Design of Novel Potent Inhibitors of Human Uridine Phosphorylase-1: Synthesis, Inhibition Studies, Thermodynamics, and in Vitro Influence on 5-Fluorouracil Cytotoxicity

Renck, Daiana; Machado, Pablo; Souto, André A.; Rosado, Leonardo Astolfi; Erig, Thaís Cristina; Campos, Maria M.; Farias, Caroline Brunetto de; Roesler, Rafaël; Timmers, Luís Fernando Saraiva Macedo; Souza, Osmar Norberto de; Santos, Daniel Silas Veras dos; Basso, Luiz Augusto

doi:10.1021/jm401389u

Cited by 16 publications

(14 citation statements)

References 62 publications

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“…Moreover, this high‐dose chemotherapy actually enhanced the efficiency of killing cancer cells, but not normal cells. Several drug candidates capable of increasing the concentration of uridine to support synergetic treatment of 5‐FU, including 5‐benzylacyclouridine (BAU) and 5‐(phenylthio)acyclouridine (PTAU), have been developed 25,47–50 . However, the mechanism of uridine rescue remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Metabolites modulate the functional state of human uridine phosphorylase I

et al. 2020

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Metabolic pathways in cancer cells typically become reprogrammed to support unconstrained proliferation. These abnormal metabolic states are often accompanied by accumulation of high concentrations of ATP in the cytosol, a phenomenon known as the Warburg Effect. However, how high concentrations of ATP relate to the functional state of proteins is poorly understood. Here, we comprehensively studied the influence of ATP levels on the functional state of the human enzyme, uridine phosphorylase I (hUP1), which is responsible for activating the chemotherapeutic pro-drug, 5-fluorouracil. We found that elevated levels of ATP decrease the stability of hUP1, leading to the loss of its proper folding and function. We further showed that the concentration of hUP1 exerts a critical influence on this ATP-induced destabilizing effect. In addition, we found that ATP interacts with hUP1 through a partially unfolded state and accelerates the rate of hUP1 unfolding. Interestingly, some structurally similar metabolites showed similar destabilization effects on hUP1. Our findings suggest that metabolites can alter the folding and function of a human protein, hUP1, through protein destabilization. This phenomenon may be relevant in studying the functions of proteins that exist in the specific metabolic environment of a cancer cell.

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Section: Discussionmentioning

confidence: 99%

Metabolites modulate the functional state of human uridine phosphorylase I

et al. 2020

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“…In certain cell lines, up-regulation of UP1 leads to increased 5-FU efficacy [ 136 ], however, in a cohort of 43 patients with gastric cancer, high expression of UP1 was associated with worse overall survival [ 287 ]. In addition, the effects of UP1 inhibitors on 5-FU toxicity are cell-line dependent and can both decrease and increase the efficacy of 5-FU as shown for three different colon cancer cell lines [ 137 ], possibly reflecting that the relative contribution mediated by different 5-FU metabolites depends on the cellular background. This is further complicated by the fact that UP1 also catalyses conversion of 5-FdUrd to 5-FU [ 288 ].…”

Section: Tumour-specific Resistance To Nucleobase/nucleoside Analomentioning

confidence: 99%

Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Tsesmetzis

Paulin

Rudd

et al. 2018

Cancers

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Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.

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“… 16 In addition, the toxicity of drugs also could be reduced via the introduction of amino acids. 17 Conjugation of amino acids/peptides with heterocycles, 18,19 especially with a quinazolinone moiety, 20–22 enhances the overall therapeutic properties of the molecule. Motivated by the aforementioned literature and the recent encouraging results from our research group, 23–25 we have directed systematic efforts towards the synthesis of new bis-hydrazones of Asp and Glu linked quinazolinone derivatives followed by the study of their antimicrobial, antioxidant and anti-inflammatory activity.…”

Section: Introductionmentioning

confidence: 99%