Conformation of Gemcitabine: An Experimental NMR and Theoretical DFT Study

Document Type : Article

Authors

Department of chemistry, Sharif University of Technology, Tehran, Iran P.O.Box 11365-9516

Abstract

The structural and conformational behavior of gemcitabine (2’, 2’-difluoro cytidine) was investigated by advanced NMR experiments and computational quantum mechanical method (DFT) using potential energy scanning (PES) in gas and solution phases at polarizable continuum model (PCM). Three stable conformers (G1, G2 and G3) were predicted from minimum points in potential energy diagram. In order to measure coupling constant values, a set of 2D spectra (H-H COSY, H-C HMQC and H-C HMBC) were analyzed. Optimized structures and spin-spin coupling constant calculations in gas and solution phases were performed by B3LYP/6-311++G(d,p) method. Both energy and NMR parameters showed that G1-form is more stable than other conformers. For coupling constant analysis, Karplus equations for 1JC-H, 2JC-H, and 3JC-Hwere derived. Also, solvent effect investigation performed and results showed both inter- and intra-molecular interactions affect stability of G1 conformer.
 

Keywords

Main Subjects


References
1. Nguyen, H.V., Sallustrau, A., Balzarini, J., Bedford,
M.R., Eden, J.C., Georgousi, N., Hodges, N.J., Kedge,
J., Mehellou, Y., Tselepis, C. and Tucker, J.H.R.
Organometallic nucleoside analogues with ferrocenyl
S. Chashmniam and M. Tafazzoli/Scientia Iranica, Transactions C: Chemistry and ... 25 (2018) 1354{1363 1361
linker groups: Synthesis and cancer cell line studies",
J. Med. Chem., 57, pp. 5817-5822 (2014).
2. Serpi, M., Ferrari, V., and Pertusati, F. Nucleoside
derived antibiotics to ght microbial drug resistance:
New utilities for an established class of drugs", J. Med.
Chem., 59, pp. 10343-10382 (2016).
3. Dracinsky, M. and Pohl, R. Determination of
the nucleic acid adducts structure at the nucleoside/
nucleotide level by NMR spectroscopy", Chem.
Res. Toxicol., 28, pp. 155-165 (2015).
4. Butora, G., Kenski, D.M., Cooper, A.J., Fu, W., Qi,
N., Li, J.J., Flanagan, W.M., and Davies, I.W. Nucleoside
optimization for RNAi: A high throughput
platform", J. Am. Chem. Soc., 133, pp. 16766-16769
(2011).
5. Zhang, W., Ntai, I., Bolla, M.L., Malcolmson, S.J.,
Kahne, D., Kelleher, N.L., and Walsh C.T. Nine
enzymes are required for assembly of the pacidamycin
group of peptidyl nucleoside antibiotics", J. Am.
Chem. Soc., 133, pp. 5240-5243 (2011).
6. Wu, R., Gong, W., Liu, T., Zhang, Y., and Cao, Z.
QM/MM molecular dynamics study of purine-speci c
nucleoside hydrolase", J. Phys. Chem. B., 116, pp.
1984-1991 (2012).
7. Slusarczyk, M., Lopez, M.H., Balzarini, J., Mason, M.,
Jiang, W.G., Blagden, S., Thompson, E., Ghazaly E.,
and McGuigan, C. Application of proTide technology
to gemcitabine: A successful approach to overcome the
key cancer resistance mechanisms leads to a new agent
(NUC-1031) in clinical development", J. Med. Chem.,
57, pp. 1531-1542 (2014).
8. Fan, M., Liang, X., Li, Z., Wang, H., Yang, D.,
and Shi, B. Chlorambucil gemcitabine conjugate
nanomedicine for cancer therapy", J. Pharm. Sci., 79,
pp. 20-26 (2015).
9. Moysan, E., Bastiat G., and Benoit, J.P. Gemcitabine
versus modi ed gemcitabine: A review of several
promising chemical modi cations", Mol. Pharmaceutics.,
10, pp. 430-444 (2013).
10. Cavalcante, L.S. and Monteiro, G. Gemcitabine:
metabolism and molecular mechanisms of action, sensitivity
and chemoresistance in pancreatic cancer", Eur.
J. Pharmacol., 741, pp. 8-16 (2014).
11. Valle, J., Wasan, H., Palmer, D.H., Cunningham,
D., Anthoney, A., Maraveyas, A., Madhusudan, S.,
Iveson, T., Hughes, S., Pereira, S. P., Roughton, M.,
and Bridgewater, J. Cisplatin plus gemcitabine versus
gemcitabine for biliary tract cancer", N. Eng.l. J.
Med., 362, pp. 1273-81 (2010).
12. Jiang, X., Li, J., Zhang, R., Zhu, Y., and Shen, J.
An improved preparation process for gemcitabine",
Organic Process Research & Development, 12, pp. 888-
891 (2008).
13. Moysan, E., Bastiat, G., and Benoit, J.P. Gemcitabine
versus modi ed gemcitabine: A review of
several promising chemical modi cations", Mol. Pharmaceutics.,
10, pp. 430-444 (2013).
14. Weiss, J.T., Dawson, J.C., Fraser, C., Rybski, W.,
Torres-Sanchez, C., Bradley, M., Patton E.E., Carragher,
N.O., and Unciti-Broceta, A. Development
and bioorthogonal activation of palladium-labile prodrugs
of gemcitabine", J. Med. Chem., 57, pp. 5395-
5404 (2014).
15. Wang, Y., Fan, W., Dai, X., Katragadda, U., Mckinley,
D., Teng, Q., and Tan, C. Enhanced tumor delivery of
gemcitabine via PEG-DSPE/TPGS mixed micelles",
Mol. Pharmaceutics, 11, pp. 1140-1150 (2014).
16. Zhang, Z., Duan, Q., Zhao, H., Liu, T., Wu, H.,
Shen, Q., Wang, C., and Yin, T. Gemcitabine treatment
promotes pancreatic cancer stemness through the
Nox/ROS/NF-B/STAT3 signaling cascade", Cancer
Letters, 382, pp. 53-63 (2016).
17. Brown, K., Wilson, A.W., and Linclau, B. A linear
synthesis of gemcitabine", Carbohydr. Res., 406, pp.
71-75 (2015).
18. Gowda, P.A.S., Polizzi, J.M., Eckert, K.A., and
Spratt, T.E. Incorporation of gemcitabine and cytarabine
into DNA by DNA polymerase and ligase
III/XRCC1", Biochemistry, 49, pp. 4833-4840 (2010).
19. Dasari, M., Acharya, A.P., Kim, D., Lee, S., Rhea, J.,
Molinaro, R., and Murthy, N. H-gemcitabine: A new
gemcitabine prodrug for treating cancer", Bioconjugate
Chem., 24, pp. 4-8 (2013).
20. Kang, H., Kim, C., Kim, D., Song, J.H., Choi, M.,
Choi, K., Kang, M., Lee, K., Kim, H.S., Shin, J.S.,
Kim, J., Han, S.B., Lee, M.Y., Lee, S.U., Lee, C.K.,
Kim, M., Ko, H.J., Kuppeveld, F.J.M., and Cho,
S. Synergistic antiviral activity of gemcitabine and
ribavirin against enteroviruses", Antiviral Res., 124,
pp. 1-10 (2015).
21. Hricovni, M. Solution structure of heparin pentasaccharide:
NMR and DFT analysis", J. Phys. Chem. B.,
119, pp. 12397-12409 (2015).
22. Dorotkova, S. Plevova, K., Bucinsky, L., Malcek, M.,
Herich, P., Kuckova, L., Bobeniccova, M., Soralova,
S., Koz_Isek, J., Fronc, M., Milata, V. and Dvoranova,
D. Conformational, spectroscopic, and molecular dynamics
DFT study of precursors for new potential
antibacterial
uoroquinolone drugs", J. Phys. Chem.
A., 118, pp. 9540-9551 (2014).
23. Tosso, R.D., Zamora, M.A., Suvire, F.D., and Enriz,
R.D. Ab initio and DFT study of the conformational
energy hypersurface of cyclic Gly-Gly-Gly", J. Phys.
Chem. A., 113, pp. 10818-10825 (2009).
24. Vargas, R., Garza, J., Hay, B.P., and Dixon, D.A.
Conformational study of the alanine dipeptide at the
MP2 and DFT Levels", J. Phys. Chem. A., 106, pp.
3213-3218 (2002).
25. Wang, L., Kefalidis, C.E., Roisnel, T., Sinbandhit,
S., Maron, L., Carpentier, J.F., and Sarazin, Y.
Structure vs 119Sn NMR chemical shift in threecoordinated
tin (II) complexes: Experimental data and
predictive DFT computations", Organometallics, 34,
pp. 2139-2150 (2015).
1362 S. Chashmniam and M. Tafazzoli/Scientia Iranica, Transactions C: Chemistry and ... 25 (2018) 1354{1363
26. Blonski, P., Birczynski, A., Lalowicz, Z.T., Datka, J.
and Lodziana, Z. Structure of the hydroxyl groups
and adsorbed D2O sites in the DX zeolite: DFT and
experimental NMR data", J. Phys. Chem. C., 119, pp.
19548-19557 (2015).
27. Latosinska, N.J., Latosinska, M. and
Tomczak, M.A. Conformational stability and
thermal pathways of relaxation in triclosan
(antibacterial/excipient/contaminant) in solidstate:
Combined spectroscopic (1H NMR) and
computational (periodic DFT) study", J. Phys.
Chem. A., 119, pp. 4864-4874 (2015).
28. Vijay, R., Mandal, A.B., and Baskar, G. 1H NMR
spectroscopic investigations on the conformation of
amphiphilic aromatic amino acid derivatives in solution:
E ect of chemical architecture of amphiphiles
and polarity of solvent medium", J. Phys. Chem. B.,
114, pp. 13691-13702 (2010).
29. Shainyan, B.A., Kirpichenko, S.V., Shlykov, S.A., and
Kleinpeter, E. Structure and conformational properties
of 1,3,3-trimethyl-1, 3-azasilinane: Gas electron
di raction, dynamic NMR, and theoretical study", J.
Phys. Chem. A., 116, pp. 784-789 (2012).
30. Krishnan, R., Rakhi, A.M., and Gopidas, K.R. Study
of -Cyclodextrin{Pyromellitic diimide complexation.
conformational analysis of binary and ternary complex
structures by induced circular dichroism and 2D NMR
spectroscopies", J. Phys. Chem. C., 116, pp. 25004-
25014 (2012).
31. Sun, P., Xu, D., Mandi, A., Kurtan, A., Li, T., Schulz,
B., and Zhang, W. Structure, absolute con guration,
and conformational study of 12- membered macrolides
from the fungus dendrodochium sp. associated with
the sea cucumber holothuria nobilis selenka", J. Org.
Chem., 78, pp. 7030-7047 (2013).
32. Hong. M., Mishanina, T.V., and Cady, S.D. Accurate
measurement of methyl 13C chemical shifts by solidstate
NMR for the determination of protein sidechain
conformation: the in
uenza M2 transmembrane peptide
as an example", J. Am. Chem. Soc., 131, pp.
7806-7816 (2009).
33. Trujillo, P.M., Nolis, P., and Parella, T. CN-HMBC:
A powerful NMR technique for the simultaneous detection
of long-range 1H, 13C and 1H, 15N connectivities",
Org. Lett., 9, pp. 29-32 (2007).
34. Marek, R., Marek, J., Dostal, J., Taborska, E.,
Slav_Ik, J., and Dommisse, R. Structural studies
of benzophenanthridine alkaloid free bases by NMR
spectroscopy", Magn. Reson. Chem., 40, pp. 147-152
(2002).
35. Shainyan, B.A., Suslova, E.N., and Kleinpeter, E.
Conformational analysis of 4,4-dimethyl-4-silathiane
and its S-oxides", J. Phys. Org. Chem., 24, pp. 1188-
1192 (2011).
36. Svetlana V., Kirpichenko, S.V., Kleinpeter, E.,
Ushakov, I.A., and Shainyan, B.A. Conformational
analysis of 3-methyl-3-silathiane and 3-
uoro-
3-methyl-3-Silathiane", J. Phys. Org. Chem., 24, pp.
320-326 (2011).
37. Pihlaja, K., Tahtinen, P., Klika, K.D., Jokela, T.,
Salakka, A. and Wahala, K. Experimental and DFT
1H NMR study of conformational equilibria in trans-
4,7-dihydroxyiso
avan-4-ol and trans-Iso
avan-4-ol",
J. Org. Chem., 68, pp. 6864-6869 (2003).
38. Chashmniam, S. and Tafazzoli, M. NMR investigation
and theoretical calculations of the solvent e ect
on the Conformation of valsartan", J. Mol. Struct.,
1148, pp. 73-80 (2017).
39. Chashmniam, S. and Tafazzoli, M. Conformation of
repaglinide: A solvent dependent structure", J. Mol.
Struct., 1143, pp. 388-396 (2017).
40. Bagno, A., Casella, G., Ferrante, F. and Saielli,
G. A DFT study of the vicinal 3J(119Sn,13C) and
3J(119Sn,1H) coupling constants in trimethyl- and
chlorodimethylstannyl propanoates", J. Organomet.
Chem., 724, pp. 139-146 (2013).
41. Dewberry, C.T., Hu , A.K., Mackenzie, R.B., and
Leopold, K.R. Microwave spectrum, van der Waals
bond length, and 131Xe quadrupole coupling constant
of Xe-SO3", J. Mol. Spectrosc., 304, pp. 43-46 (2014).
42. Shahkhatuni, A.A., Shahkhatuni, A.G., Minasyan,
N.S., Panosyan, H.A., and Sahakyan, A.B. Revealing
the speci c solute-solvent interactions via the measurements
of the NMR spin-spin coupling constants", J.
Mol. Struct., 1083, pp. 175-178 (2015).
43. Schuquel, I.T.A., Ducati, L.C., Tormena, C.F., Freitas,
M.P., Kowalewski, D.G., and Rittner, R. 13C
NMR: nJCH and 1JCC scalar spin-spin coupling
constants (SSCCs) for some 3-monosubstituted 2-
methylpropenes", J. Mol. Struct., 1068, pp. 170-175
(2014).
44. Coxon, B. A Karplus equation for 3JHCCN in amino
sugar derivatives", Carbohydr. Res., 342, pp. 1044-
1054 (2007).
45. Ghiasi, M., Oskouie, A.A., and Saeidian, H. Dynamic
stereochemistry of topiramate (anticonvulsant drug)
in solution: Theoretical approaches and experimental
validation", Carbohydr. Res., 348, pp. 47-54 (2012).
46. Frisch, M.J., Trucks, G.W., Schlegel, H.B., et al.,
Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford,
CT (2009).
47. Becke, A.D. A new mixing of Hartree-Fock and local
density-functional theories", J. Chem. Phys., 98, pp.
1372-1377 (1993).
48. Lee, C., Yang, W., and Parr, R.G. Development
of the Colle-Salvetti correlation-energy formula into a
functional of the electron density", Phys. Rev. B., 37,
pp. 785-789 (1988).
49. Asiri, A.M., Karabacak, M., Kurt, M., and Alamry,
K.A. Synthesis, molecular conformation, vibrational
and electronic transition, isometric chemical shift,
polarizability and hyperpolarizability analysis of 3-
(4-methoxy-phenyl)-2-(4-nitro-phenyl) acrylonitrile: A
combined experimental and theoretical analysis", Spectrochimica
Acta Part A., 82, pp. 444-455 (2011).
S. Chashmniam and M. Tafazzoli/Scientia Iranica, Transactions C: Chemistry and ... 25 (2018) 1354{1363 1363
50. Tomasi, J., Mennucci, B., and Cammi, R. Quantum
mechanical continuum solvation models", Chem. Rev.,
105, pp. 2999-3093 (2005).