as described.31 Log P values used in calculations are shown in Table III.Acknowledgment. We are grateful to the Pharmaceutical Society of New South Wales for support to Peter J. Little during part of this study. We thank C. Harwood for excellent assistance with the preparation of the manuscript.

The oligonucleotide building blocks 4b-d derived from 7-bromo-, 7-chloro-, and 7-methyl-substituted 7-deaza-2'-deoxyadenosines 3bd were prepared. They were employed in the solid-phase synthesis of the oligonucleotides 7-25. The dA residues of the homomer d(A12), the alternating d[(A-T),], and the palindromic d(G-T-A-G-A-A-T-T-C-T-A-C) were replaced by 3 M as well as by the parent 7-deaza-2'-deoxyadenosine (3a). The melting profiles and CD spectra of oligonucleotide duplexes, showing this major groove modification: were measured, and the T,,, values as well as the thermodynamic data were determined. It was found that small substituents such as Br, CI, or Me introduced in the 7-position of a 7-deazaadenine residue increase the duplex stability compared to oligonucleotides containing adenine.

The syntheses of six 6-substituted-9-,B-~-ribofuranosplpurines from 6-chloro-9-P-~-ribofuranosylpurine have been accomplished.i o 0

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9-(3,3-Dimethyl-5-phosphonopentyl)guanine was synthesized and found to be a potent inhibitor of purine nucleoside phosphorylase (PNP) (IC50 = 44 nM). A number of other functional end groups were investigated as phosphate mimics attached to the 9-position of guanine by this same alkyl side chain, which provided a sensitive method for the detection of any interaction of these groups with the phosphate binding site of PNP. Both the sulfonic acid (compound 13) and the carboxylic acid (compound 15) end groups interact significantly with the phosphate binding site, but in different ways, as determined by X-ray crystallographic analysis of the complexes. The sulfonic acid of 13, which binds about one-fourth as tightly as the phosphonate 12, binds in the phosphate subsite much like the phosphonic acid. The carboxylic acid, the interaction of which is much weaker, turns away from the center of the phosphate binding site to form hydrogen bonds with Ser 200 and Met 219. Thus, the only phosphate mimics that bind like phosphate itself are themselves highly ionic, probably with limited ability to penetrate cell membranes.

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