A new class of shape-modified nucleosides is introduced. These novel "fleximers" feature the purine ring systems of adenosine, inosine, and guanosine split into their individual imidazole and pyrimidine components (as in 1-3). This structural modification serves to introduce flexibility into the nucleoside while still retaining the elements essential for recognition. As a consequence, these novel fleximers should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis are described.

The purine ring system is undoubtedly one of the most ubiquitous heterocyclic ring systems in nature as it has the distinction of being the parent ring in countless derivatives of biological relevance. It is not surprising then that modified purines possess the potential to impact several areas, including a better understanding of the biological effects of DNA damaging agents, enzyme/substrate interactions, and in the development of more potent medicinal agents. One focus for our research at Georgia Tech has centered around the design and synthesis of a series of extended purine analogues containing a heterocyclic spacer ring, with sites set on investigations into their use as (i) potential anticancer and antiviral agents, (ii) dimensional probes for enzyme and coenzyme binding sites, and (iii) structural probes of the minor groove of DNA. The synthesis and preliminary antitumor activity of two thieno-separated purine analogues are described herein. Tricyclic 1 was synthesized in 12 steps from tribromoimidazole and with an overall yield of 7%. Tricyclic 2 was synthesized in 9 steps with an overall yield of 13%. Both 1 and 2 exhibited growth inhibitory effects on HCT116 colorectal cancer cells in vitro.

[structure: see text] A new class of shape-modified nucleosides is introduced. The purine heterobases of adenosine and guanosine have been split into their imidazole and pyrimidine components, thereby introducing flexibility while retaining the elements necessary for recognition. As a consequence, these novel "fleximers" should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis is described.

The second series of flexible shape-modified nucleosides is introduced. The "fleximers" feature the purine ring systems split into their individual imidazole and pyrimidine components. This structural modification serves to introduce flexibility to the nucleoside while still retaining the elements essential for recognition. As a consequence, these structurally innovative nucleosides can more readily adapt to their environment and should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis is described.

A detailed (1)H NMR conformational study complemented with ab initio computations was performed in solution on fleximer nucleosides 1, 3, and 5 in relation to their natural counterparts. The substitution of the purine nucleobase found in the natural nucleosides with a more flexible two-ring heterocyclic system strongly increased the population of anti conformation around the glycosidic bond. This was accompanied by a large shift toward a north-type sugar conformation, which was explained by the interplay of anomeric, gauche, and steric effects. The formal separation of the bicyclic purine base into its imidazole and pyrimidine moieties allows for formation of a hydrogen bond between the NH(2) and 2'-OH groups and facilitates favorable conjugation between the two heterocyclic rings. Our results show that the interplay of stereoelectronic effects, combined with the flexibility of the nucleobase and possible conjugation effects within the nucleobase, plays a crucial role in the search for shape-mimic nucleosides that will interact with flexible binding sites.