This invention presents novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as "antisense" agents--agents that are capable of specific hybridization with a nucleotide sequence of an RNA. Oligonucleotides are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins, and cleaving RNA in site specific fashions. The compounds of the invention include novel heterocyclic bases, nucleosides, and nucleotides. When incorporated into oligonucleotides, the compounds of the invention can be useful for modulating the activity of RNA.

Oligonucleotides containing N-2 substituted purines

A number of investigation have been published in which attempts are made to correlate the chemical or physical properties of substances with the intensity of their toxic action. Among these may be instanced the work of Moore (1917) on the toxicity of fumigants towards insects, the extensive work of Tattersfield and his collaborators on contact insecticides and fumigants (Tattersfield and others 1920, 1925, 1926, 1927), the bacteriological investigations of Tilley ans Schaffer (1926, 1928) and others (Coulthard, Marshall and Pyman 1930; Dohme, Cox and Millar 1926; Klatman, Gatyas and Shternov 1931), work on fungicides (Morris and Stirk 1932; Stiles and Rees 1935). In each of the investigations just quoted a more or less wide range of chemical compounds was examined. The experiments consisted in the determination of the molar concentrations of the compounds which produced equi-toxic on a selected organism. The toxicities of the compounds studied were then usually assumed to be inversely proportional to the values of these equi-toxic concentrations.

The Use of Chemical Potentials as Indices of Toxicity

The reactions of iodobenzene with azole compounds, 1,2-disubstituted imidazoles and 2-substituted oxazoles and thiazoles, were examined in the presence of catalytic amounts of Pd(OAc)2 and PPh3 in DMF using alkali metal carbonates as bases. It was found that the coupling products, 5-arylazoles, could be selectively produced in good yields by using Cs2CO3. In the case that their 2-position is unsubstituted, the site could also be arylated. In reactions using bromobenzene in place of iodobenzene, K2CO3 was also as effective as Cs2CO3. The addition of a stoichiometric amount of CuI appeared to specifically promote the reactions of thiazoles as well as those of thiophene derivatives. The reactions of 2-unsubstituted azole compounds with aryl iodides could be mediated by CuI to some extent without using the palladium species to give 2-arylazoles.

Palladium-Catalyzed Arylation of Azole Compounds with Aryl Halides in the Presence of Alkali Metal Carbonates and the Use of Copper Iodide in the Reaction

Stereocontrol in the synthesis of acyclic systems: applications to natural product synthesis

Frank Lee Pyman

Papers

XXVI.—Nitro-, arylazo-, and amino-glyoxalines

XXII.—Derivatives of glyoxaline-4(or 5)-formaldehyde and glyoxaline-4(or 5)-carboxylic acid. A new synthesis of histidine

LXXIV.—A new synthesis of 4(or 5-)-β-aminoethylglyoxaline, one of the active principles of ergot

CIX.—Bromo-derivatives of glyoxaline

CCCLV.—The relation between chemical constitution and pungency in acid amides