1. Effects of methylation on zebularine studied by density functional theory Lalitha Selvam 1, Vladislav Vasilyev 2 and FengWang 1 1 Centre for Molecular Simulation, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia 2 National Computational Infrastructure, Australian National University, Canberra, ACT 0200, Australia June 22-26, 2009

2. Outline Nucleoside analog - Zebularine Molecular properties in position space - Geometry - Hirshfeld charges - Condensed Fukui analysis Ionization spectra - Valence - Core Momentum distribution Summary Acknowledgements

3. Zebularine or zeb Chemically called as 1-β-D-ribofuranosyl- 2-pyrimidone Cytidine analogue – lacks exocyclic amino group at C5 position Zeb - effective inhibitor of Cytidine deaminase and DNA methyltransferases Acts as an anti-tumor and anti-cancer drug Stability and Minimal toxicity - advantages of zebularine as drug *Holy, A. et. al., Collect. Czech. Chem. Commun. 1985, 50, 393-417 *Driscoll, J.S. et. al., J. Med. Chem. 1991, 34, 3280 cytidine zeb

4. Methylation of zebularine Zebularine (zeb)1-β-D-ribofuranosyl-5-methyl- 2-pyrimidinone (d5) C1’ C2’ C3’ C4’ C5’ C6 C5 C4 N3 C2 C7 C4 O5’ C5 C6 N3 C2 N1 C5’ O4’ C4’ C3’ C2’ O5’ N1 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted) O2 O2’O3’ O2’ O4’

5. Geometry Molecular PropertiesZebd5 E ele + ZPE (E h )-836.080026-874.949037 R6(Å)R6(Å)8.25 R5(Å)R5(Å)7.49 N(1)-C(1’)(Å)1.45  C(4)C(5)C(6) ( ◦ ) 114.61116.24  O(5’)C(5’)C(4’) ( ◦ ) 111.06111.23  C(6)N(1)C(2)N(3) ( ◦ ) 0.870.85  C(2)N(1)C(1’)C(2’) ( ◦ ) 114.85117.05  N(1)C(1’)-O-C(4’) ( ◦ ) -160.81-163.25  C(6)N(1)C(1’)C(2’) ( ◦ ) -66.04-63.44  C(1’)C(2’)C(3’)C(4’) ( ◦ ) -30.2-27.69  C(1’)OC(4’)C(3’) ( ◦ ) 17.3321.58 µ (D)6.816.75 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted) B3LYP/cc-pVTZ

6. Conformation of sugar PropertiesZebd5 χ-129.2 (anti)-127.37 (anti) γ-65.81-65.10 Pseudorotational angle, d P(deg) 137.07 (south)131.23 (south) Puckering amplitude, e v max ( ◦ ) 41.2442.01 v0v0 -37.21-39.78 v1v1 41.5041.37 v2v2 -30.20-27.69 v3v3 9.605.48 v4v4 17.3321.58 TypePYR, C1’-exo *Sun. G. et. al., J.Chem. Inf. Comput. Sci., 2004, 44, 1752-1762 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted) B3LYP/cc-pVTZ

7. Hirshfeld charge* LB94/et-pVQZ *Guerra, C. F. et. al., J Comp. Chem. 2004, 25, 189 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

8. Condensed Fukui Function* LB94/et-pVQZ *Saha, S. et. al., Mol. Simul. 2006, 32, 1261 *Zhu, Q. et. al., J. Synchrotron Radiat. May 2009 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

9. Molecular Electrostatic potential (MEP) projected on the base plane of C(5)-N(3)-N(1) zebd5 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

10. MEP (contd.) Cut through sugar plane of C(1’)-O(4’)-C(4’) zebd5 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

11. Valence Ionization Potentials Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

12. Valence spectra SAOP/et-pVQZ calculation with an FWHM of 0.40 eV Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

13. O-k and N-k spectra LB94/et-pVQZ calculation with an FWHM of 0.40 eV Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

14. C-k spectra Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

15. Momentum distribution (MD) MD – molecular orbital wavefunctions in momentum space Calculation of MD Provides qualitative structural information to understand chemical bonding Wavefunctions from both coordinate space and momentum space - to access information from both sides of the coin. Experimental – Electron Momentum Spectroscopy (EMS) Theoretical – Fourier transformation of coordinate space wavefunction

16. MD HOMOTotal = Valence + core Calculated using HEMS* code developed in Tsinghua university

17. Summary Zebularine and 1-β-D-ribofuranosyl- 5-methyl-2- pyrimidinone – structurally differ in base composition Valence spectra clearly provides a scenario of methyl effect which is more significant in outer valence region than the inner valence MO’s 8, 18 and 37 – primarily dominant methyl related orbital Core shell spectra of O, N and C atoms differentiates the species locally with global red shifts in d5 To understand the inter and intra molecular interactions and will be applied for other nucleosides analogues which are under study

18. Acknowledgements Prof.Feng Wang (Supervisor) Dr.Vladislav Vasilyev, ANU, Australia (3-D pdf) Dr.Quan Zhu and Dr.Saumitra Saha for useful discussions Group members - Fangfang, Aravindhan, Anoja and Yangyang Funding: Swinburne University of Techonology for SUPRA award National Computational Infrastructure (NCI) and Supercomputing facility at Swinburne for computing time

19. lselvam@ict.swin.edu.au Centre for Molecular Simulation Swinburne University of Techonology, Australia http://www.ict.swin.edu.au/ictstaff/lselvam