Journal of Computer-Aided Molecular Design

, Volume 24, Issue 12, pp 961–970 | Cite as

Prodrugs of aza nucleosides based on proton transfer reaction

Article

Abstract

DFT calculation results for intramolecular proton transfer reactions in Kirby’s enzyme models 17 reveal that the reaction rate is quite responsive to geometric disposition, especially to distance between the two reactive centers, rGM, and the angle of attack, α (the hydrogen bonding angle). Hence, the study on the systems reported herein could provide a good basis for designing aza nucleoside prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1ProD is predicted to be about 1010 times faster than that for prodrug 7ProD and about 104 times faster than prodrug 3ProD: rate1ProD > rate3ProD > rate7ProD. Hence, the rate by which the prodrug releases the aza nucleoside drug can be determined according to the structural features of the linker (Kirby’s enzyme model).

Keywords

Aza nucleosides prodrugs Decitabine prodrugs DFT calculations Proton transfer reaction Kirby’s enzyme model Effective molarity (EM) 

Notes

Acknowledgments

The Karaman Co. and the German-Palestinian-Israeli fund agency are thanked for support of our computational facilities. Special thanks are given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance.

Supplementary material

10822_2010_9389_MOESM1_ESM.doc (100 kb)
Xyz Cartesian coordinates for the calculated GM and TS optimized structures in processes 1–7 (DOC 100 kb)

References

  1. 1.
    The Leukemia & Lymphoma Society (2001) Myelodysplastic syndrome. White Plains, NYGoogle Scholar
  2. 2.
    Wijermans P, Lübbert M, Verhoef G et al (2000) Low-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18:956–962Google Scholar
  3. 3.
    Silverman LR, Demakos EP, Peterson BL et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440CrossRefGoogle Scholar
  4. 4.
    Silverman LR, McKenzie DR, Peterson BL et al () Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006(24):3895–3903CrossRefGoogle Scholar
  5. 5.
    Kantarjian H, Issa JP, Rosenfeld CS et al (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803CrossRefGoogle Scholar
  6. 6.
    Blum W, Klisovic RB, Hackanson B et al (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884–3891CrossRefGoogle Scholar
  7. 7.
    Testa B, Mayer J (2003) Hydrolysis in drug and prodrug metabolism—chemistry, biochemistry and enzymology. Wiley, ZurichCrossRefGoogle Scholar
  8. 8.
    Testa B, Mayer JM (2001) Concepts in prodrug design to overcome pharmacokinetic problems. In: Testa B, van de Waterbeemd H, Folkers G, Guy R (eds) Pharmacokinetic optimization in drug research: biological, physiochemical and computational strategies. Wiley, Zurich, pp 85–95CrossRefGoogle Scholar
  9. 9.
    Wang W, Jiang J, Ballard CE, Wang B (1999) Prodrug approaches in the improved delivery of peptide drugs. Curr Pharm Design 5:265–287Google Scholar
  10. 10.
    Karaman R (2008) Analysis of Menger’s spatiotemporal hypothesis. Tet Lett 49:5998–6002CrossRefGoogle Scholar
  11. 11.
    Karaman R (2009) Reevaluation of Bruice’s proximity orientation. Tet Lett 50:452–456CrossRefGoogle Scholar
  12. 12.
    Karaman R (2009) A new mathematical equation relating activation energy to bond angle and distance: a key for understanding the role of acceleration in the lactonization of the trimethyl lock system. Bioorg Chem 37(1):11–25CrossRefGoogle Scholar
  13. 13.
    Karaman R (2009) Accelerations in the lactonization of trimethyl lock systems is due to proximity orientation and not to strain effects. Res Lett Org Chem. doi: 10.1155/2009/240253
  14. 14.
    Karaman R (2009) The effective molarity (EM) puzzle in proton transfer reactions. Bioorg Chem 37:106–110CrossRefGoogle Scholar
  15. 15.
    Karaman R (2009) Cleavage of Menger’s aliphatic amide: a model for peptidase enzyme solely explained by proximity orientation in intramolecular proton transfer. J Mol Struct (Theochem) 910:27–33CrossRefGoogle Scholar
  16. 16.
    Karaman R (2009) The gem-disubstituent effect-computational study that exposes the relevance of existing theoretical models. Tet Lett 50:6083–6087CrossRefGoogle Scholar
  17. 17.
    Karaman R (2010) Affects of substitution on the effective molarity (EM) for five membered ring-closure reactions- a computational approach. J Mol Struct (Theochem) 939:69–74CrossRefGoogle Scholar
  18. 18.
    Karaman R (2009) Analyzing Kirby’s amine olefin—a model for amino-acid ammonia lyases. Tet Lett 50:7304–7309CrossRefGoogle Scholar
  19. 19.
    Karaman R (2010) The effective molarity (EM) puzzle in intramolecular ring-closing reactions. J Mol Struct (Theochem) 940:70–75CrossRefGoogle Scholar
  20. 20.
    Karaman R (2010) The efficiency of proton transfer in Kirby’s enzyme model, a computational approach. Tet Lett 51:2130–2135CrossRefGoogle Scholar
  21. 21.
    Karaman R (2010) A general equation correlating intramolecular rates with “attack” parameters distance and angle. Tet Lett 51:5185–5190CrossRefGoogle Scholar
  22. 22.
    Karaman R (2010) The effective molarity (EM)—a computational approach. Bioorg Chem 38:165–172CrossRefGoogle Scholar
  23. 23.
    Karaman R (2010) Proximity vs. strain in ring-closing reactions of bifunctional chain molecules—a computational approach. J Mol Phys 108:1723–1730CrossRefGoogle Scholar
  24. 24.
    Milstien S, Cohen LA (1970) Concurrent general-acid and general-base catalysis of esterification. J Am Chem Soc 92:4377–4382CrossRefGoogle Scholar
  25. 25.
    Milstien S, Cohen LA (1970) Rate acceleration by stereo population control: models for enzyme action. Proc Natl Acad Sci U S A 67:1143–1147CrossRefGoogle Scholar
  26. 26.
    Milstien S, Cohen LA (1972) Stereopopulation control I. Rate enhancement in the lactonizations of o-hydroxyhydrocinnamic acids. J Am Chem Soc 94:9158–9165CrossRefGoogle Scholar
  27. 27.
    Winans RE, Wilcox CF Jr (1976) Comparison of stereopopulation control with conventional steric effects in lactonization of hydrocoumarinic acids. J Am Chem Soc 98:4281–4285CrossRefGoogle Scholar
  28. 28.
    Dorigo AE, Houk KN (1987) The origin of proximity effects on reactivity: a modified MM2 model for the rates of acid-catalyzed lactonizations of hydroxy acids. J Am Chem Soc 109:3698–3708CrossRefGoogle Scholar
  29. 29.
    Houk KN, Tucker JA, Dorigo AE (1990) Quantitative modeling of proximity effects on organic reactivity. Acc Chem Res 23:107–113CrossRefGoogle Scholar
  30. 30.
    Menger FM (1985) On the source of intramolecular and enzymatic reactivity. Acc Chem Res 18:128–134CrossRefGoogle Scholar
  31. 31.
    Menger FM, Chow JF, Kaiserman H, Vasquez PC (1983) Directionality of proton transfer in solution: three systems of known angularity. J Am Chem Soc 105:4996–5002CrossRefGoogle Scholar
  32. 32.
    Menger FM (1983) Directionality of organic reactions in solution. Tetrahedron 39:1013–1040CrossRefGoogle Scholar
  33. 33.
    Menger FM, Grossman J, Liotta DC (1983) Transition-state pliability in nitrogen-to-nitrogen proton transfer. J Org Chem 48:905–907CrossRefGoogle Scholar
  34. 34.
    Menger FM, Galloway AL, Musaev DG (2003) Relationship between rate and distance. Chem Comm 2370–2371Google Scholar
  35. 35.
    Menger FM (2005) An alternative view of enzyme catalysis. Pure Appl Chem 77:1873–1886CrossRefGoogle Scholar
  36. 36.
    Bruice TC, Pandit UK (1960) The effect of geminal substitution ring size and rotamer distribution on the intramolecular nucleophilic catalysis of the hydrolysis of monophenyl esters of dibasic acids and the solvolysis of the intermediate anhydrides. J Am Chem Soc 82:5858–5865CrossRefGoogle Scholar
  37. 37.
    Bruice TC, Pandit UK (1960) Intramolecular models depicting the kinetic importance of “Fit” in enzymatic catalysis. Proc Natl Acad Sci U S A 46:402–404CrossRefGoogle Scholar
  38. 38.
    Brown RF, Van Gulick NM (1956) The geminal alkyl effect on the rates of ring closure of bromobutylamines. J Org Chem 21:1046–1049CrossRefGoogle Scholar
  39. 39.
    Galli C, Mandolini L (2000) The role of ring strain on the ease of ring closure of bifunctional chain molecules. Eur J Org Chem 3117–3125, and references thereinGoogle Scholar
  40. 40.
    Kirby AJ (1997) Efficiency of proton transfer catalysis in models and enzymes. Acc Chem Res 30:290–296CrossRefGoogle Scholar
  41. 41.
    Brown CJ, Kirby AJ (1997) Efficiency of proton transfer catalysis: intramolecular general acid catalysis of the hydrolysis of dialkyl acetals of benzaldehyde. J Chem Soc Perkin Trans 2:1081–1093Google Scholar
  42. 42.
    Craze GA, Kirby AJ (1974) The role of carboxy-group in intramolecular catalysis of acetal hydrolysis: the hydrolysis of substituted 2-methoxymethoxybenzoic acids. J Chem Soc Perkin Trans 2:61–66Google Scholar
  43. 43.
    Barber SE, Dean KES, Kirby AJ (1999) A mechanism for efficient proton-transfer catalysis: intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid. Can J Chem 77:792–801CrossRefGoogle Scholar
  44. 44.
    Asaad N, Davies JE, Hodgson DRW, Kirby AJ (2005) The search for efficient intramolecular proton transfer from carbon: the kinetically silent intramolecular general base-catalysed elimination reaction of o-phenyl 8-dimethylamino-1-naphthaldoximes. J Phys Org Chem 18:101–109CrossRefGoogle Scholar
  45. 45.
    Kirby AJ, Parkinson A (1994) Most efficient intramolecular general acid catalysis of acetal hydrolysis by the carboxyl group. J Chem Soc Chem Commun 707–708Google Scholar
  46. 46.
    Kirby AJ, Lima MF, de Silva D, Roussev CD, Nome F (2006) Efficient intramolecular general acid catalysis of nucleophilic attack on a phosphodiester. J Am Chem Soc 128:16944–16952CrossRefGoogle Scholar
  47. 47.
    Hartwell E, Hodgson DRW, Kirby AJ (2000) Exploring the limits of efficiency of proton-transfer catalysis in models and enzymes. J Am Chem Soc 122:9326–9327CrossRefGoogle Scholar
  48. 48.
    Kirby AJ, Williams NH (1994) Efficient intramolecular general acid catalysis of enol ether hydrolysis: hydrogen-bonding stabilization of the transition state for proton transfer to carbon. J Chem Soc Perkin Trans 2:643–648Google Scholar
  49. 49.
    Kirby AJ, Williams NH (1991) Efficient intramolecular general acid catalysis of vinyl ether hydrolysis by the neighbouring carboxylic acid group. J Chem Soc Chem Commun 1643–1644Google Scholar
  50. 50.
  51. 51.
    Casewit CJ, Colwell KS, Rappé AK (1992) Application of a universal force field to main group compounds. J Am Chem Soc 114:10046–10053CrossRefGoogle Scholar
  52. 52.
    Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107:3902–3909CrossRefGoogle Scholar
  53. 53.
    Murrell JN, Laidler KJ (1968) Symmetries of activated complexes. Trans Farad Soc 64:371–377CrossRefGoogle Scholar
  54. 54.
    Muller K (1980) Reaction paths on multidimensional energy hypersurfaces. Angew Chem Int Ed Eng 19:1–13CrossRefGoogle Scholar
  55. 55.
    Perrin DD, Dempsey B, Serjeant EP (1981) pKa prediction for organic acids and bases. Champan & Hall, LondonGoogle Scholar
  56. 56.
    The percentage of the ionized and unionized forms was calculated using Henderson-Hasselbach equationGoogle Scholar
  57. 57.
    Kirby AJ (1980) Effective molarities for intramolecular reactions. Adv Phys Org Chem 17:183 and references thereinGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Faculty of PharmacyAl-Quds UniversityJerusalemPalestine

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