Biomaterial Database

2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes. 2020

Sanjay Bhattarai, and Jan Pippel, and Emma Scaletti, and Riham Idris, and Marianne Freundlieb, and Georg Rolshoven, and Christian Renn, and Sang-Yong Lee, and Aliaa Abdelrahman, and Herbert Zimmermann, and Ali El-Tayeb, and Christa E Müller, and Norbert Sträter

PharmaCenter Bonn, Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.

CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5'-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.

UI	MeSH Term	Description	Entries
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000244	Adenosine Diphosphate	Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position.	ADP,Adenosine Pyrophosphate,Magnesium ADP,MgADP,Adenosine 5'-Pyrophosphate,5'-Pyrophosphate, Adenosine,ADP, Magnesium,Adenosine 5' Pyrophosphate,Diphosphate, Adenosine,Pyrophosphate, Adenosine
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015720	5'-Nucleotidase	A glycoprotein enzyme present in various organs and in many cells. The enzyme catalyzes the hydrolysis of a 5'-ribonucleotide to a ribonucleoside and orthophosphate in the presence of water. It is cation-dependent and exists in a membrane-bound and soluble form. EC 3.1.3.5.	5'-AMP Nucleotidase,AMP Phosphatase,Adenylate Phosphatase,Antigens, CD73,CD73 Antigens,Cytidylate Phosphatase,Ecto-5'-Nucleotidase,IMP Nucleotidase,IMP Phosphatase,Inosinate Phosphatase,Pyrimidine 5'-Nucleotidase,Thymidine Phosphatase,Uridylate 5'-Nucleotidase,5'-Nucleotidase Phosphoribolase,Antigen, CD73,IMPase,5' AMP Nucleotidase,5' Nucleotidase,5' Nucleotidase Phosphoribolase,CD73 Antigen,Ecto 5' Nucleotidase,Pyrimidine 5' Nucleotidase,Uridylate 5' Nucleotidase
D051381	Rats	The common name for the genus Rattus.	Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D058851	GPI-Linked Proteins	A subclass of lipid-linked proteins that contain a GLYCOSYLPHOSPHATIDYLINOSITOL LINKAGE which holds them to the CELL MEMBRANE.	GPI-Anchored Proteins,GPI-Linked Membrane Proteins,Glycosylphosphatidylinositol Linked Proteins,GPI Anchored Proteins,GPI Linked Membrane Proteins,GPI Linked Proteins,Membrane Proteins, GPI-Linked,Proteins, GPI-Anchored,Proteins, GPI-Linked,Proteins, GPI-Linked Membrane,Proteins, Glycosylphosphatidylinositol Linked
D062105	Molecular Docking Simulation	A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein.	Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking