Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors

Zhang, Yanming; Ye, Shuang; Wang, Yuan; Wang, Chuanhao; Zhu, Yazhao; Wu, Yang‐Chang; Zhang, Yongqiang; Zhang, Huojun; Miao, Zhenyuan

doi:10.1016/j.bmc.2022.116672

Cited by 8 publications

(2 citation statements)

References 22 publications

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“…Adenosine generated by overexpressed h-ecto-5′-NT accumulates in the tumor microenvironment, where it activates immunosuppressive pathways that favor the development of neoplasia. − Accumulated adenosine can also regulate angiogenesis and proliferation, migration, differentiation, and apoptosis of parenchymal cancer cells, contributing to tumor progression and metastasis. − The effects of h-ecto-5′-NT overexpression in tumorigenesis and its role in tumor immune escape and tumor metastasis have been shown in vivo . − In addition to its participation in tumor progression, h-ecto-5′-NT plays a central role in the course of several pathophysiological events and diseases, including inflammation and autoimmune, infectious, and neurological diseases. , Therefore, h-ecto-5′-NT has been recognized as a well-established biological target for cancer therapy and for the treatment of many other diseases. Several h-ecto-5′-NT inhibitors have been reported so far, ,− some of which are currently being tested in clinical trials. , Nevertheless, as discussed in the literature, ,, many of the known inhibitors have physicochemical and/or pharmacological characteristics that limit their applicability as drug candidates, such as low inhibitory potency, poor water solubility, and lack of selectivity. For this reason, considerable efforts have been made by the scientific community and the pharmaceutical industry to search for novel h-ecto-5′-NT inhibitors …”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Viviani

Kokh

Wade

et al. 2023

J. Chem. Inf. Model.

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Human ecto-5′-nucleotidase (h-ecto-5′-NT, CD73) is a homodimeric Zn 2+ -binding metallophosphoesterase that hydrolyzes adenosine 5′-monophosphate (5′-AMP) to adenosine and phosphate. h-Ecto-5′-NT is a key enzyme in purinergic signaling pathways and has been recognized as a promising biological target for several diseases, including cancer and inflammatory, infectious, and autoimmune diseases. Despite its importance as a biological target, little is known about h-ecto-5′-NT dynamics, which poses a considerable challenge to the design of inhibitors of this target enzyme. Here, to explore h-ecto-5′-NT flexibility, all-atom unbiased molecular dynamics (MD) simulations were performed. Remarkable differences in the dynamics of the open (catalytically inactive) and closed (catalytically active) conformations of the apo-h-ecto-5′-NT were observed during the simulations, and the nucleotide analogue inhibitor AMPCP was shown to stabilize the protein structure in the closed conformation. Our results suggest that the large and complex domain motion that enables the h-ecto-5′-NT open/closed conformational switch is slow, and therefore, it could not be completely captured within the time scale of our simulations. Nonetheless, we were able to explore the faster dynamics of the h-ecto-5′-NT substrate binding site, which is mainly located at the C-terminal domain and well conserved among the protein's open and closed conformations. Using the TRAPP ("Transient Pockets in Proteins") approach, we identified transient subpockets close to the substrate binding site. Finally, conformational states of the substrate binding site with higher druggability scores than the crystal structure were identified. In summary, our study provides valuable insights into h-ecto-5′-NT structural flexibility, which can guide the structure-based design of novel h-ecto-5′-NT inhibitors.

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Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Viviani

Kokh

Wade

et al. 2023

J. Chem. Inf. Model.

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“…Natural products are one of the most promising components and precursors of anticancer drugs with various mechanisms of action and relatively low toxicity . Terpenes have been recognized as relevant secondary metabolites, − among which betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BetA) and related lupane-type pentacyclic triterpenoids have attracted a great interest in current drug discovery. − The ability of betulinic and betulonic acids to inhibit cancer cell growth was well established on different cell lines and primary cells from solid tumors. − …”

mentioning

confidence: 99%

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

Tsepaeva,

Salikhova,

Ishkaeva

et al. 2023

J. Nat. Prod.

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A convenient synthesis is presented for a new class of bioactive bifunctionalized conjugates of lupane-type triterpenoids with triphenylphosphonium (TPP) and glycopyranosyl targeting moieties. The main synthesis steps include glycosylation of haloalkyl esters of the triterpene acid at the C-3 position by the imidate derivatives of glycopyranose followed by the product modification at the C-28 position with triphenylphosphine. The conjugates of betulinic acid (BetA) with TPP and d-glucose, l-rhamnose, or d-mannose moieties were thus synthesized as potential next-generation BetA-derived anticancer compounds. LC-MS/MS analysis in glucose-free physiological solution indicated that the glycosides showed better accumulation in PC-3 prostate cancer cells than both BetA and TPP–BetA conjugate, while the transporting effect of monosaccharide residues increased as follows: d-mannose < l-rhamnose ≈ d-glucose. At saturated concentrations, the glycosides caused a disturbing effect on mitochondria with a more drastic drop in transmembrane potential but weaker overproduction of mitochondrial reactive oxygen species (ROS) compared to TPP–BetA conjugate. Cytotoxicity of the glycosides in culture medium was comparable with or higher than that of the nonglycosylated conjugate, depending on the cancer cell line, whereas the compounds were less active toward primary fibroblasts. Glycosylation tended to increase pro-apoptotic and decrease pro-autophagic activities of the BetA derivatives. Cytotoxicity of the synthesized glycosides was considered in comparison with the summarized data on the natural and modified BetA glycosides. The results obtained are important for the development of bifunctionalized conjugates of triterpenoids with an increased cancer cell targetability.

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Discovery of the ((diaryl)methyl)phosphonic acid derivatives as novel CD73 inhibitors

Yang,

Chen,

Ning

et al. 2023

Journal of Heterocyclic Chem

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Ecto‐nucleotidase CD73 inhibits immune function by overproducing adenosine. A series of important studies have shown that CD73 is over‐expressed in many cancers, and CD73 inhibitors are promising drugs for cancer (immunotherapy). Here, we describe the structure optimization of a hit compound obtained through screening an in‐house chemical library, (3‐(4‐(3‐aminophenyl)‐1H‐1,2,3‐triazol‐1‐yl)phenyl‐(naphthalen‐1‐yl)methyl)phosphonic acid (1). A series of ((diphenylmethyl) phosphonic acid) derivatives were synthesized, and all target compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Then structure–activity relationship analysis using the in vitro enzymatic inhibition assay was performed, which led to the discovery of a number of compounds (11, 13, 14, 17, 19, 23, and 27) that exhibited greater inhibitory activity than the lead compound 1. Among them, the compounds 14 and 23, with p‐Cl and p‐ethyl substitution on the terminal phenyl ring respectively, showed the strongest inhibitory activity against CD73, with IC50 values of 2.35 and 2.55 μM respectively. And we believe that compounds 14 and 23 can serve as lead compounds for further research on specific CD73 inhibitors.

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Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors

Cited by 8 publications

References 22 publications

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics

Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability

Discovery of the ((diaryl)methyl)phosphonic acid derivatives as novel CD73 inhibitors

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