2-({3-[(2R,4S,5R)-4-Hydr­oxy-5-hydroxy­methyl-2,3,4,5-tetra­hydro­furan-2-yl]-5-methyl-2,6-dioxo-1,2,3,6-tetra­hydro­pyrimidin-1-yl}meth­yl)isoindoline-1,3-dione

Mark Daniel Bartholomä; Wayne Ouellette; Jon Zubieta

doi:10.1107/S1600536809003365

. 2009 Jan 31;65(Pt 2):o432–o433. doi: 10.1107/S1600536809003365

2-({3-[(2R,4S,5R)-4-Hydroxy-5-hydroxymethyl-2,3,4,5-tetrahydrofuran-2-yl]-5-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-1-yl}methyl)isoindoline-1,3-dione

Mark Daniel Bartholomä ^a, Wayne Ouellette ^b, Jon Zubieta ^a,^*

PMCID: PMC2968204 PMID: 21582018

Abstract

The title compound, C₁₉H₁₉N₃O₇, is a thymidine derivative and serves as an intermediate in the synthesis of a ^99mTc radiolabeled nucleoside analog. Intermolecular O—H⋯O hydrogen bonding is observed between the hydroxy functionalities of the ribose unit themselves as well as between a hydroxy group and an O atom of the phthalimide group of an adjacent molecule. The molecules are stacked on top of each other in the direction of the a axis. The crystal packing is further stabilized by weak intra- and intermolecular C—H⋯O hydrogen bonds. The absolute configuration of the compound is known from the synthesis.

Related literature

For general background on human thymidine kinase 1 (hTK-1), see: Arner & Eriksson (1995 ▶); Bello (1974 ▶); Eriksson et al. (2002 ▶). For related literature, see: Wei et al. (2005 ▶); Bartholomä et al. (2009 ▶); Flack (1983 ▶). For crystal structure of hTK-1, see: Welin et al. (2004 ▶).

Experimental

Crystal data

C₁₉H₁₉N₃O₇
M _r = 401.37
Monoclinic,
a = 4.9334 (4) Å
b = 11.6287 (9) Å
c = 15.3208 (12) Å
β = 91.430 (2)°
V = 878.67 (12) Å³
Z = 2
Mo Kα radiation
μ = 0.12 mm⁻¹
T = 90 (2) K
0.28 × 0.22 × 0.08 mm

Data collection

Bruker SMART APEX diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 1998 ▶) T _min = 0.968, T _max = 0.991
9291 measured reflections
4344 independent reflections
3949 reflections with I > 2σ(I)
R _int = 0.028

Refinement

R[F ² > 2σ(F ²)] = 0.045
wR(F ²) = 0.097
S = 1.08
4344 reflections
269 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.30 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: SMART (Bruker, 1998 ▶); cell refinement: SAINT (Bruker, 1998 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: DIAMOND (Brandenburg & Putz, 1999 ▶); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809003365/fb2127sup1.cif

e-65-0o432-sup1.cif^{(22KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809003365/fb2127Isup2.hkl

e-65-0o432-Isup2.hkl^{(212.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

Cg1 and Cg2 are the centroids of the N1/C6/C7/C9/N2/C10 and N3/C12/C13/C18/C19 rings, respectively.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O2ⁱ	0.81 (3)	2.02 (3)	2.815 (2)	170 (3)
O2—H2A⋯O6ⁱ	0.84 (3)	1.92 (3)	2.698 (2)	155 (3)
C3—H3⋯O6ⁱⁱ	1.00	2.45	3.445 (2)	171
C8—H8A⋯O7ⁱⁱⁱ	0.98	2.43	3.341 (3)	154
C14—H14⋯O5^iv	0.95	2.44	3.116 (3)	128
C15—H15⋯O7^iv	0.95	2.60	3.484 (3)	155
C5—H5⋯O4	1.00	2.33	2.740 (2)	104
C11—H11A⋯O4	0.99	2.29	2.747 (2)	107
C11—H11B⋯O7	0.99	2.52	2.915 (3)	104
C8—H8B⋯Cg1^v	0.98	2.71	3.534 (2)	143
C11—H11A⋯Cg2^vi	0.99	2.73	3.611 (2)	149

Open in a new tab

Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) ; (vi) .

Acknowledgments

The authors gratefully acknowledge the support of the National Science Foundation (grant No. CHE-0604527) and Molecular Insight Pharmaceuticals Inc.

supplementary crystallographic information

Comment

In recent years, the development of radiolabeled nucleosides and nucleoside analogs has gained increased interest because of their potential use as probes for tumor cell proliferation. The targeted enzyme is the human cytosolic thymidine kinase (hTK-1), an enzyme of the pyrimidine salvage pathway, which catalyzes the phosphorylation of thymidine and uridine as natural substrates to their corresponding 5'-monophosphates (Welin et al., 2004). These monophosphates are precursors of the DNA synthesis. Further conversion to the di- and triphosphates by nucleoside mono- and diphosphate kinases finally results in DNA incorporation. Most important, proliferating cells such as tumor cells show a dramatically increased hTK-1 activity compared to quiescent cells which makes hTK-1 an attractive target for selective imaging and therapeutic applications (Bello, 1974). Moreover, nucleosides are taken up by proliferating cells through facilitated diffusion but the cellular efflux of the corresponding negatively charged 5'-monophosphates is retarded (Arner & Eriksson, 1995). Thus, a radiolabeled nucleoside analog would be trapped inside the cell resulting in an accumulation in tissue with elevated hTK-1 activity such as tumor cells. The main challenge is the development of a nucleoside derivative which retains its substrate activity since hTK-1 has a narrow substrate specifity (Eriksson et al., 2002). The literature on the interaction of thymidine derivatives with hTK-1 is not totally unambiguous about the effects of various substitutions. In general, major modifications of thymidine or uridine, respectively, led to a highly decreased activity of the corresponding compound. On the other hand, several derivatives modified either at the ribose and the base site are reported which retain their activity. To shed light on the effects of various modifications on the substrate activity, we prepared a library of nucleoside analogs that had been modified at different positions of the ribose and base moiety. With this library, we expand our SAAC concept (single amino acid chelate) on nucleosides for radioimaging and radiotherapeutic purposes (Wei et al. 2005, Bartholomä et al., 2009).

2-((2,3-dihydro-3-((2R,4S,5R)-tetrahydro-4-hydroxy-5- (hydroxymethyl)furan-2-yl)-5-methyl-2,6-dioxopyrimidin-1(6H)-yl) methyl)isoindoline-1,3-dione is an intermediate in the synthesis of a ⁹⁹^mTc radiolabeled nucleoside analog. The corresponding final product is a representative of the N-3 derivatized thymidine analogs with the shortest tether length applicable between the bioactive molecule and the chelate. The entire synthetic pathway will be described elsewhere. The SAAC chelate enables a chemically robust and inert coordination of the [M(CO)₃]⁺ core (M = ¹⁸⁶Re, ¹⁸⁸Re, ⁹⁹^mTc). ⁹⁹^mTc with its ideal decay properties, low cost and good availability can be used for imaging purposes while the corresponding rhenium complexes would act as therapeutic counterparts.

2-((2,3-dihydro-3-((2R,4S,5R)-tetrahydro-4-hydroxy-5- (hydroxymethyl)furan-2-yl)-5-methyl-2,6-dioxopyrimidin-1(6H)-yl) methyl)isoindoline-1,3-dione shows strong intermolecular hydrogen bonding interactions of the type O—H···O as well as weak intra- and intermolecular C—H···O hydrogen bonds (Tab. 1). The O—H···O hydrogen bonding interaction occurs between the hydroxyl group at the 5' position of the sugar moiety (O1—H1C) and the oxygen atom O2 at the 2' position of an adjacent molecule (O2) with a O1—H1C···O2 distance of 2.815 (2) Å (Tab. 1). Another O—H···O hydrogen bonding interaction is observed between the hydroxy group at the 2' position of the ribose moiety (O2—H2A) and the oxygen atom of the phthalimide residue (O6) of the adjacent molecule. The corresponding O2—H2A···O6 distance is 2.698 (2) Å. The molecules are stacked on top of each other in direction of the a axis. There are π-π electron interactions between the aromatic rings N3\C12\C13\C18\C19 and C13\C14\C15\C16\C17\C18 of the phthalimide moiety. The distance between the centroids of these rings is 3.7245 (12) Å. Moreover, there are also C-H···π-electron ring interactions (Tab. 1). The ribose moiety of the nucleoside analog adopts a twist conformation with C2, O3, and C5 in plane. The atoms C3 and C4 are out of plane with d = 0.2356 (25) Å and d = -0.4099 (25) Å, respectively. The distance between C6 and C7 with 1.334 (3) Å is representative for the double bond character. The phthalimide residue has essentially a planar geometry. The absolute configuration of the compound is known by synthesis. All the bond lengths and angles are in expected ranges.

Experimental

1 g (4.13 mmol) of 1-(2-deoxy-β-D-ribofuranosyl)thymine, 1.862 g (4.54 mmol) of phthalimidomethylpyridinium p-toluenesulfonate and 1.141 g (8.26 mmol) of K₂CO₃ were suspended in anhydrous N,N-dimethylformamide and kept at 50°C for 2 d. The solvent was removed in vacuum. 50 ml of water were added to the yellowish suspension and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried with MgSO₄ and evaporated to dryness. The crude product was purified by silica gel column chromatography using CH₂Cl₂:MeOH 15:1. The last fraction contained the product. Single crystals suitable for X-ray diffraction were obtained by recrystallizing the product in methanol yielding colorless plates. ¹H NMR (d₄-MeOD): δ = 1.90 (s, 3 H), 2.35 (m, 2 H), 3.87 (m, 2 H), 3.98 (dd, J = 3.20 Hz, 3.30 Hz, 1 H), 3.56 (dd, J = 4.41 Hz, J = 9.18 Hz, 1 H), 5.90 (s, 2 H), 6.24 (t, J = 6.53 Hz, 1 H), 7.52 (s, 1 H), 7.72 (m, 2 H), 7.84 (m, 2 H). p.p.m.. IR: ν = 3088, 2963, 2542, 1789, 1728, 1703, 1646, 1466, 1428, 1406, 1347, 1272, 1248, 1218, 1178, 1118, 1070, 1037, 1014, 992, 935, 892, 847, 769, 729, 716, 632, 608, 567, 532, 515, 491 cm^-1.