Current Medicinal Chemistry - Volume 30, Issue 11, 2023

Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review, we focus on the differences in energy metabolism between cancer and normal cells to better understand their resistance and how to develop drugs targeting energy metabolism and nucleotide synthesis. One of the differences between cancer and normal cells is the higher nicotinamide adenine dinucleotide (NAD⁺) level, a cofactor for the tricarboxylic acid cycle (TCA), which enhances their proliferation and helps cancer cells survive under hypoxic conditions. An important change is a metabolic switch called the Warburg effect. This effect is based on the change of energy harvesting from oxygen-dependent transformation to oxidative phosphorylation (OXPHOS), adapting them to the tumor environment. Another mechanism is the high expression of one-carbon (1C) metabolism enzymes. Again, this allows cancer cells to increase proliferation by producing precursors for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice and development targeting NAD⁺, OXPHOS, and 1C metabolism. Combining novel drugs with conventional antineoplastic agents may prove to be a promising new way of anticancer treatment.

Adenosine triphosphate (ATP) is one of the most important molecules of life, present both inside the cells and extracellularly. It is an essential building block for nucleic acids biosynthesis and crucial intracellular energy storage. However, one of the most interesting functions of ATP is the role of a signaling molecule. Numerous studies indicate the involvement of ATP-dependent pathways in maintaining the proper functioning of individual tissues and organs. Herein, the latest data indicating the ATP function in the network of intra- and extracellular signaling pathways including purinergic signaling, MAP kinase pathway, mTOR and calcium signaling are collected. The main ATP-dependent processes maintaining the proper functioning of the nervous, cardiovascular and immune systems, as well as skin and bones, are summarized. The disturbances in the ATP amount, its cellular localization, or interaction with target elements may induce pathological changes in signaling pathways leading to the development of serious diseases. The impact of an ATP imbalance on the development of dangerous health dysfunctions such as neurodegeneration diseases, cardiovascular diseases (CVDs), diabetes mellitus, obesity, cancers and immune pathogenesis are discussed here.

Nucleoside analogues are widely used as anti-infectious and antitumoral agents. However, their clinical use may face limitations associated with their physicochemical properties, pharmacokinetic parameters, and/or their peculiar mechanisms of action. Indeed, once inside the cells, nucleoside analogues require to be metabolized into their corresponding (poly-)phosphorylated derivatives, mediated by cellular and/or viral kinases, in order to interfere with nucleic acid biosynthesis. Within this activation process, the first-phosphorylation step is often the limiting one and to overcome this limitation, numerous prodrug approaches have been proposed. Herein, we will focus on recent literature data (from 2015 and onwards) related to new prodrug strategies, the development of original synthetic approaches and novel applications of nucleotide prodrugs (namely pronucleotides) leading to the intracellular delivery of 5’-monophosphate nucleoside analogues.

Background: Nucleoside and nucleobase antimetabolites are an important class of chemotherapeutic agents for the treatment of cancer as well as other diseases. Introduction: In order to avoid undesirable side effects, several prodrug strategies have been developed. In the present review, we describe a relatively unknown strategy that consists of using oligonucleotides modified with nucleoside antimetabolites as prodrugs. Methods: The active nucleotides are generated by enzymatic degradation once incorporated into cells. This strategy has attracted large interest and is widely utilized at present due to the continuous developments made in therapeutic oligonucleotides and the recent advances in nanomaterials and nanomedicine. Results: A large research effort was made mainly in the improvement of the antiproliferative properties of nucleoside homopolymers, but recently, chemically modified aptamers, antisense oligonucleotides and/or siRNA carrying antiproliferative nucleotides have demonstrated a great potential due to the synergetic effect of both therapeutic entities. In addition, DNA nanostructures with interesting properties have been built to combine antimetabolites and enhancers of cellular uptake in the same scaffold. Finally, protein nanoparticles functionalized with receptor-binders and antiproliferative oligomers represent a new avenue for a more effective treatment in cancer therapy. Conclusion: It is expected that oligonucleotides carrying nucleoside antimetabolites will be considered as potential drugs in the near future for biomedical applications.

In recent years, RNA has emerged as a medium with a broad spectrum of therapeutic potential, however, for years, a group of short RNA fragments was studied and considered therapeutic molecules. In nature, RNA plays both functions, with coding and non-coding potential. For RNA, like any other therapeutic, to be used clinically, certain barriers must be crossed. Among them, there are biocompatibility, relatively low toxicity, bioavailability, increased stability, target efficiency and low off-target effects. In the case of RNA, most of these obstacles can be overcome by incorporating modified nucleotides into its structure. This may be achieved by both, in vitro and in vivo biosynthetic methods, as well as chemical synthesis. Some advantages and disadvantages of each approach are summarized here. The wide range of nucleotide analogues has been tested for their utility as monomers for RNA synthesis. Many of them have been successfully implemented, and a lot of pre-clinical and clinical studies involving modified RNA have been carried out. Some of these medications have already been introduced into clinics. After the huge success of RNA-based vaccines that were introduced into widespread use in 2020, and the introduction to the market of some RNA-based drugs, RNA therapeutics containing modified nucleotides appear to be the future of medicine.