Purines are heterocyclic compounds composed of a pyrimidine ring and an imidazole ring and are the main components of nucleic acids. Their derivatives, such as adenine, guanine, and xanthine, are abundant in living organisms (Figure 1). They form 9-glycosides with ribose or deoxyribose and exist in the organism as nucleotides with phosphates. Purines, purine derivatives, and their isomers are the most widely distributed nitrogen-containing heterocyclic compounds in nature. As a new type of atypical antibiotic connected to ribose, they have antibacterial, antifungal, anticancer, antiproliferative, antiviral, and other effects.
Nucleosides are organic compounds in which a nitrogen-containing heterocyclic base is linked to a 5-carbon sugar, and analogs have modified bases linked to modified sugars or sugar derivatives. Nucleotides/nucleoside analogs are essential heterocycles in pharmacology (Figure 2), and they are the basis of RNA and DNA synthesis. Many nucleoside analogs have been approved for the treatment of various viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), varicella-zoster virus (VZV), and Ebola virus.
Sugar compounds are the most abundant organic compounds in nature, with diverse types and complex structures, and their structural complexity also gives rise to their functional diversity (Figure 3). From the composition of biological organisms, and energy supply, to various biological recognition processes, signal transduction pathways, and the occurrence and development of various diseases, sugar molecule building blocks play an irreplaceable role.
Application of purine & nucleoside & sugar molecule building blocks
In the synthesis of small-molecule drugs, the distinctive features of purine & nucleoside & sugar molecule building blocks offer small-molecule drugs greater possibilities and wider applications in the field of medicine.
Caffeine is a well-known purine alkaloid widely used as a central nervous system stimulant (Figure 4a). When an excess of adenosine is produced in the brain, binding of adenosine with A1 receptors can stimulate nerves, but when used in conjunction with A2 receptors, it can cause drowsiness. When the stimulation received by A2 receptors exceeds that of A1 receptors, the body signals the need for rest. After entering the human body, caffeine can bind to both types of adenosine receptors without activating them, thereby reducing the activity of adenosine and increasing the activity of the neurotransmitter dopamine.
Theobromine is a methylxanthine discovered in cocoa beans that can inhibit adenosine A1 receptor signaling (Figure 4b). It is also an endogenous metabolite of the human body. When its concentration in the body exceeds 25 μM, it can reduce lipid accumulation in these cells by inhibiting the expression of PPARγ, C/EBPα, and other factors.
Cangrelor is a platelet P2Y12 antagonist developed by the Medicine’s Company for the treatment of thrombotic cardiovascular diseases, coronary artery diseases, and myocardial infarction. It was approved by the FDA for sale in 2015 (Figure 5). Cangrelor is also a competitive and reversible nucleotide analog of adenine purine, which is characterized by its fast onset of action, low reversal, and low metabolic stress.
Remdesivir is a prodrug of phosphoramidite nucleotide that is typically easier to penetrate cells and further metabolized into an active form, a nucleotide triphosphate derivative. Its primary mode of action is to compete with endogenous nucleotides and replicate viral RNA on RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication. It is therefore considered a broad-spectrum antiviral drug for the treatment of COVID-19. As a structurally complex molecule, Remdesivir consists of three key segments (Figure 6): an adenine analog base, a pentose unit, and a phosphate side chain.
Synthesis of purine, nucleoside, and carbohydrate drugs
The use of purine, nucleoside, and carbohydrate building blocks in drug synthesis has broad application prospects in the field of drug development. With the study of their mechanisms of action, there will be more new drug molecules designed and synthesized using purine, nucleoside, and carbohydrate building blocks.
Entecavir is an HBV reverse transcriptase inhibitor containing a purine skeleton. It was developed by Bristol-Myers Squibb and is used for the treatment of chronic hepatitis B. The drug was approved by the US FDA in 2005.
Duvelisib is a novel oral inhibitor of PI3K protein kinase developed by Verastem. It can simultaneously inhibit the activity of PI3K-δ and PI3K-γ, two protein kinases that help support the survival and growth of cancerous B cells. The drug was approved by the US FDA in 2018 for the treatment of B-cell chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma.
Emtricitabine is an HIV-1 reverse transcriptase inhibitor developed by Gilead and approved by the US FDA in 2003 for the treatment of HIV infection. The drug is typically used in combination with other drugs for the treatment of acquired immune deficiency syndrome (AIDS).
Namodenoson is a highly selective oral adenosine A3 receptor agonist developed by Can-Fite BioPharma. By blocking NF-κB and Wnt, two cancer signaling pathways, it induces apoptosis in tumor cells. The drug is currently in phase III clinical trials and has received orphan drug designation from the European Medicines Agency (EMA) and the US FDA, as well as fast-track designation from the US FDA.
References
1. Elzagheid, Mohamed Ibrahim. Nucleosides and Nucleoside Analogues as Emerging Antiviral Drugs. Mini-Reviews in Organic Chemistry (2021), 18(6), 672-679
2. Hricovini, Milos. Structural aspects of carbohydrates and the relation with their biological properties. Current Medicinal Chemistry (2004), 11(19), 2565-2583
3. Rammohan, Aluru; Zyryanov, Grigory V. Minireview: Remdesivir, A Prominent Nucleotide/Nucleoside Antiviral Drug. Polycyclic Aromatic Compounds (2022), 42(8), 5824-5831
4. Rosemeyer, Helmut. The chemodiversity of purine as a constituent of natural products. Chemistry & Biodiversity (2004), 1(3), 361-401
5.Ying, Dan-Xia; Zhao, Peng-Cheng; Zhang, Wen; Rao, Guo-Wu. Research progress of purine competitive antagonists. Current medicinal chemistry (2023), 30(34), 3880-3904