Chapter 2: Ring-Expanded (‘Fat‘) Purines and their Nucleoside/Nucleotide Analogues as Broad-Spectrum Therapeutics

This chapter describes a family of ring-expanded purines, informally referred to as “fat” or f-purines, as well as their nucleoside/nucleotide analogues (RENs/RENTs) that have broad applications in chemistry, biology, and medicine. Although purine itself has never been found in nature, substituted purines, such as adenine and guanine, or their respective nucleoside derivatives, adenosine and guanosine, are the most ubiquitous class of nitrogen heterocycles and play crucial roles in wide variety of functions of living beings As nucleotides (AMP,GMP), they are the building blocks of nucleic acids (RNA/DNA). They serve as energy cofactors (ATP, GTP), as part of coenzymes (NAD/FAD) in oxidation-reduction reactions, as important second messengers in many intracellular signal transduction processes (cAMP/cGMP), or as direct neurotransmitters by binding to purinergic receptors (adenosine receptors). Therefore, it is not surprising that the analogues of purines have found utility both as chemotherapeutics (antiviral, antibiotic, and anticancer agents) and pharmacodynamic entities (the regulation of myocardial oxygen consumption and cardiac blood flow). While they can act as substrates or the inhibitors of the enzymes of purine metabolism to render their chemotherapeutic action, their ability to act as agonists or antagonists of A1/A2A receptors is the basis for the modulation of pharmacodynamic property.