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

Recent developments in the synthesis of C-glycosides

The palladium-catalyzed vinylation of organic halides provides a very convenient method for forming carboncarbon bonds at unsubstituted vinylic positions. Generally the reaction does not require anhydrous or anaerobic conditions although it is advisable to limit access of oxygen when arylphosphines are used as a component of the catalyst. The transformation is valuable because it cannot be carried out in a single step by any other known method (except in certain Meerwein reactions).



The organic halide employed is limited to aryl, heterocyclic, benzyl, or vinyl types, with bromides and iodides seen most often. Halides with an easily eliminated beta-hydrogen atom (i.e., alkyl derivatives) cannot be used since they form only olefins by elimination under the normal reaction conditions. The base needed may be a secondary or tertiary amine, sodium or potassium acetate, carbonate, or bicarbonate.



When nucleophilic secondary amines are used as coreactants with most vinylic halides, a variation occurs that often produces tertiary allylic amines as major products. The catalyst is commonly palladium acetate, although palladium chloride or preformed triarylphosphine palladium complexes, as well as palladium on charcoal, have been used. A reactant, product, or solvent may serve as the ligand in reactions involving organic iodides, but generally a triarylphosphine or a secondary amine is required when organic bromides are used. The reaction, which occurs between ca. 50° and 160° proceeds homogeneously. Solvents such as acetonitrile, dimethylformamide, hexamethylphosphoramide, N-methylpyrrolidinone, and methanol have been used, but are often not necessary. The procedure is applicable to a very wide range of reactants and yields are generally good to excellent.



Several variations of the reaction are known in which the organic halide is replaced by other reagents such as organometallics, diazonium salts, or aromatic hydrocarbons. These reactions are not discussed in detail, but are only briefly compared with the halide reaction. Other related reactions such as the palladium-catalyzed replacement of allylic substituents with carbanionic reagents, the palladium-promoted nucleophilic substitutions at olefinic carbons, and the numerous palladium-catalyzed coupling reactions of halides and organometallics are also beyond the scope of this review. The palladium-catalyzed vinylic substitution reaction has not yet received much attention from organic chemists, but its broad scope and simplicity demonstrate that it is a useful method for the synthesis of a variety of olefinic compounds.


Keywords:

palladium catalyst;
vinylation;
organic halides;
scope;
limitations;
experimental procedures;
vinylic substitution;
ethylene;
acrylic acid;
butenol;
methyl acrylate;
styrene;
pentadiene;
acrolein dimethyl acetal;
olefins

Palladium‐Catalyzed Vinylation of Organic Halides

Publisher Summary This chapter reviews recent advances in the chemistry and biochemistry of C-nucleosides, the literature concerning C-arylglycoside (i.e., nonnitrogen heterocyclic C-nucleoside) antibiotics, and recent significant advances in the synthesis of C-nucleosides and C-glycosides. It also discusses biological test data and data that are relevant to structure–activity relationships. Modification of readily available natural C-nucleosides is an attractive route to new C-nucleoside analogs and derivatives, because one starting material often possesses much of the desired functionality and chiral properties. The chapter illustrates this approach with examples. The most frequently used strategy for C-nucleoside synthesis involves the construction of a heterocyclic aglycone from the C-1 substituent of a functionalized sugar intermediate.

The chemistry and biochemistry of C-nucleosides and C-arylglycosides.

C-glycoside synthesis by palladium-mediated glycal-aglycon coupling reactions

Publisher Summary This chapter discusses the C-nucleoside literature. With respect to the naturally occurring C-nucleosides, most work published since 1970 has been discussed. In reviewing work relevant to the synthesis of C-nucleosides, the various synthetic strategies that have been developed have been discussed. Numerous new compounds for biological testing have been achieved by modification of natural C-nucleosides. synthetic approaches to C-nucleosides have utilized preformed carbohydrates as starting material. Successful syntheses have involved: (a) direct linkage of preformed base and carbohydrate precursors; and/or (b) stepwise construction of a heterocyclic base onto a preformed carbohydrate derivative. The chapter discusses c-nucleosides in biology and medicine. The elegant biological experiments using formycin have made great contributions by calling attention to the subtle and critical roles conformation and conformational flexibility of biomolecules play in their normal functioning. Numerous, perhaps a majority, of the synthetic C-nucleosides are becoming available for study in biological systems.

The chemistry and biochemistry of C-nucleosides.

Publisher Summary This chapter lists some pyrimidines of biological and medicinal interest, including 5-hydroxypy rimidines, barbituric acid and its derivatives, aminohydroxypyrimidines, pyrimidine amino acids, and nitro and nitrosopyrimidines. The chapter also discusses pyrimidines containing biological alkylating functions. A large number of derivatives of the original nitrogen mustard and other biological akylating agents, such as ethylenimines and epoxides have been prepared as potential anticancer agents. The chapter further explains that the alkylating agents consist of a carrier and the alkylating group, and that differences in selectivity of action upon the tumour, or ability to reach the site of desired action, with minimum damage to the host, are dependent upon the carrier. The chapter also reviews that some pyrimidines containing two ethylenimine functions have also been found to possess anticancer activity. 2, 4-Bis (aziridinyl)-6-chloropyrimidine (CV, ethymidine, etimidin) significantly inhibits growth of many transplantable mouse and rat tumours.

C.C. Cheng

Papers

The chemistry and biochemistry of C-nucleosides.

3 Some Pyrimidines of Biological and Medicinal Interest—Part III