Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1990 Nov;116(6):615–622. doi: 10.1007/BF01637083

Structural requirements for inhibitors of poly(ADP-ribose) Polymerase

P Sestili 1, G Spadoni 2, C Balsamini 2, I Scovassi 3, F Cattabeni 1, E Duranti 2, O Cantoni 3,✉, D Higgins 5, C Thomson 5
PMCID: PMC12200768  PMID: 2123880

Abstract

The purpose of this study was to examine the structure/activity relationships of a series of substituted benzamides as poly(ADP-ribose) polymerase inhibitors. The experimental approach has involved the use of in vitro and in vivo assays in order to gather information either on the intrinsic activity of the benzamides or on the effect of various pharmacodynamic parameters on the activity in vivo. Although some discrepancies between the data obtained in vivo and in vitro were found in this study, results seem to indicate that most powerful inhibitors were characterized by acylation of the -NH2 function in the 3 position or by substitution in this same position with hydroxy or methoxy groups. The best inhibitors were not cytotoxic under these experimental conditions. Computed calculations of molecular electrostatic potential of these molecules were also performed and a good correlation was found between the similarity index and the experimental inhibitory activity.

Key words: Poly(ADP-ribose) polymerase, Inhibitors, Benzamide

Abbreviations

ADP-Rib polymerase

poly(ADP-ribose) polymerase

SSF

strand scission factor

MEP

molecular electrostatic potential

References

  1. Bogert MT, Beans HT (1904) Metaminobenzonitrile and some of its derivatives. J Am Chem Soc 26:476–482 [Google Scholar]
  2. Bollum FJ (1966) In: Cantoni GL, Davies DR (eds) Procedures in nucleic acids research Harper and Row, New York, p 296 [Google Scholar]
  3. Bonaccorsi R, Scrocco E, Tomasi J (1970) Theoretical section progress report 1969/1970. Laboratorio di Chimica Quantistica ed Energetica Molecolare del C.N.R. ed Instituto di ChimicaFisica del' Università di Pisa, Pisa, Italy, pp 35–39 [Google Scholar]
  4. Bonaccorsi R, Pullman A, Scrocco E, Tomasi J (1972a) The molecular electrostatic potentials for the nucleic acid bases: adenine, thymine and cytosine. Theor Chim Acta 4:51–60 [Google Scholar]
  5. Bonaccorsi R, Petrongolo C, Scrocco E, Tomasi J (1972b) Theoretical investigations on the solvation process. Theor Chim Acta 20:331–342 [Google Scholar]
  6. Bowen-Jenkins PE, Richards WG (1986) Quantitative measures of similarity between pharmacologically active compounds. Int J Quant Chem 30:764–768 [Google Scholar]
  7. Bray HG, Ryman BE (1948) Fate of certain organic acids in the rabbit. 0- and m-hydroxybenzoic acids and amides. Biochem J 43:568–572 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Campaigne E, Le Suer WH (1948) 3-Substituted thiophenes. J Am Chem Soc 70:1555–1558 [DOI] [PubMed] [Google Scholar]
  9. Cantoni O, Murray D, Meyn RE (1986a) Effect of 3-aminobenzamide on DNA-strand-break rejoining and cytotoxicity in CHO cells treated with hydrogen peroxide. Biochim Biophys Acta 867:135–143 [DOI] [PubMed] [Google Scholar]
  10. Cantoni O, Peruzzi G, Cattabeni F (1986b) A method for disposing lysates from cells analyzed for DNA damage by filter elution assay. J Biochem Biophys Methods 12:363–364 [DOI] [PubMed] [Google Scholar]
  11. Carbo R, Leyda L, Arnau M (1980) How similar is a molecule to another? An electronic density measure of similarity between two molecular structures. Int J Quant Chem 17:1185–1189 [Google Scholar]
  12. Connolly ML (1981) MS molecular surface program. Announced in QCPE Bull 1:75 [Google Scholar]
  13. Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 7:3902–3909. [Google Scholar]
  14. Gaal JC, Pearson CK (1985) Eukariotic nuclear ADP-ribosylation reactions. Biochem J 230:1–18 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Higgins D (1988) Theoretical calculations on large molecules: development of new techniques and the study of enzyme inhibitors. Ph.D. thesis, University of St. Andrews
  16. Hunting DJ, Gowans BJ, Henderson JF (1985) Specificity of inhibitors of poly(ADP-ribose) synthesis: effects on nucleotide metabolism in cultured cells. Mol Pharmacol 28:200–206 [PubMed] [Google Scholar]
  17. Iwasa I, Fujita T, Hasch C (1965) Substituents constants for aliphatic functions obtained from partition coefficients. J Med Chem 8:150–154 [DOI] [PubMed] [Google Scholar]
  18. Jacobs WE, Heidelberger M (1917) Methods for acylation of aromatic amino compounds and ureas with a special reference to chloroacetylation. J Am Chem Soc 39:1442–1447 [Google Scholar]
  19. James MR, Lehmann AR (1982) Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry 21:4007–4013 [DOI] [PubMed] [Google Scholar]
  20. Kohn KW, Ewig RAG, Erickson LC, Zwelling LC (1981) Measurement of strand breaks and cross-links by alkaline elutiuon. In: Friedberg E, Hanawalt P (eds) DNA repair: a laboratory manual of research procedures. Dekker, New York, pp 379–401 [Google Scholar]
  21. Milam KM, Cleaver JE (1984) Inhibitors of poly(adenosine diphosphate-ribose) synthesis: effect on other metabolic processes. Science 223:589–591 [DOI] [PubMed] [Google Scholar]
  22. Ohashi Y, Ueda K, Hayaishi O, Ikai K, Niwa O (1985) Induction of murine teratocarcinoma cell differentiation by suppression of poly(ADP-ribose) synthesis. Proc Natl Acad Sci USA 81:7132–7136 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Purnell RM, Whish WD (1980) Novel inhibitors of poly(ADP-ribose) synthetase. Biochem J 178:775–777 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Purnell RM, Kidwell WR, Minshall L, Whish WD (1985) Specificity of poly/ADP-ribose) synthetase inhibitors. In:Althaus FR, Hilz H, Shall S (eds) ADP-ribosylation of proteins. Springer, Berlin Heidelberg New York, pp 98–105 [Google Scholar]
  25. Rankin PW, Jacobson EL, Benjamin RC, Moss J, Jacobson MK (1989) Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 264:4312–4317 [PubMed] [Google Scholar]
  26. Shall S (1984) Inhibition of DNA repair by inhibitors of nuclear ADP-ribosyl transferase. In Collins A, Downes ML, Johnson RT (eds) DNA repair and its inhibition. IRL Press, Oxford, pp 143–191 [PubMed] [Google Scholar]
  27. Sims JL, Sikorski GW, Catino DM, Berger SJ, Berger NA (1982) Poly(adenosinediphosphoribose) polymerase inhibitors stimulate unscheduled deoxyribonucleic acid synthesis in normal human lymphocytes. Biochemistry 21:1813–1821 [DOI] [PubMed] [Google Scholar]
  28. Smulson ME, Hough C, Kasid U, Dritschilo A, Lubet R (1985) In: Althaus, FR, Hilz H, Shall S (eds) ADP-ribosylation of proteins. Springer, Berlin Heidelberg New York, pp 207–216 [Google Scholar]
  29. Stewart JJP (1985) MOPAC program package. Announced in QCPE Bull 5:133 [Google Scholar]
  30. Sugimura T, Miwa M (1983) Poly(ADP-ribose)transferase and cancer research. Carcinogenesis 4:1503–1506 [DOI] [PubMed] [Google Scholar]
  31. Thomson C, Higgins D, Edge C (1988) Theoretical studies of the electrostatic potential of some enzyme inhibitors using computer graphics techniques. J Mol Graphics 6:171–177 [Google Scholar]
  32. Weinstein H, Osman R, Green JP, Topiol S (1981) In: Politzer P, Truhlar DG (eds) Chemical applications of atomic and molecular electrostatic potentials. Plenum Press, New York [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES