9628
J. Phys. Chem. B 2007, 111, 9628-9633
Unsaturated Didehydrodeoxycytidine Drugs. 1. Impact of CdC Positions in the Sugar Ring Feng Wang* Centre for Molecular Simulation, Swinburne UniVersity of Technology, P.O. Box 218, Hawthorn, Melbourne, Victoria, 3122, Australia ReceiVed: March 13, 2007; In Final Form: May 8, 2007
The chemical names of a pair of recently synthesized antitumor drugs are given in the present study as 1′,2′didehydro-3′,4′-deoxycytidine and 3′,4′-didehydro-2′,4′-deoxycytidine. The order of stabilities, geometries, and ionization potentials of the unsaturated sugar-modified cytidine derivatives is investigated quantum mechanically. Our density functional theory calculations based on the B3LYP/6-311++G** model reveal that 3′,4′-didehydro-2′,4′-deoxycytidine (SD-C2) is slightly more stable than its isomer, 1′,2′-didehydro-3′,4′deoxycytidine, by an energy of 5.28 kJ‚mol-1 in isolation. The isomers structurally differ by only the CdC location in the sugar ring. However, the compounds exhibit an unusual orientation with a less puckered sugar ring; that is, 3′,4′-didehydro-2′,4′-deoxycytidine is determined to be a β-nucleoside, which is a C1′-endo, north conformer with an anticlinal sugar ring, whereas 1′,2′-didehydro-3′,4′-deoxycytidine is neither an R-nucleoside nor a β-nucleoside but is a C4′-endo, south conformer with an antiperiplanar sugar ring. The present study further indicates that the CdC double bond location imposes significant effects on their ionization potentials (IPs) and other important molecular properties such as molecular electrostatic potential (MEP). In addition, inner shell binding energy spectral variations with respect to the CdC bond exhibit more site dependence. The valence shell binding energy spectral changes are, on the other hand, significant and delocalized. The latter indicates that such changes in valence space are not isolated effects but are within the entire nucleoside. Finally, the present study suggests that the nearly 0.6 eV difference in the first ionization potentials (highest occupied molecular orbital) of the isomers is sufficiently large to identify them by further spectroscopic measures.
Introduction Biomolecules such as nucleosides are significant in the life sciences as DNA/RNA fragments,1 in the medicinal and pharmaceutical sciences as prodrugs and antibiotics,2-5 and in other applications such as molecular electronics6 and semiconductor quantum dots.7 Nucleosides consist of a free nucleic acid base such as cytosine and a furanose-type ring (sugar), connecting at the N1 position of pyrimidine bases or the N9 position of purine bases by a β-glycosyl bond. In addition to the basic nucleosides of adenosine (A), guanosine (G), cytidine (C), thymidine (T), and uridine (U), numerous naturally occurring and chemically synthesized or modified nucleosides, i.e., nucleoside analogues exist. Compounds with a wide variety of modifications of sugar (ribose moiety) have been synthesized and tested for activities. Many nucleoside analogues exhibit antibiotic activities and have important medicinal and pharmaceutical applications.2-5 Nucleoside analogue antibiotics are easily incorporated in growing chains of DNA/RNA by mimicking their parent nucleosides to bring about the inhibition of protein; DNA/RNA syntheses hereby exhibit a wide variety of antiviral and antitumor properties.5,8 A serious drawback to the advances in medicinal and pharmaceutical applications of nucleosides as antibiotics is that the compound structural identification processes have been behind the pace of new drug discovery. Medical chemistry over the past several years has brought a similar philosophy in synthesis of peptides and oligonucleotides to the construction of more “druglike” small molecules.9 In a search for novel * E-mail:
[email protected].
compounds for genotype-specific effects, the recently synthesized cytidine nucleoside analogues, sulfinylcytidine derivatives (SC-D1 and SC-D2), which are given the names of 1′,2′didehydro-3′,4′-deoxycytidine (1′,2′-D3C) and its isomer 3′,4′didehydro-2′,4′-deoxycytidine (3′,4′-D3C) in the present study, were reported by Torrance et al.10 Although the drug pair was claimed10 to meet the standard criteria for drugs established by the National Cancer Institute (NCI, USA, http://wwww.cancer.gov), very little information about the new drugs, such as their chemical names, their structures, and the relative stabilities of the pair, was known. The isomer pair was originally described by library sources as sulfinylcytidine,10 but mass spectrometric analysis revealed that D3C represents a deoxycytidine analogue containing an unsaturated sugar moiety, an analogue of 2′,3′D4C.11 However, at the discovery, it was unable to determine whether the CdC bond resided at either the 1′,2′-position or the 3′,4′-position of the sugar ring, or if a mixture of both isomers was present.10 The sugar moiety occupies a central position in the structure of nucleic acids, and is of crucial importance in shaping their structures and dynamics, as evidenced by the striking difference in properties between DNA and RNA, which differ only by the chemical nature of a sugar. Previous statistics based on crystal structures of ribonucleosides (R) and 2′-deoxyribonucleosides (dR)12 indicated that important changes occurring upon the nucleoside conformational transitions were those related to the sugar moiety, whereas the base moiety was relatively rigid structurally.13 Nucleoside analogues that possess unsaturated Cd C bonds and lack a hydroxyl group (OH) have been extensively studied as potential drugs for the treatment of AIDS.11
10.1021/jp072014y CCC: $37.00 © 2007 American Chemical Society Published on Web 07/21/2007
Unsaturated Didehydrodeoxycytidine Drugs
J. Phys. Chem. B, Vol. 111, No. 32, 2007 9629
Attempts at correlating structure with activity have been made for a number of modified nucleosides,16-19 but little information is available for analogues with an unsaturated sugar. Of those studies on unsaturated sugar nucleoside analogues, such as D4N,11,18,19 it was found that nucleosides with an unsaturated sugar are usually more active than their saturated analogues, in particular when the pyrimidine base is thymine or cytosine.11 The highly active compounds adopt unusual conformations, e.g., C3′-exo/C4′-endo sugar ring puckering, which may indicate the need to facilitate enzymatic phosphorylation.11 Previous studies on nucleosides and analogues are largely synthetic,20,21 medicinal/pharmaceutical,2-5 andcrystallographic.22-24 Detailed analyses of the conformational properties of nucleoside analogues concentrated on their saturated sugar moieties. Due to the size of this class of molecules, rather low levels of theory in these studies, such as semiempirical molecular mechanics, were employed.11 Some structural studies on geometries and conformationalenergiesofnucleosideswithsaturatedsugar12,13,24-28 using density functional theory have appeared in recent years. Nevertheless, being given just the shape (geometry in threedimensional space) does not tell us about distributions of the electrons, and it is the distributions of electrons that are responsible for chemical structures, properties, and reactions.29 The present study investigates the unsaturated D3C compounds at the molecular level, using accurate quantum mechanical methods, such as density functional theory (DFT), in order to reveal the most likely location of the CdC bond in the sugar ring, as well as the impact of the positions of the CdC bond on electron distributions, through prediction of electronic properties such as dipole moments and ionization spectra of the nucleoside pair. Methods and Computational Details Geometries of the nucleoside pair are measured by their corresponding ring perimeters30 of the hexagon and pentagon rings, R6 and R5, respectively. The ring perimeters are calculated as the sums of all the bonds in the respective rings. The present study will concentrate on the modified sugar ring, but variations to the base (cytosine) moiety are incorporated implicitly through geometry optimizations. The three-dimensional (3D) shape of the nucleosides is determined by the following:1,31 (a) The glycosyl torsional angle, χ, determines the orientation of the hexagon (base) ring to the pentagon (sugar) ring: χ ) ∠O4′C1′-N1-C2 in pyrimidine nucleosides. If χ ∈ [90°, 270°], the base-sugar orientation is anti, but if χ ∈ [-90°, 90°], the basesugar orientation is syn. (b) The 3D shape of the nucleosides is also determined by the sugar puckering modes in an envelope (E) form in which four atoms are in a plane and the fifth atom is out of the plane, and in a twist (T) form in which two adjacent atoms are displaced on opposite sides of a plane through the other three atoms; or (c) endo, when atoms are displaced from these three- or four-atom planes and on the same side as C5′, and exo, those on the opposite side are called exo; e.g., C3′endo. (d) The pseudorotation angle P1,31 is defined by
P ) tan-1
(
(ν4 + ν1) - (ν3 + ν0)
)
2ν2(sin 36° + sin 72°)
where the νi’s (i ) 0, 1, 2, 3, and 4) are the endocyclic torsion angles1,31,32 of the sugar. (e) The torsional angle, γ, where γ ) ∠C3′-C4′-C5′-O5′, defines the orientation of the O5′-endo atom with respect to the ribose ring as γ ∈ [(30°, (90°] for (gauche and if γ ∈ [150°, 210°] for trans, etc.
Density functional theory based models such as B3LYP/6311++G**, LB94/pVQZ,33 and SAOP/pVQZ34 are employed to study the electronic structures of the nucleoside pair 1′,2′D3C and 3′,4′-D3C. Here SAOP34 is one of the recently developed asymptotically correct forms of Vxc in DFT, which is available in the Amsterdam Density Functional (ADF) computational chemistry package.35 Here the pVQZ basis set is the Slater basis set and has been found to produce good agreement of anisotropic properties to experiment.36,37 Singlepoint DFT calculations with LB94/pVQZ (for inner shell) and SAOP/pVQZ (for valence shell) are based on the optimized geometries of 1′,2′- and 3′,4′-didehydrodeoxycytidine, respectively, using the B3LYP/6-311++G** model. The LB94 functional has been found to produce core ionization potentials (IPs) for cytidine38 and other molecules39 using “meta”Koopman’s theorem with reasonable accuracy. The LB94 model achieves accuracy in the prediction of inner shell IPs similar to that of a recently developed CV-B3LYP functional40 when calculating the inner shell IPs for cytidine.41 All single-point calculations were based on the ADF computational chemistry package,35 and the optimization calculations were based on the Gaussian 03 computational chemistry package.42 Results and Discussion Optimization calculations of the nucleosides in the present study are based on the initial geometries of their parent deoxycytidine with the removal of appropriate hydrogen atoms and relocation of one of the hydroxyl groups. Although it is still not absolutely certain that the conformers we obtained represent the deepest minimal structures without a thorough study of the conformational potential energy surface (landscape) of the nucleosides, the true minimal structures are likely to mimic their parent moieties without significant energy input. In addition, even though full conformational potential energy surfaces of the species will be available in the future, the impact of the CdC bond positions on the properties of the conformers may yield more chemically significant information than whether the conformers represent the deepest minima or the next deepest minima on the potential energy surfaces. The obtained geometries in the present work, through full optimization from their parent nucleosides, likely represent the global minimum structures of the isomers or at least very stable local minima. Fully optimized structures of 1′,2′-D3C and 3′,4′-D3C molecules in 3D space are given in Scheme 1. Relocation of the CdC bond, from the C1′dC2′ position to the C3′dC4′ position in the sugar ring, results in an energy lowering of 5.28 kJ‚mol-1 based on our B3LYP/6-311++G** model. That is, from an energy point of view, 3′,4′-D3C (SC-D2,10 II) is more stable in isolation than its isomer 1′,2′-D3C (SC-D1,10 I). Table 1 lists related geometric and molecular properties of the compounds. Positions of the CdC bond do not change the bond lengths noticeably, but have significantly changed the shape of the nucleosides in the 3D space. For example, the perimeters30 of the hexagon and pentagon rings, R6 and R5, remain almost unchanged with respect to locations of the CdC bond. Only the sugar ring perimeters exhibit a small relaxation (within 0.03 Å) with respect to CdC positions, whereas the cytosine base remains rigid. This is because CdC locations, either C1′dC2′ or C3′dC4′, do not alter the number of C-C and CdC bonds in the rings of the compounds. The molecule size (〈R2〉), however, reflects the distortion in 3D space. In response to the CdC relocation, anisotropic properties such as dipole moments (µ) exhibit a significant variation of 1.25 D between the two sugar-modified unsaturated cytidine derivatives, from 6.79 D
9630 J. Phys. Chem. B, Vol. 111, No. 32, 2007
Wang
SCHEME 1: Optimized Structures of 1′,2′-Didehydro-3′,4′-deoxycytidine and 3′,4′-Didehydro-2′,4′-deoxycytidinea
a
The numbering of atoms is based the nomenclature of nucleosides.
TABLE 1: Selected Geometric and Molecular Properties of 1′,2′-D3C (SC-D1) and 3′,4′-D3C(SC-D2)a 1′,2′-D3C
3′,4′-D3C
structures
CdC position -CΗ2-OH location -ΟΗ location Eele + ZPE (Eh) ZPE (kcal‚mol-1) 〈R2〉 (au) µ (D) R6 (Å) R5 (Å) χ ) ∠O4′-C1′-N1C2 (deg) γ ) ∠C5′-O5′-C3′C4′ (deg) pseudorotation angle,d P (deg) puckering amplitude, e ν (deg) m type
C1′dC2′ C4′ C3′ -814.748 294 130.2014 4460.97 6.79 8.30 7.21 175.76, antib
C3′dC4′ C4′ C2′ -814.750 306 130.3454 4132.69 5.54 8.30 7.23 -109.51, ∼antic
-64.54
-5.66
221.97 (south)
322.97 (north)
10.01 (central)
9.54 (central)
Cyt, C4′-endo, unknown type
Cyt, C1′-endo, β-nucleoside
a Produced by the B3LYP/6-311++G** model. b Periplanar as 150°< χ
