ChemInform Abstract: Selective Demethylations in 2,3,4‐Trimethoxyaryl Carbonyl Compounds.

Kaisalo, Leena; Latvala, Anita; Hase, Tapio

doi:10.1002/chin.198646156

Cited by 2 publications

(2 citation statements)

References 1 publication

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“…Melting points were determined in an open glass capillary with an SMP3 apparatus (Stuart Scientific, Stone, Staffordshire, UK), and values are uncorrected. The following compounds were prepared according to literature procedures: CA-4 1 and (E)-combretastatin A-4 (Gaukroger et al, 2001); 3,4,5-trimethoxybenzyltriphenylphosphonium bromide 6 (Kong et al, 2005); 2,3-dihydroxy-4-methoxy-benzaldehyde 20 (Kaisalo et al, 1986); and 3,5-dihydroxy-4-methoxy-benzoic acid methyl ester 12 (Cardona et al, 1986).…”

Section: Methodsmentioning

confidence: 99%

In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver Microsomes

Aprile

Grosso²,

Tron³

et al. 2007

Drug Metab Dispos

100

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ABSTRACT:The phase I biotransformation of combretastatin A-4 (CA-4) 1, a potent tubulin polymerization inhibitor with antivascular and antitumoral properties, was studied using rat and human liver subcellular fractions. The metabolites were separated by high-performance liquid chromatography and detected with simultaneous UV and electrospray ionization (ESI) mass spectrometry. The assignment of metabolite structures was based on ESI-tandem mass spectrometry experiments, and it was confirmed by comparison with reference samples obtained by synthesis. O-Demethylation and aromatic hydroxylation are the two major phase I biotransformation pathways, the latter being regioselective for phenyl ring B of 1. Indeed, incubation with rat and human microsomal fractions led to the formation of a number of metabolites, eight of which were identified. The regioselectivity of microsomal oxidation was also demonstrated by the lack of metabolites arising from stilbenic double bond epoxidation. Alongside the oxidative metabolism, Z-E isomerization during in vitro study was also observed, contributing to the complexity of the metabolite pattern. Moreover, when 1 was incubated with a cytosolic fraction, metabolites were not observed. Aromatic hydroxylation at the C-6 of phenyl ring B and isomerization led to the formation of M1 and M2 metabolites, which were further oxidized to the corresponding paraquinone (M7 and M8) species whose role in pharmacodynamic activity is unknown. Metabolites M4 and M5, arising from O-demethylation of phenyl ring B, did not form the ortho-quinones. O-Demethylation of phenyl ring A formed the metabolite M3 with a complete isomerization of the stilbenic double bond.

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Section: Methodsmentioning

confidence: 99%

In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver Microsomes

Aprile

Grosso²,

Tron³

et al. 2007

Drug Metab Dispos

100

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“…Initially the copper-catalyzed arylation 15 of 1 with phenols 3a−e delivered the corresponding diaryl ether intermediates 4a−e, which were then converted into 2-hydroxy-diaryl ethers 5a−e, by selective deprotection of the methoxy (OMe) group with boron trichloride (BCl 3 ). 16 Intermediates 5a−e were treated with triflic anhydride (Tf 2 O) in the presence of pyridine to give the triflates 6a−e, which were further subjected to Buchwald-Hartwig cross coupling with various substituted anilines 7a-l to give the key anthranilate intermediates 8a−q (Scheme 1). 14,17 Conversely, synthesis of anthranilate intermediates 12a−j and 17a−f, key synthons in the synthesis of acridones 43−52 and 53−58, commenced with the coupling of 2 with corresponding anilines 7m−q and boronic acids 13a−d under standard Buchwald-Hartwig and Suzuki cross-coupling reaction conditions to derive intermediates 9a−e and 14a−d, respectively.…”

Section: Synthesis Of 6-aryloxy- 6-arylamino-and 6-aryl-acridones (1mentioning

confidence: 99%

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

Kancharla

Dodean

et al. 2020

J. Med. Chem.

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The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dualstage targeting acridones as novel drug candidates for further preclinical development.

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ChemInform Abstract: Selective Demethylations in 2,3,4‐Trimethoxyaryl Carbonyl Compounds.

Abstract: Die Spaltung von Methylphenolethern mit Bortrihalogeniden wird beschrieben.

Cited by 2 publications

References 1 publication

In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver Microsomes

In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver Microsomes

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

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