BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors

Vlasceanu, Alexandru; Jessing, Mikkel; Kilburn, John Paul

doi:10.1016/j.bmc.2015.06.019

Cited by 64 publications

(29 citation statements)

References 34 publications

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“…Kilburn has likewise generated a series of BN-naphthalene derivatives to test as inhibitors of phosphodiesterase 10A (PDE10A), an enzyme localized in human brain tissue and a target for treatment of various neurological diseases. 43 Two members of the series ( 21 and 22 ) displayed markedly greater activity against PDE10A than their all-carbon equivalents (although quinoline-based variants proved the most potent overall) (Table 4). While these results, in conjunction with those reported by Zécri and Liu ( vide supra ), are indeed encouraging, much further study is likely required before BN-isosterism becomes a standard tool of drug discovery efforts.…”

Section: 2-bn-naphthalenesmentioning

confidence: 99%

The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications

2018

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Boron-nitrogen heteroarenes hold great promise for practical application in many areas of chemistry. Enduring interest in realizing this potential has in turn driven perennial innovation with respect to these compounds' synthesis. This Perspective discusses in detail the most recent advances in methods pertaining to the preparation of BN-isosteres of benzene, naphthalene, and their derivatives. Additional focus is placed on the progress enabled by these syntheses toward functional utility of such BN-heterocycles in biochemistry and pharmacology, materials science, and transition-metal-based catalysis. The prospects for future research efforts in these and related fields are also assessed.

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Section: 2-bn-naphthalenesmentioning

confidence: 99%

The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications

2018

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“…9 More recently, BN isosteres of naphthalene have been profiled in vitro and in vivo in terms of biological activity and ADME (absorption, distribution, metabolism, excretion) properties. 10,11 …”

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confidence: 99%

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

et al. 2016

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Protein crystallography and calorimetry were used to characterize the binding of 1,2-azaborines to model cavities in T4 lysozyme in direct comparison to their carbonaceous counterparts. In the apolar L99A cavity, affinity for Ab dropped only slightly versus benzene. In the cavity designed to accommodate a single hydrogen bond (L99A/M102Q), Gln102=O⋯H—N hydrogen bonding for Ab and BEtAb was observed in the crystallographic complexes. The strength of the hydrogen bonding was estimated as 0.94 and 0.64 kcal/mol for Ab and BEtAb, respectively. This work unambiguously demonstrates that 1,2-azaborines can be readily accommodated in classic aryl recognition pockets and establishes one of 1,2-azaborine’s distinguishing features from its carbonaceous isostere benzene: its ability to serve as an NH hydrogen bond donor in a biological setting.

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“…More recently, through isothermal titration calorimetry and protein crystal structure analysis, we have demonstrated the increased binding strength of benzene and ethylbenzene BN-analogues in the polar binding pocket of T4 lysozyme mutants through a hydrogen bonding interaction unavailable in the carbonaceous compounds 6. As a pharmacophore in medicinal chemistry, BN analogues of naphthalene-containing biologically active compounds have been studied through ADMET (absorption, distribution, metabolism, excretion, toxicity) and biological activity profiling, both in vivo and in vitro 8,9. We have shown, also through ADMET profiling, that the 1,2-azaborine analogues of biologically active compounds can increase the bioavailability of the drug without significantly altering the activity of the all-carbon substrate 10.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of an unnatural boron and nitrogen-containing tryptophan analogue and its incorporation into proteins

et al. 2019

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BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors

Cited by 64 publications

References 34 publications

The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications

The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

Synthesis and characterization of an unnatural boron and nitrogen-containing tryptophan analogue and its incorporation into proteins

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