4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies

Ghoteimi, Rayane; Braka, A.; Rodriguez, Céline; Cros‐Perrial, Emeline; Nguyen, Tai Van; Uttaro, Jean‐Pierre; Mathé, Christophe; Chaloin, Laurent; Ménétrier‐Caux, Christine; Jordheim, Lars Petter; Peyrottes, Suzanne

doi:10.1016/j.bioorg.2020.104577

Cited by 16 publications

(14 citation statements)

References 38 publications

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“…First, the key intermediate diisopropyl {[(azidomethyl) (ethoxy)phosphoryl]methyl}phosphonate (3) was synthesized from a commercially available diisopropyl methyl phosphonate in three steps and a 36% overall yield (Scheme 1) as described by Ghoteimi and co-workers. 5 In the next step, the terminal alkynes 5a-f were prepared from natural products and were the starting compounds for the synthesis of the drugs. Murrayafoline A and zerumbone are the two promising anti-cancer agents.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous report, a series of 1,2,3-triazoles containing a bisphosphonate unit (P-C-P-C) was prepared and their CD73 inhibitory and cytotoxic activities were documented. 5 In addition, the non-adenosine bisphosphonates (Figure 1) were reported to inhibit the growth of human cancer cell lines. These findings encouraged us to investigate the cytotoxicity of new non-adenosine pyrophosphate analogues.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Pyrophosphates and their analogues often have a high negative charge and subsequent poor bioavailability. 5 Because of their high charge at physiological pH, pyrophosphates and their analogues can have difficulty diffusing across cell membranes. 6 To remedy this, pyrophosphonates have been considered as replacements for pyrophosphates so enabling a problematic molecule to overcome a biological obstacle.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of pyrophosphate analogues and their cytotoxic activities

Nguyen

Quan

et al. 2021

Journal of Chemical Research

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Six pyrophosphate analogues are prepared from zerumbone, murrayafoline A, acridone, and 4-hydroxycoumarin via 1,3-dipolar cycloaddition reactions. Their in vitro cytotoxic activity is evaluated against HepG2, LU-1, and HeLa cancer cell lines. Among them, diisopropyl ((ethoxy((4-((1-methoxy-3-methyl-9 H-carbazol-9-yl)methyl)-1 H-1,2,3-triazol-1-yl)methyl)phosphoryl)methyl)phosphonate (6a) and diisopropyl ((ethoxy((4-(((3-methyl-9 H-carbazol-1-yl)oxy)methyl)-1 H-1,2,3-triazol-1-yl)methyl)phosphoryl)methyl)phosphonate (6b) are found to show activity against HepG2, LU-1, and HeLa cancer cell lines, with IC50 values ranging from 7.31 to 17.88 μM.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of pyrophosphate analogues and their cytotoxic activities

Nguyen

Quan

et al. 2021

Journal of Chemical Research

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“…The rotation and bending of these two domains provide the open and closed transition of the conformation to bind to the substrate and released [14]. In recent years, based on the structure of adenosine, a series of competitive nucleotide derivative inhibitors have been designed, the most effective of them is AOPCP, which is also one of ideas to design more effective inhibitors [15]. Although these compounds show potential inhibition to CD73, they have negatively charge under physiological pH because they contain phosphorus atoms so that their bioavailability is very low [16].…”

Section: Introductionmentioning

confidence: 99%

Computational investigation of adenosine 5′-(α,β-methylene)-diphosphate (AMPCP) derivatives as ecto-5′-nucleotidase (CD73) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

et al. 2022

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CD73, as a surface enzyme anchored on the outside of the cell membrane via glycosylphosphatidylinositol (GPI), can convert the AMP in the tumor cell microenvironment into adenosine to promote the growth of tumor cells. It has been overexpressed in many different types of human tumors, such as gastric cancer, pancreatic cancer, liver cancer and other tumor cells. Therefore, targeted inhibitors of CD73 are considered as potential tumor treatment methods. Due to the low bioavailability of nucleoside CD73 inhibitors, it is necessary to develop new inhibitors. In this study, through molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics (MD) simulations, a series of CD73 inhibitors were calculated and studied to reveal their structure-activity relationships. Through molecular docking studies, explore the possible mode of interaction between inhibitors and protein. Subsequently, a 3D-QSAR model was established by comparative molecular eld analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q 2 and R 2 values are 0.708 and 0.983, respectively, while for the best CoMSIA model, the Q 2 and R 2 values are 0.809 and 0.992, respectively. In addition, the stability of the complex formed by the two inhibitors and CD73 was evaluated by molecular dynamics simulation, and the results are consistent with the results of molecular docking and 3D-QSAR research. Finally, the binding free energy was calculated by the surface area method (MM-GBSA), and the results are consistent with the activities that Van Der Waals and Coulomb contribute the most during the binding process of the molecule to the CD73 protein. In conclusion, our research provides valuable information for the further development of CD73 inhibitors.

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“…CD73-deficient mice have been largely studied since their development [ 7 , 8 ], and cN-II-deficient mice were more recently described [ 9 , 10 ]. We have been interested in these proteins from a therapeutic viewpoint, and developed inhibitors for both CD73 [ 11 , 12 , 13 , 14 ] and cN-II [ 15 , 16 , 17 ] over the last few years. We also demonstrated that cN-II knockdown in cell lines from hematological malignancies was associated with increased sensitivity to nucleoside-based treatments such as 6-mercaptopurine [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional and Metabolic Investigation in 5′-Nucleotidase Deficient Cancer Cell Lines

Cadassou

Forey

Machon

et al. 2021

Cells

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Enzymes of nucleoside and nucleotide metabolism regulate important cellular processes with potential impacts on nucleotide-unrelated parameters. We have used a set of CRISPR/Cas9-modified cell models expressing both, one, or none of the 5′-nucleotidases cN-II and CD73, together with RNA sequencing and targeted metabolomics, to decipher new regulatory roles of these proteins. We observed important transcriptional modifications between models as well as upon exposure to adenosine. Metabolite content varied differently between cell models in response to adenosine exposure but was rather similar in control conditions. Our original cell models allowed us to identify a new unobvious link between proteins in the nucleotide metabolism and other cellular pathways. Further analyses of our models, including additional experiments, could help us to better understand some of the roles played by these enzymes.

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4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies

Cited by 16 publications

References 38 publications

Synthesis of pyrophosphate analogues and their cytotoxic activities

Synthesis of pyrophosphate analogues and their cytotoxic activities

Computational investigation of adenosine 5′-(α,β-methylene)-diphosphate (AMPCP) derivatives as ecto-5′-nucleotidase (CD73) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

Transcriptional and Metabolic Investigation in 5′-Nucleotidase Deficient Cancer Cell Lines

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