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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.

1. INTRODUCTION

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 [3]. 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 For example, nucleoside analogs in which the furanose ring has been replaced by other heterocyclic rings such as isoxazoles, isoxazolines, or triazoles [4]. Furthermore, some important prototypes analogs in which saturated, unsaturated [5-8], or fused carbon rings replace the furanose moiety [9]. 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 [22]. Furthermore, compound 4c showed very interesting activity with 10 [micro]M against leukemia.

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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 [23]. 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 [24] and correlation functional by Lee, Parr and Yang [25] (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 [28] 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] [29]) 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] [29]) 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).

4. CONCLUSION

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

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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: boutalib@uca.ma

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
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Author:Elayadi, Hanane; Boutalib, Abderrahim; Lazrek, Hassan Bihi
Publication:Orbital: The Electronic Journal of Chemistry
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Geographic Code:6MORO
Date:Oct 1, 2013
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