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Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses.

A novel strategy was developed for the synthesis of N(7)-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p-methoxyphenyloxy)ethoxy]methyl chloride and N(9)-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N(7)-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than acyclovir (2). N(7)-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine d

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… For example, upregulation of pyrimidine synthesis rate limiting enzymes phosphoribosyl pyrophosphate synthase (PRPS) is common in various cancers [ 6 ]. In addition, abnormal accumulation of nucleotide metabolites can lead to various metabolic and inflammatory diseases. … Thioguanine's antitumor activity is also attributable to the suppression of nucleotide biosynthesis, specifically through its metabolite methylthioguanine monophosphate, which inhibits the crucial purine biosynthesis enzyme phosphoribosyl pyrophosphate amidotransferase [ 215 ]. …

Biosynthesis of anticancer phytochemical compounds and their chemistry.

Cancer is a severe health issue, and cancer cases are rising yearly. New anticancer drugs have been developed as our understanding of the molecular mechanisms behind diverse solid tumors, and metastatic malignancies have increased. Plant-derived phytochemical compounds target different oncogenes, tumor suppressor genes, protein channels, immune cells, protein channels, and pumps, which have attracted much attention for treating cancer in preclinical studies. Despite the anticancer capabilities of these phytochemical compounds, systemic toxicity, medication resistance, and limited absorption re

Распознавание ксантиновой реберосколочной структуры и металлическое ионопосредованное распознавание лиганда.

Рибосколки сохраняют функциональные области в MRNA, которые в основном существуют в бактериях. Они регулируют генное выражение в ответ на различные концентрации метаболитов или металлических ионов. Недавно был выявлен мотив РНК NMT1 для селективной привязки ккантиновой и мочевой кислот, соответственно, к метаболическому пути деградации пурины. Вот, мы сообщаем о кристаллической структуре этой РНК, связанной с ксантиной. В целом рибосуха имеет стержень, постоянно сложенный в сложенном виде three стебли и two внутренние перекрестки. Связующий карман определяется высокоохранной соединенной послед

Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.

BackgroundCancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.MethodsAn extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.ResultsThe rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nu

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… pyrophosphate phosphoserine transaminase renal cell carcinoma ribonucleic acid solute carriers SLC7A11‐Antisense RNA 1 Sterol regulatory element binding protein transcriptionally active form of the p73 protein tricarboxylic acid testicular germ cell tumors thymidine kinase 1 transketolase‐like … The salvage process supports cells in recovering nucleotides and nucleobases from the intra‐ and extracellular environment through a reaction with phosphoribosyl pyrophosphate (PRPP) [ 24 , 108 ]. …

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… Phosphoribosyl pyrophosphate; PRPS1. Phosphoribosyl pyrophosphate synthetase 1; PRPS2. Phosphoribosyl pyrophosphate synthetase 2; REV-ERBα. Nuclear receptor subfamily 1 group D member 1; SCD1. Stearoyl-CoA desaturase 1; SCFAs. Short-chain fatty acids; SIRT. Sirtuin; SREBP1c. … Phosphorylated CLOCK is translocated to the cytoplasm, where acetylation stabilizes the rate-limiting nucleotide synthesis enzymes phosphoribosyl pyrophosphate synthetase 1/2 (PRPS1/2), thereby driving de novo nucleotide synthesis and supporting tumor proliferation [112] . …

MTAP-Null Tumors: A Comprehensive Review on Synthetic Vulnerabilities and Therapeutic Strategies.

Homozygous deletion of the 9p21.3 genomic locus spanning the CDKN2A/B and MTAP genes is an event affecting 15% of cancers. While CDKN2A is a well-established tumor suppressor gene, the role of MTAP in tumorigenesis varies across cancer types. MTAP codes for methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway, and its loss has been associated with several downstream synthetic vulnerabilities. Despite multiple efforts to exploit MTAP loss for targeted therapies, none of these efforts have yielded substantial results in clinical trials. In this review, we consolidate

Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.

Circadian rhythm is a self-regulating 24-hour system that synchronizes with the day and night cycle in organisms. The regulation of this system is controlled by clock genes, which function to harmoniously express molecular levels that facilitate the orderly coordination of various cellular processes, such as sleep, metabolism, endocrine function, cell proliferation and immunity. The root cause of tumorigenesis is that the body loses its normal regulation of cell growth at the genetic level. Long-term disruptions in circadian rhythms caused by factors such as shift work, jet lag, and unstable s

Nrf2-Независимое антивоспалительное воздействие диметилфумарата: проблемы и перспективы развития электрофильных Nrf2 активаторов нейродегенеративных заболеваний.

Связанный с NF-E2 путь 2 (Nrf2)-антиоксидантный элемент реакции (ARE) является потенциальной терапевтической целью для заболеваний центральной нервной системы. В настоящем обзоре подчеркивается роль окислительного стресса и нейронного воспаления в нейродегенеративных заболеваниях с уделением особого внимания терапевтическому потенциалу таких активаторов Nrf2, как диметилфумарат (ДМФ). ДМФ, первоначально применяемый для лечения псориаза, продемонстрировал эффективность при множественном склерозе и метаболизируется до монометила фумарата, что может оказывать значительное терапевтическое воздейст

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… Other regulated pathways involve the pentose phosphate pathway (e.g., glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase), nucleotide biosynthesis (e.g., phosphoribosyl pyrophosphate amidotransferase and methylenetetrahydrofolate dehydrogenase 2), serine/glycine biosynthesis (e.g., …

Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen meta

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… Abbreviations: ASS1: Argininosuccinate Synthetase 1; NOS2: Nitric Oxide Synthase 2; GLS1: Glutaminase 1; OTC: Ornithine Transcarbamylase; CPS1: Carbamoyl Phosphate Synthetase 1; PPAT: Phosphoribosyl Pyrophosphate Amidotransferase; ARG1: Arginase 1; ARG2: Arginase 2; OAT: Ornithine Aminotransferase; GLUL …

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations.

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sen

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… The PPP ultimately generate phosphoribosyl pyrophosphate (PRPP), the precursor for nucleotide synthesis. Cancer cells have increased G6PD levels and PPP activity [ 146 , 147 , 148 , 149 ]. … Purines are assembled on the ribose sugar PRPP, wherein carbon and nitrogen molecules are donated by non-essential amino acids and one-carbon formyl units from the tetrahydrofolate (THF) cycle. mTORC1 has been implicated in the increased expression of phosphoribosyl pyrophosphate synthase 2 (PRPS2), …

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies.

Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, an

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… Besides that, different P2Y and P2Y-related receptor agonist such as ATP, UDP-glucose, phosphoribosyl pyrophosphate, α-ketoglutarate, leukotrienes, and phospholipids were analyzed to intend its capacity on activate GPR87 but only LPA significantly increased GPR87-mediated [Ca 2+ ] i levels. 64 Furthermore …

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

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… Acute lymphoblastic leukaemia (ALL); acute myeloid leukaemia (AML); phosphoribosyl pyrophosphate aminotransferase (PPAT); thymidylate synthase (TS). …

Prodrugs in Oncology: Bioactivation and Impact on Therapeutic Efficacy and Toxicity.

A prodrug is a molecule that lacks pharmacological activity, but upon enzymatic bioactivation, it can generate a therapeutically active molecule. The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associate

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… This can occur directly, with the reaction being catalyzed by orotate phosphoribosyltransferase (OPRT) using phosphoribosyl pyrophosphate (PRPP) as the cofactor [ 122 ]. …

Another Weapon against Cancer and Metastasis: Physical-Activity-Dependent Effects on Adiposity and Adipokines.

Physically active behavior has been associated with a reduced risk of developing certain types of cancer and improved psychological conditions for patients by reducing anxiety and depression, in turn improving the quality of life of cancer patients. On the other hand, the correlations between inactivity, sedentary behavior, and overweight and obesity with the risk of development and progression of various cancers are well studied, mainly in middle-aged and elderly subjects. In this article, we have revised the evidence on the effects of physical activity on the expression and release of the ad

Tumor microenvironment signaling and therapeutics in cancer progression.

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss t

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.

Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs

DNA Damaging Drugs

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Invited Lectures : Overviews Purinergic signalling: past, present and future.

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In vitro расширила человека CD4+CD25+ регуляционные T клетки, подавляющие распространение Т клеток.

Регулирующие Т клетки (Tregs) оказались критически важными в балансе между автоиммунизацией и терпимостью и были связаны с несколькими аутоиммунными заболеваниями человека. Однако небольшое число трегов в периферии крови ограничивает их терапевтический потенциал. Поэтому мы разработали протокол, который позволит расширить "Трегз" при сохранении их подавляющей активности. Мы изолировали клетки CD4+CD25 hi от человеческой периферической крови и расширили их in vitro в присутствии anti-CD3 и anti-CD28 Магнитные кситы и высокие концентрации внешнего интерлейкина (IL) -2. Траги были эффективно расш