Effects of methylation on zebularine studied by density functional theory

Lalitha Selvam1, Vladislav Vasilyev2 and FengWang1

1Centre for Molecular Simulation, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia

2National Computational Infrastructure, Australian National University, Canberra, ACT 0200, Australia

June 22-26, 2009

Outline

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

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

OH

O

OH

NN

O

OH

HH

OH

O

OH

NN

O

OH

HH

NH2

*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

Methylation of zebularine

Zebularine (zeb) 1-β-D-ribofuranosyl-5-methyl-2-pyrimidinone (d5)

C1’

C1’

C2’C3’

C4’

C5’

C6

C5C4

N3

C2

C7

C4

O5’

C5

C6

N3

C2N1

C5’ O4’

C4’

C3’ C2’

O5’

N1

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

O2

O2

O2’O3’O3’

O2’

O4’

GeometryMolecular Properties Zeb d5

Eele + ZPE (Eh) -836.080026 -874.949037

R6(Å) 8.25 8.25

R5(Å) 7.49 7.49

N(1)-C(1’)(Å) 1.45 1.45

C(4)C(5)C(6) (◦) 114.61 116.24

O(5’)C(5’)C(4’) (◦) 111.06 111.23

C(6)N(1)C(2)N(3) (◦) 0.87 0.85

C(2)N(1)C(1’)C(2’) (◦) 114.85 117.05

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’) (◦) 17.33 21.58

µ (D) 6.81 6.75

OH

OH

O

OH

N

N

O

H3C

OH

OH

O

OH

N

N

O

1'2'

3' 4'

2'

3'

123

45

6

5'

2

7

41'

2'3' 4'

2'

3'

12

345

6

5'

4'

2

zeb d5

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

B3LYP/cc-pVTZ

Conformation of sugar

Properties Zeb d5

χ -129.2 (anti) -127.37 (anti)

γ -65.81 -65.10

Pseudorotational angle,dP(deg)

137.07 (south) 131.23 (south)

Puckering amplitude,evmax(

◦)41.24 42.01

v0 -37.21 -39.78

v1 41.50 41.37

v2 -30.20 -27.69

v3 9.60 5.48

v4 17.33 21.58

Type PYR, C1’-exo PYR, C1’-exo

*Sun. G. et. al., J.Chem. Inf. Comput. Sci., 2004, 44, 1752-1762Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)

B3LYP/cc-pVTZ

Hirshfeld charge*

LB94/et-pVQZ

rrr

rd)(

)(

)(ZQ molecule

epromolecul

AA

HirshfeldA

*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)

Condensed Fukui Function*

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

Molecular Electrostatic potential (MEP)

projected on the base plane of C(5)-N(3)-N(1)

zeb d5

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

MEP (contd.)

Cut through sugar plane of C(1’)-O(4’)-C(4’)

zeb d5

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

Valence Ionization Potentials

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

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)

O-k and N-k spectra

LB94/et-pVQZ calculation with an FWHM of 0.40 eV

OH

OH

O

OH

N

N

O

H3C

OH

OH

O

OH

N

N

O

1'2'

3' 4'

2'

3'

123

45

6

5'

2

7

41'

2'3' 4'

2'

3'

12

345

6

5'

4'

2

zeb d5

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

C-k spectra

OH

OH

O

OH

N

N

O

H3C

OH

OH

O

OH

N

N

O

1'2'

3' 4'

2'

3'

123

45

6

5'

2

7

41'

2'3' 4'

2'

3'

12

345

6

5'

4'

2

zeb d5

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

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 – Fouriertransformation of coordinate space wavefunction

MD

HOMO Total = Valence + core

Calculated using HEMS* code developed in Tsinghua university

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

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

lselvam@ict.swin.edu.au

Centre for Molecular SimulationSwinburne University of Techonology, Australia

http://www.ict.swin.edu.au/ictstaff/lselvam