Exploring the Effect of Halogenation in a Series of Potent and Selective A_2B Adenosine Receptor Antagonists

Abstract

The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (K i < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.

Multicomponent Reaction-Assisted Drug Discovery: A Time- and Cost-Effective Green Approach Speeding Up Identification and Optimization of Anticancer Drugs

“…The study also demonstrated a marked effect on immune system cells, recovering from adenosine-mediated immunosuppression and increasing the production of proinflammatory cytokines. This effect in the immune system has been recently verified [ 138 ].…”

“…With the initiative to develop novel cancer immunotherapeutic agents via the modulation of the A 2B adenosine receptor, Sotelo et al [ 134 , 135 , 136 , 137 , 138 ] discovered several families of (monocyclic, bicyclic or tricyclic) pyrimidine derivatives ( Scheme 16 ) that were readily and efficiently assembled through a three-component Biginelli reaction.…”

Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery

“…[327] The subsequent modification of the structures of pyrimidobenzimidazoles was associated with the replacement of Me groups by CF 3 , [328] the bioisosteric substitution of the heterocycle at the C-4 atom, [329] and the introduction of halogen atoms into the benzimidazole fragment. [330] To establish the relationship between the stereochemical structure and the ability to bind to A 2B ARs, four single diastereomers and two diastereomeric pairs of pyrimidobenzimidazole with a CF 3 substituent in the ester group were obtained (Figure 9). [328] The most active were (3R,4S)-278 c and (3S,4S)-279 c isomers.…”

Engineering Saccharomyces cerevisiae for the de novo Production of Halogenated Tryptophan and Tryptamine Derivatives

“… [9] Halogenation of drug candidates can increase membrane permeability, [10] enhance blood‐brain barrier transport, [11] and strengthen the binding interactions between a ligand and its target, thereby increasing the ligand potency. [ 9 , 12 ] The halogenation of the indole ring in particular has been proven to tune some properties of multiple cancer drug leads isolated from marine environments. [13] Furthermore, halogenated indoles serve as versatile precursors for the synthesis of more complex structures, as they facilitate cross‐coupling reactions and other synthetic transformations.…”

“…In such drug discovery processes, halogenation is commonly used as a means to improve the properties of a lead drug candidate, [8] and consequently, the presence of halogens is frequent in drugs, with approximately 25 % of all commercialized pharmaceuticals containing a halogen atom in their structure [9] . Halogenation of drug candidates can increase membrane permeability, [10] enhance blood‐brain barrier transport, [11] and strengthen the binding interactions between a ligand and its target, thereby increasing the ligand potency [9,12] . The halogenation of the indole ring in particular has been proven to tune some properties of multiple cancer drug leads isolated from marine environments [13] .…”