Endo-puckerings

X-Ray diffraction analyses of vincristine methiodide (39) and vinzoli-dine 1-naphthalene sulfonate (40) provide atomic coordinates of compounds that are either modified in the velbanamine portion (alkylation at N-6, Fig. 3) or in the vindoline portion (a spiro-fused oxazolidinedione at C-3 and C-23, Fig. 4). These structures show a chair-boat conformation for ring C with C-8 exhibiting an endo pucker. Ring D is clearly in a chair conformation, but, in contrast to the conclusions drawn from C-NMR studies, the N-6 -C-7 bond is axial relative to the piperidine ring. 

Many of the structural differences between B-DNA and A-DNA arise from different puckcrings of their ribose units (Figure 28,4). In A-DNA, C-3 lies out of the plane (a conformation referred to as C-3 endo) formed by the other four atoms of the furanose ring in B- DNA, C-2 lies out of the plane (a conformation called C-2 endo). The C-3 -endo puckering in A-DNA leads to an 11 -degree tilting of the base pairs away from the normal to the helix. The phosphates and other groups in the A helix bind fewer H>0 molecules than do those in B-DNA. Hence, dehydration favors the A form. 

In order to preserve optimal stability in the hybridization of RNA by sugar-modified oligonucleotides, nucleosides substituted at the 2 -position must retain a C3 -endo puckered conformation. To this end, the 2 -0- 2-[iV,N-(dimethylamino)oxy]ethyl and the 2 -0- 2-[Ar,lV-(diethylamino)oxy]-ethyl 3 -phosphoramidite derivatives of thymidine (38a, 38b) have been synthesised. The nucleoside precursors were prepared from a phthalimido-derivative obtained from 2,2 -anhydro-5-methyluridine which had been treated, after appropriate protection, with a borate ester generated in situ and then reacted with PPha, DEAD and AT-hydroxyphthalimide. The incorporation of (38a) and (38b) in oligonucleotides and oligodeoxynucleotides resulted in high binding affinity for... 

NMR structure of a 2 -deoxy-2 -fluoro-D-arabinose (aF) nucleic acid duplex has been reported. The structure is a hybrid hairpin duplex containing a ribose-aF stem duplex and a four-residue DNA loop (177). The RNA strand adopted the classical A-form structure with endo sugar puckers, whilst the aF strand contained O -endo puckers and was intermediate between A- and B-form, similar to that found in DNA-RNA structures. 

P212121 Z = 4 Dx = 2.108 R = 0.07 for 1,104 reflections 75 R = 0.035 for 1,551 reflections.76 The distorted, square-pyramidal coordination around the cadmium atom includes N-3 of the cytosine residue, three oxygen atoms of different phosphate groups, and a water molecule. The nucleotide exhibits the anti conformation for the base, the C-3 endo pucker for the D-ribosyl group, and the g orientation around the C-4 -C-5 bond. 

C222j Z = 4 R = 0.078 for 2,404 reflections. The platinum atom lies on a crystallographic, two-fold axis and is bonded to N-7 of two 5 -IMP molecules. The two NH3 groups and the N-7 atoms form a square-planar arrangement around the Pt atom. The metal is markedly displaced (0.59 A, 59 pm) from the base plane. The nucleotide assumes the anti disposition for the base, the C-2 endo pucker for the D-ribosyl group, and the orientation around the exocyclic C-4 -C-5 bond. 

Fig. 11.2 Ring puckers in 4-substituted Ac-Pro-OMe. The O-endo pucker (right) is favored when X = H, OH, or F and...

In the context of the collagen triple helix it can be concluded that the Cf-exo pucker of the proline in Yaa position is favored by stereoelectronic effects of a (4R)-OH substituent which also stabilizes the traus-Xaa-(4R)-Hyp peptide bond, thus preorganizing this residue in a conformation that best befits a triple helix. Conversely, in the Xaa position the Pro residue is preferred in the Cy-endo pucker the related dihedral angles are reported in Table 11.3. 

A comparative analysis of the fluorine-substituents at C4 or C3 of the pyrrolidine ring as cis and trans isomers (8, 9, 11, and 12 in Fig. 11.3) [15,32,50] as well as of the difluoro derivative 10 in model compounds such as Ac-FPro-OMe [50-52] confirmed the expected effect of a stronger electron withdrawal both in terms of y-exo and y-endo puckering of the 5-membered ring and of cis/trans isomerization of the acyl-FPro imide bond, as shown in Tables 11.3 and 11.4. 

Fig. 18.3. a Definition of backbone torsion angles a to C and standard numbering for ribose atoms. The ribose shown adopts a C(3 )-endo pucker purine or pyrimidine bases are designated with a capital B. Hydrogens at carbon atoms C(3 ) and C(4 ) have been omitted for clarity, b Conformational ranges of torsion angles. 

N(4), and C-8 on the other. When this angle is such that the plane C-5, C-6, C-7 is bent into the fold of the pyrrolizidine nucleus, ring A is said to be endo-puckered. Conversely, when this plane is bent out from the fold of the pyrrolizidine system, ring A is said to be exo-puckered. In heliotrine the puekering angle is 45°. 

Recognition of the nucleotide base is mediated by tt-tt interactions with a conserved phenylalanine (Phe-372 in PDE4D2) that shapes the roof of the hydrophobic pocket and van der Waals interactions that line both the roof and the base. Additional hydrophobic interactions to the ribose ring, which has a C3 -endo puckering configuration, contributes to substrate recognition. 

Fig. 17.7. Ribbon diagram of the active site of PDE4D2. The AMP phosphate group binds two divalent zinc icons and forms hydrogen bonds with His-160, Asp-201, and Asp-318. The adenine group of AMP adopts an anticonformation and orients toward the hydrophobic pocket made up of residues Tyr-159 (not shown), Leu-319, Asn-321, Thr-333, lle-336, Gln-369, and Phe-372. It forms three hydrogen bonds with Gln-369 and Asn-321 and buttresses against Phe-372. The ribose of AMP has a C3 -endo puckering configuration and makes van der Waals contacts with residues His-160, Met-273, Asp-318, Leu-319, lle-336, Phe-340, and Phe-372 (24). (See color plate.)...

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