Molecular structure of deoxyadenjlyl–3′–methylphosphonate–5′thymldine dlhydrate, (d-ApT-2H₂O), a dinudeodde monophosphate with neutral pbosphodiester backbone. An X-ray crystal study

Abstract

dApT, a modified deoxyribose dinucleoside phosphate with an uncharged methylphosphonate group, crystallizes as dihydrate in space group P2(1)2(1)2, a = 9.629(3), b = 20.884(6) and c = 14.173(4)A, Z = 4. The structure has been determined using 2176 X-ray diffractometer reflections and refined to a final R of 0.105. Torsion angles about P-O(5') and P-O(3') bonds are -91.8 degrees and 117.8 degrees. The former is in the normal (-)gauche range while the latter is eclipsed. Bases are oriented anti, the sugar of adenosine is puckered 2T3 (C(2')endo) whereas that of thymidine displays puckering disorder with major and minor occupancy sites. Major site is a half-chair 2T (C(2')endo-C(1')exo) and minor site an envelope 3T2 (C(3(1)endo). Adenine and thymine bases of symmetry related molecules form reversed Hoogsteen type base pairs, water molecules are disordered in the crystal lattice.

Stereoselective synthesis of P-homochiral oligo(thymidine methanephosphonates)

“…Such differences could lead to cnarnes in the N-glycosyl torsion angle as well as to changes in weaK intramolecular interactions (1). Comparison of published CD profiles of fast-and slow-isomers of d(ApeA) (18), d(ApMeT) (14), d(CpMeG) and d(GpMC) (19), d(TpMeTp)4TpT (11) with the CD profiles recorded for d(TpM)3T shows that they are qualitatively similar, and that the fast-Isomer exhibits a mere intense CD pattern than does the other isomr. Unfortunately, if chromatographic mobi I ity and CD criteria are related to the absolute configuration at phosphorus of the methanephosphonate function, they are not always consistent with absolute configuration assignments by instrumental or chemical methods.…”

The SP Diastereomer of a Dinucleoside Methylphosphonate Methanol Solvate Containing Thymine and N3-Methyl-4-thiothymine Bases

“…The absolute configuration at the phosphorus centre in (1) is S. The atoms around this centre form a distorted tetrahedron with bond lengths and angles similar to those found in the crystal structures of the other dinucleoside methylphosphonates (Chacko et al, 1983;Han et al, 1990;Szab6 et al, 1993). The compound adopts an extended completely unstacked conformation with a distance between the two anomeric C atoms of 7.71 (2)A.…”

“…methylphosphonates) and their potential applications in the antisense strategy for the artificial control of gene expression has stimulated wide interest in this class of compounds (Englisch & Gauss, 1991;Miller, 1989). In contrast, only three solid-state structures of dinucleoside methylphosphonates are known to date, namely SpdAp(Me)T (Chacko, Lindner, Saenger & Miller, 1983), Rp-dCp(Me)G (Han et al, 1990) and SpTp(Me)sT (where sT is 4-thiothymidine) (Szab6, Norrus, Norrestam & Stawifiski, 1993).…”

Interactions of oligonucleotide analogs containing methylphosphonate internucleotide linkages and 2′-O-methylribonucleosides

“…In addition to the expected nucleosides, a peak whose mobility corresponded to one of the diastereoisomers of the diimer, d-ApT, was also observed. The dimer obtained from the first peak corresponded to authentic Rp-d-ApT, whereas the dimer obtained from the second peak corresponded to authentic Sp-d-ApT (25)(26)(27). The retention times of these two diastereomers differed by 0.22 min on the C-18 column using a linear gradient of 2-3 % acetonitrile for the first 12 min of elution followed by a linear gradient of 3-30% acetonitrile for the next 8 min.…”