DFT study of conformational flexibilities and interaction profiles of new class of nucleoside analogs having nucleic acid bases pairs (pyrimidine analogues-adenine) linked through a 1,2,3-triazole spacer.
Synthesis of nucleoside analogs with biomimetically modified sugar or the nucleobase moieties is an area of tremendous interest due to their potential to target pathogens such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and cytomegalovirus (CMV) [1,2] and cancer. Given the involvement of the Matrix metalloproteinases (MMPs) in the latter pathology, MMP-specific inhibitors would be very valuable as therapeutic agents . On the other hand, nucleoside analogs with varying degrees of conformational flexibilities have been investigated. For example, nucleoside analogs in which the furanose ring has been replaced by other heterocyclic rings such as isoxazoles, isoxazolines, or triazoles . Furthermore, some important prototypes analogs in which saturated, unsaturated [5-8], or fused carbon rings replace the furanose moiety . Synthetic compounds having these moieties exhibit a wide range of biological activities, and most of the ongoing research is aimed at identifying new skeletons with a correct balance of potency and selectivity. Recently, the Huisgen 1,3 dipolar cycloaddition of azides to alkynes to yield 1,2,3 triazoles has emerged as a highly useful and premier example of click chemistry [10-15]. In previous work we described the synthesis of several 1,2,3 triazole analogues [16-21].
In continuation of our works, we report in the present paper conformational flexibilities details and interaction profiles of new class of nucleoside analogs hybrids in which the nucleic acid bases pairs (Uracil analogues-Adenine) are linked through a 1,2,3-triazole spacer replacing the sugar ring (Scheme 1). Since hydrogen bound interactions had proven to be particularly important to stabilize double helix DNA, we opted to increase the number of heteroaromatic units (1,2,3-triazole, Adenine, pyrimidine residues) in the hybrid molecule, in an attempt to maximase binding (hydrogen bond) between Adenine and pyrimidine residues (Scheme 1).The structure-activity relation study and biological evaluation of such compounds will be reported in due course . Furthermore, compound 4c showed very interesting activity with 10 [micro]M against leukemia.
[FORMULA EXPRESSION NOT REPRODUCIBLE IN ASCII]
Taking these factors into consideration, we have designed a series of triazole-centred ligands, flanked by adenine and pyrimidine residues and we studied three conformations (one opened and two closed conformations) of the new class of nucleoside with various substituents (X = H, C[H.sub.3], F, Cl, and Br) stabilized by intramolecular hydrogen bond aimed to confirm this anti-leukemic activity.
2. MATERIAL AND METHODS
Calculations were performed using the Gaussian 09W program . The geometries for all structures presented here were optimized at the density functional theory (DFT) level by using Becke's three parameter hybrid exchange functional  and correlation functional by Lee, Parr and Yang  (B3LYP) in order to take into account the effect of electron correlation. The double split-valence 6-31G(d,p) basis set of Pople, which included a d-type polarization functions on all non-hydrogen atoms and p-type polarization functions on hydrogen atom was used in the calculations [26,27]. Harmonic vibrational frequencies and intensities for the studied molecules were obtained at the same level of theory using the same basis set. The absence of imaginary wavenumber values confirms that all the structures correspond to equilibrium minima on the potential energy surfaces. The assignment of the calculated wavenumbers is aided by the animation option of the GaussView 5.0 graphical interface  for the Gaussian program, which gives a visual presentation of the shape vibrational modes.
3. RESULTS AND DISCUSSION
We have localized and optimized three structures of the selected molecules with various substituents (X = H, C[H.sub.3], F, Cl, and Br): two hydrogen bonded conformations (closed conformations) and one non hydrogen bonded conformation (opened conformation). The first hydrogen bonded conformation is stabilized by two [N.sub.10]-[H.sub.49] ... [O.sub.48] and [N.sub.17]-[H.sub.34] ... [N.sub.8] intramolecular hydrogen bonds. The second one (Closed_2) is stabilized by one [N.sub.10]-[H.sub.49] ... [O.sub.48] intramolecular hydrogen bond. It is obtained by internal rotation by 180[degrees] around the [C.sub.19]-[N.sub.16] bond from the first one. The open conformation, without hydrogen bond is obtained from the first one by internal rotation around the [C.sub.26]-[C.sub.27] and around the [C.sub.30]-[C.sub.44] bonds (Figure 1). All the optimized conformations were characterized as minima. The optimized bond lengths around the N-H and C=O bonds and relative energies of the calculated structures in their minima are presented in Table 1.
The data in Table 1 shows the lengths of the [C.sub.14]-[X.sub.50] (X = H, C[H.sub.3], F, Cl, and Br) and [N.sub.10]-[H.sub.13] bonds are almost equal in the closed_2, closed_1 and open conformation of the studied molecules. However, the [N.sub.10]-[H.sub.49] and [C.sub.47]-[O.sub.48] bonds are all contracted on going from the open conformation to closed ones indicating the intramolecular [C.sub.47]-[O.sub.48] ... [H.sub.49] hydrogen bond formation in the later conformations. There are shortened by more than 0.58 [Angstrom] with respect to the sum of van der Waals radii (2.72 [Angstrom] ) indicating the formation of the relevant hydrogen bonds.
On the other hand, the [N.sub.17]-[H.sub.34] bonds is strongly contracted by about 0.021-0.025 [Angstrom] on going from the open conformation to closed_1 conformation indicating the intramolecular [N.sub.17]-[H.sub.34] ... N hydrogen bond formation in the later conformation. Indeed, the optimized intramolecular bonds in the closed_1 conformers (X =H, C[H.sub.3], F, Cl, and Br) are 1.945, 1.950, 1.942, 1.911, and 1.913 [Angstrom], respectively. There are shortened by more than 0.8 [Angstrom] with respect to the sum of van der Waals radii (2.75 [Angstrom] ) indicating the formation of the strong hydrogen bonds. zzz The harmonic vibrational frequencies for all the studied structures were calculated. For the sake of simplicity, we report in Table 2 the calculated wavenumbers for the C=O, C=N, and N-H stretches, involving in hydrogen bonding. It is interesting to reminder that in experimental or theoretical results, an important way to indentify the formation of hydrogen bond is to compare the vibration spectra between the molecules without hydrogen bond and the molecules with intramolecular hydrogen bond. For a classical H-bond, the red shift of the involving bond stretching frequency should be observed and its infrared intensity would increase greatly.
According to the vibrational frequencies analysis, the [N.sub.17]-[H.sub.34] stretching vibrational frequency moves to lower frequencies in the closed_1 conformation with respect to the open conformation. Indeed, large red shifts of about 380-455 [cm.sup.-1], due to the intramolecular [N.sub.17]-[H.sub.34] ... N hydrogen bonding, are exhibited for all studied molecules. The corresponding infrared intensities also increase greatly. On the other hand, it should be stressed that the positions of the symmetric and antisymmetric N[H.sub.2] ([N.sub.10]-[H.sub.49] and [N.sub.10]-[H.sub.13]) stretching vibrations also moved to lower frequencies on going from the opened to the closed_1 and closed_2 conformations. Therefore, a red shift of the N[H.sub.2] mode due to the intramolecular [N.sub.10]-[H.sub.49] ... [O.sub.48] hydrogen bonding in the two closed conformations is accompanied by an increase of the intensity of this stretching vibration mode. These changes are more important for the symmetric stretching (Table 2). Thus the two intramolecular hydrogen bonds in the closed_1 conformation are classical H bond.
On the other hand, the DFT calculations show that the closed_1 conformation of the studied structures with various substituents (X = H, C[H.sub.3], F, Cl, and Br) stabilized by the two intramolecular N-H ... O and N-H ... N hydrogen bonds is lower in energy by 23.33, 22.50, 23.69, 33.76, and 33.81 KJ/mol, respectively, than the open conformation (Table 1), in agreement with previously vibrational frequencies analysis. On the other hand, the closed_2 conformation of the studied structures (X = H, C[H.sub.3], F, Cl, and Br) stabilized by the intramolecular N-H ... O hydrogen bond is lower in energy only by 10.09, 20.74, 14.81, 11.73, and 16.25 KJ/mol, respectively, than the open conformation (Table 1).
Quantum calculations predicted the existence of three stable conformations, (closed_1, closed_2, and opened) of the new class of nucleoside with various substituents (X = H, C[H.sub.3], F, Cl, and Br). The structure of the closed_2 conformations is stabilized by the intramolecular hydrogen bond between the N[H.sub.2] group and [O.sub.48] atom. On the other side, the structure of the closed_1 conformers is stabilized by two intramolecular hydrogen bonds between the N[H.sub.2] group and [O.sub.48] atom and [N.sub.17][H.sub.34] group and [N.sub.8] atom. The strength of this hydrogen bond is demonstrated by the short [O.sub.48] ... [H.sub.49] (2.023-2.141 [Angstrom]) and [N.sub.8] ... [H.sub.34] (1.911-1.950 [Angstrom]) distances. The vibrational frequencies analysis shows that these intramolecular hydrogen bonds are classical H-bonds. On the other hand, these compounds were tested as anticancer agents and compound 4c showed very interesting activity with 10 microM against leukemia.
5. REFERENCE AND NOTES
 a) Siddiqui, A. Q.; Ballatore, C.; MacGuigan, C.; De Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 393. [CrossRef] b) Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Nature Reviews Drug Discovery 2013, 12, 447. [CrossRef]
 a) Mathe, C.; Gosselin, G. Antiviral Res. 2006, 71, 276. [CrossRef] b) Bobeck, D. R.; Schinazi, R. F.; Coats, S. J. Antiviral Therapy 2010, 15, 935. [CrossRef]
 Lee, M.; Fridman, R.; Mobashery, S. Chem. Soc. Rev. 2004, 33, 401. [CrossRef]
 Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110, 3337. [CrossRef]
 El Ashry, E. S. H.; El Kilany, Y. Adv. Heterocycl. Chem. 1997, 68, 1. [CrossRef]
 Shaban, M. A. E.; Nasr, A. Z. Adv. Heterocycl. Chem. 1997, 68, 223. [CrossRef]
 El Ashry, E. S. H.; El Kilany, Y. Adv. Heterocycl. Chem. 1997, 69, 129. [CrossRef]
 Yan, Z.; Zhou, S.; Kern, E.R.; Zemlicka, J. Tertrahedron 2006, 62, 2608. [CrossRef]
 Stambasky, J.; Hocek, M.; Kocovsky, P. Chem. Rev. 2009, 109, 6729. [CrossRef]
 Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. [CrossRef]
 Tornee, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. [CrossRef]
 Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 24, 1128. [CrossRef]
 Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. [CrossRef]
 Rodionov, V. O.; Presolski, S. I.; Diaz, D. D.; Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12705. [CrossRef]
 Elayadi, H.; Smietana, M.; Pannecouque, C.; Leyssen, P.; Neyts, J.; Vasseur, J. J.; Lazrek, H. B. Bioorg. Med. Chem. Lett. 2010, 20, 7365. [CrossRef]
 Kabbaj, Y.; Lazrek, H. B.; Barascut, J. L.; Imbach, J. L. Nucleosides Nucleotides & Nucleic Acids 2005, 24, 161. [CrossRef]
 Elayadi, H.; Mesnaoui, M.; Korba, B. E.; Smietana, M.; Vasseur, J. J.; Secrist, J. A.; Lazrek, H. B. Arkivoc viii 2012, 76. [CrossRef]
 Elayadi, H.; Ait Ali, M.; Mehdi A., Lazrek, H. B. Catalysis comm. 2012, 26, 155. [CrossRef]
 Lazrek, H. B.; Taourirte, M.; Oulih, T.; Barascut, J. L.; Imbach, J. L.; Pannecouque, C.; Witrouw, M.; Clercq, E. D;. Nucleosides Nucleotides & Nucleic Acids 2001, 20, 1949. [CrossRef]
 Moukha-chafiq, O.; Taha, M. L.; Lazrek, H. B.; Vasseur, J. J.; Pannecouque, C.; Witvrouw, M.; Clercq, E. D. Farmaco 2002, 57, 27. [CrossRef]
 Moukha-chafiq, O.; Taha, M.L.; Lazrek, H. B.; Vasseur, J. J.; Pannecouque, C.; Witvrouw, M.; Clercq, E.D. Nucleosides Nucleotides & Nucleic Acids 2001, 20, 1811.[CrossRef]
 Elayadi, H.; Faraj, A.; Boutalib, A.; Lazrek, H. B. to be published.
 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr. J.A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09 (Revision A.02), Gaussian, Inc.: Wallingford, CT, 2009.
 Beke, A. D. J. Chem. Phys. 1993, 98, 5648. [CrossRef]
 Lee, C.; Yang, W.; Parr, R. P. Phys. Rev. 1988, B37, 785. [CrossRef]
 Krishman, R.; Binkley, J. S.; Seeger, S.; Pople, J. A. J. Chem. Phys. 1980, 72, 650. [CrossRef]
 Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v. R. J. Comput. Chem. 1983, 4, 294.
 Dennington, R.; Keith, T;. Millam, J.; GaussView, Version 5, Semichem Inc., Shawnee Mission KS, 2009.
Hanane Elayadi (a), Abderrahim Boutalib (b) * and Hassan Bihi Lazrek (a)
(a) Unite de Chimie Biomoleculaire et Medicinale (URAC 16) Departement de Chimie, Universite Cadi Ayyad, Faculte des Sciences Semlalia, B.P. 2390 Marrakech, Morocco.
(b) Unite Reactivite Chimique(URAC 16) Departement de Chimie, Universite Cadi Ayyad, Faculte des Sciences Semlalia, B.P. 2390 Marrakech, Morocco.
Article history: Received: 10 March 2013; revised: 22 October 2013; accepted: 30 October 2013. Available online: 30 December 2013.
* Corresponding author. E-mail: email@example.com
Table 1. Selected optimized bond lengths and relative energies of the studied conformers. Compound Conformer [DELTA]E Bond Lengths, [Angstrom] (KJ/mol) [O.sub.48] ... [N.sub.8] ... [H.sub.49] [H.sub.34] X = H Closed_1 0 2.023 1.945 Closed_2 13.24 2.141 Opened 23.33 X = Closed_1 0 2.030 1.950 C[H.sub.3] Closed_2 1.76 2.111 Opened 22.50 X = F Closed_1 0 2.049 1.942 Closed_2 8.89 2.119 Opened 23.72 X = Cl Closed_1 0 2.059 1.911 Closed_2 22.03 2.136 Opened 33.76 X = Br Closed_1 0 2.063 1.913 Closed_2 16.85 2.138 Opened 33.81 Compound Conformer Bond Lengths, [Angstrom] [N.sub.10]- [N.sub.10]- [N.sub.17]- [H.sub.49] [H.sub.13] [H.sub.34] X = H Closed_1 1.019 1.009 1.035 Closed_2 1.015 1.009 1.013 Opened 1.007 1.007 1.013 X = Closed_1 1.019 1.009 1.034 C[H.sub.3] Closed_2 1.015 1.009 1.013 Opened 1.007 1.007 1.013 X = F Closed_1 1.018 1.009 1.038 Closed_2 1.010 1.008 1.013 Opened 1.007 1.007 1.013 X = Cl Closed_1 1.018 1.009 1.039 Closed_2 1.013 1.007 1.013 Opened 1.007 1.007 1.013 X = Br Closed_1 1.018 1.009 1.038 Closed_2 1.013 1.007 1.013 Opened 1.007 1.007 1.013 Compound Conformer Bond Lengths, [Angstrom] [C.sub.47]= [C.sub.14]- [O.sub.48] [X.sub.50] X = H Closed_1 1.231 1.081 Closed_2 1.228 1.082 Opened 1.220 1.081 X = Closed_1 1.233 1.501 C[H.sub.3] Closed_2 1.229 1.501 Opened 1.222 1.501 X = F Closed_1 1.228 1.341 Closed_2 1.221 1.339 Opened 1.217 1.339 X = Cl Closed_1 1.226 1.737 Closed_2 1.221 1.733 Opened 1.215 1.735 X = Br Closed_1 1.226 1.889 Closed_2 1.222 1.882 Opened 1.216 1.887 Table 2: Computational IR frequencies ([cm.sup.-1]) and intensities (km/mol) of the studied conformers. Compound Closed_1 Closed_2 Freq. Int. Freq. Int. X = H 1692 323 1682 235 1768 620 1779 726 1802 379 1803 407 3225 794 3615 70 3468 459 3530 285 3682 92 3691 80 X = C 1692 278 1682 391 [H.sub.3] 1753 555 1763 648 1799 443 1799 456 3233 812 3617 62 3472 458 3537 264 3682 91 3697 91 X = F 1692 325 1669 467 1775 578 1797 824 1800 333 1805 177 3179 922 3614 78 3491 389 3604 141 3686 99 3736 68 X = Cl 1692 351 1678 619 1774 496 1787 614 1807 428 1805 371 3160 1035 3618 64 3496 381 3551 229 3683 101 3724 108 X = Br 1692 349 1678 592 1769 468 1783 579 1807 454 1804 439 3163 1051 3615 68 3496 384 3553 231 3683 99 3726 105 Compound Opened Assignment Freq. Int. X = H 1675 750 C(6)=N(10) str. 1811 445 C(48)=O(49) str 1798 699 C(18)=O(20) str 3617 70 N(17)-H(34) str. 3618 113 N(10)[H.sub.2] sym. str 3757 53 N(10)[H.sub.2] asym. str X = C 1675 684 C(6)=N(10) str. [H.sub.3] 1811 323 C(48)=O(49) str 1802 745 C(18)=O(20) str 3614 81 N(17)-H(34) str. 3618 114 N(10)[H.sub.2] sym. str 3758 54 N(10)[H.sub.2] asym. str X = F 1675 744 C(6)=N(10) str. 1815 447 C(48)=O(49) str 1800 627 C(18)=O(20) str 3615 79 N(17)-H(34) str. 3618 114 N(10)[H.sub.2] sym. str 3758 54 N(10)[H.sub.2] asym. str X = Cl 1675 756 C(6)=N(10) str. 1815 379 C(48)=O(49) str 1802 697 C(18)=O(20) str 3615 81 N(17)-H(34) str. 3619 114 N(10)[H.sub.2] sym. str 3758 54 N(10)[H.sub.2] asym. str X = Br 1675 684 C(6)=N(10) str. 1811 323 C(48)=O(49) str 1802 745 C(18)=O(20) str 3614 81 N(17)-H(34) str. 3618 114 N(10)[H.sub.2] sym. str 3759 54 N(10)[H.sub.2] asym. str
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Full Paper|
|Author:||Elayadi, Hanane; Boutalib, Abderrahim; Lazrek, Hassan Bihi|
|Publication:||Orbital: The Electronic Journal of Chemistry|
|Date:||Oct 1, 2013|
|Previous Article:||Aplicacao da cromatografia de permeacao em gel na avaliacao da interacao entre metais pesados e a materia organica--Lagoa de Patos, RS, Brasil.|
|Next Article:||Montagem de uma celula universal para ensaios de permeacao em membranas semipermeaveis solidas em escala laboratorial.|