Discovery and structure–activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents

Akama, Tsutomu; Chen, Dong; Virtucio, Charlotte; Freund, Yvonne R.; Chen, Daitao; Orr, Matthew D.; Jacobs, Robert T.; Zhang, Yongkang; Hernandez, Vincent; Liu, Yang; Wu, Aibin; Bu, Wei; Liu, Liang; Jarnagin, Kurt; Plattner, Jacob J.

doi:10.1016/j.bmcl.2013.08.096

Cited by 20 publications

(15 citation statements)

References 24 publications

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“…Currently, many pharmaceutical companies and manufacturers have strong interests in the RhoA/Rho-kinase signaling and the development of its inhibitors. 3,112,125,237 Among them, Akama et al 238 performed a kinome-wide screen to investigate the members of the benzoxaborole family and identified Rho-kinase as a target. They observed a competitive behavior, with respect to ATP, and determined the ROCK2-drug cocrystal structure.…”

Section: Rho-kinase As a Therapeutic Targetmentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

352

235

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Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.

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Section: Rho-kinase As a Therapeutic Targetmentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

352

235

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“…Our in silico modeling predicts that the dithio- or thiocarbamate group both functions as a structural linker connecting two essential pharmacophores and also interacts with the hydrophobic pocket of GGTase I itself. Although no benzoxaborole GGTase I inhibitors have been previously reported, this class of compounds has proven a rich source of useful human therapeutics from antifungal drugs to anti-inflammatory agents. , In support of drug-development efforts, structure–activity relationship (SAR) studies with 6-substituted benzoxaboroles have been performed across a wide variety of targets and made clear the importance of modifications to the 6-substitution for improving bioactivity either by increasing target affinity or by altering lipophilicity to decrease susceptibility to drug efflux pumps. − Here, we observed major differences in bioactivity, chemical stability, and target engagement and inhibition based on variation in substitutions at the 6-position for our benzoxaborole compounds. Carbamate containing compound 9 showed no antifungal activity, while dithiocarbamate containing compound 7 showed reduced chemical stability in aqueous buffer at pH 7.4.…”

Section: Resultsmentioning

confidence: 71%

Inhibiting Protein Prenylation with Benzoxaboroles to Target Fungal Plant Pathogens

Kim

Liu²,

Zhou³

et al. 2020

ACS Chem. Biol.

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Fungal pathogens pose an increasing threat to global food security through devastating effects on staple crops and contamination of food supplies with carcinogenic toxins. Widespread deployment of agricultural fungicides has increased crop yields but is driving increasingly frequent resistance to available agents and creating environmental reservoirs of drug-resistant fungi that can also infect susceptible human populations. To uncover non-cross-resistant modes of antifungal action, we leveraged the unique chemical properties of boron chemistry to synthesize novel 6-thiocarbamate benzoxaboroles with broad spectrum activity against diverse fungal plant pathogens. Through whole genome sequencing of Saccharomyces cerevisiae isolates selected for stable resistance to these compounds, we identified mutations in the protein prenylation-related genes, CDC43 and ERG20. Alleleswapping experiments confirmed that point mutations in CDC43, which encodes an essential catalytic subunit within geranylgeranyl transferase I (GGTase I) complex, were sufficient to confer resistance to the benzoxaboroles. Mutations in ERG20, which encodes an upstream farnesyl pyrophosphate synthase in the geranylgeranylation pathway, also conferred resistance. Consistent with impairment of protein prenylation, the compounds disrupted membrane localization of the classical geranylgeranylation substrate Cdc42. Guided by molecular docking predictions, which favored Cdc43 as the most likely direct target, we overexpressed and purified functional GGTase I complex to demonstrate direct binding of benzoxaboroles to it and concentration-dependent inhibition of its transferase activity. Further development of the boron-containing scaffold described here offers a promising path to the development of GGTase I inhibitors as a mechanistically distinct broad spectrum fungicide class with reduced potential for cross-resistance to antifungals in current use.

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“…Benzoxaboroles also have potential to be effective antibiotics, with one study examining their activity against S. pneumoniae relative to clarithromycin, an antibiotic that is active against Gram-positive strains [ 94 ]. Benzoxaboroles have also been explored for anti-inflammatory activity, with some candidates inhibiting the release of proinflammatory cytokines [ 95 , 96 , 97 ] and others acting through the inhibition of PDE4 [ 98 ], similar to crisaborole. Benzoxaboroles have also been studied as HCV NS3 protease inhibitors [ 99 ], β-lactamase inhibitors [ 100 ], and as LeuRS inhibitors [ 101 ].…”

Section: Boron Medicinal Chemistrymentioning

confidence: 99%

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

2022

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In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron’s emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development.

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Discovery and structure–activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents

Cited by 20 publications

References 24 publications

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Inhibiting Protein Prenylation with Benzoxaboroles to Target Fungal Plant Pathogens

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

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