scholar
  38. 38.
    Chollet, M., Legouin, B., Burgot, J. L. 1998Assessment of the substituent constants of the 3-thioxo-1,2-dithiol-4-and -5-yl groups through pKa values measurements of 4 and 5-(hydroxy-or amino-phenyl)-1,2-dithiole-3-thiones in water at 298KJ. Chem. Soc. Perkin Trans.222272231Google Scholar
  39. 39.
    Chollet, M., Burgot, J. L. 1998pKa values of 3-thioxo-1,2-dithiole-4- and -5-carboxylic acids and of 3-oxo-1,2-dithiole-4-and -5-carboxylic acids in aqueous solution at 298KJ. Chem. Soc. Perkin Trans.2387391Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Sylvain Gargadennec
    • 1
  • Gwenola Burgot
    • 1
  • Jean-Louis Burgot
    • 1
  • Raimund Mannhold
    • 2
  • Roelof F. Rekker
    • 3
  1. 1.Laboratoire de Chimie Analytique, Upres EA 2231, Faculté des Sciences Pharmaceutiques et BiologiquesUniversité de Rennes 1Rennes cedexFrance
  2. 2.Department of Laser Medicine, Molecular Drug Research GroupHeinrich-Heine-Universität, Universitätsstr. 1DüsseldorfGermany
  3. 3.1065 BB AmsterdamThe Netherlands

Personalised recommendations