Tyrosine Kinase Inhibitors. 9. Synthesis and Evaluation of Fused Tricyclic Quinazoline Analogues as ATP Site Inhibitors of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor

Rewcastle, Gordon W.; Palmer, Brian D.; Bridges, Alexander J.; Showalter, H. D. Hollis; Sun, Lixin; Nelson, James M.; McMichael, Amy; Kraker, Alan J.; Fry, David W.; Denny, William A.

doi:10.1021/jm950692f

Cited by 171 publications

(110 citation statements)

References 21 publications

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“…Indeed, as shown in Figure 15, 35 nM PD168393, which alkylates a Cys residue in the ATP binding pocket of tyrosine kinases in the erbB family (120), eliminates the ability of the PT to respond to changes in [CO 2 ] B (121). Similarly, 10 nM BPIQ-I, which also targets members of the erbB family (122), blocks the ability of the tubule to respond to increased [CO 2 ] B . Indeed, preliminary work suggests that exposing tubule suspensions to CO 2 / HCO 3 Ϫ leads to the phosphorylation of erbB1 (i.e., EGF receptor) at Tyr residues (123).…”

Section: Role Of Tyrosine Kinasesmentioning

confidence: 99%

Acid-Base Transport by the Renal Proximal Tubule

Boron

2006

Journal of the American Society of Nephrology

170

144

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One of the major tasks of the renal proximal tubule is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered HCO 3 ؊ as well as generating new HCO 3 ؊ for regulating blood pH. This review summarizes the cellular and molecular events that underlie four major processes in HCO 3 ؊ reabsorption. The first is CO 2 entry across the apical membrane, which in large part occurs via a gas channel (aquaporin 1) and acidifies the cell. The second process is apical H ؉ secretion via Na-H exchange and H ؉ pumping, processes that can be studied using the NH 4 ؉ prepulse technique. The third process is the basolateral exit of HCO 3 ؊ via the electrogenic Na/HCO 3 co-transporter, which is the subject of at least 10 mutations that cause severe proximal renal tubule acidosis in humans. The final process is the regulation of overall HCO 3 ؊ reabsorption by CO 2 and HCO 3 ؊ sensors at the basolateral membrane. Together, these processes ensure that the proximal tubule responds appropriately to acute acid-base disturbances and thereby contributes to the regulation of blood pH.

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Section: Role Of Tyrosine Kinasesmentioning

confidence: 99%

Acid-Base Transport by the Renal Proximal Tubule

Boron

2006

Journal of the American Society of Nephrology

170

144

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“…Its derivatives have been designed and synthesized as therapeutic agents [21][22][23][24], as herbicides, fungicides, pesticides and as fluorescent dyes [25,26]. They have been commonly used as scaffolds for natural product synthesis (e.g., NAD nucleotides, pyridoxol (vitamin B6), and pyridine alkaloids) [27][28][29].…”

Section: Pyridines Dihydropyridines Piperidinesmentioning

confidence: 99%

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

et al. 2016

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This review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed.

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“…Nitration of 2 with a mixture of nitric acid and sulfuric acid at 100°C afforded compound 3 in 76% yield, 12 which was Nbenzylated in position 3 of the quinazolin-4-one skeleton by reaction with sodium hydride and benzyl bromide in anhydrous DMF (compound 4). Subsequent reduction of the nitro group was accomplished with iron/acetic acid in refluxing ethanol 13 to give the corresponding amine 5 (yield 93%).…”

Section: Abstract: Candida Aspergillus Zygomycetes Antifungal Agenmentioning

confidence: 99%

Discovery of a Novel Broad-Spectrum Antifungal Agent Derived from Albaconazole

Guillon

Pagniez

Picot

et al. 2013

ACS Med. Chem. Lett.

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Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed preliminary in vivo antifungal efficacy in a mice model of systemic candidiasis.KEYWORDS: Candida, Aspergillus, zygomycetes, antifungal agents, azoles, thiazolo[4,5-g]quinazolin-8(7H)-one A zoles (fluconazole, itraconazole, voriconazole, and posaconazole) are important drugs for the treatment of invasive fungal infections (IFIs), which continue to be a major cause of morbidity and mortality in immunocompromised or severely ill patients. 1 These compounds target the biosynthesis of ergosterol by inhibiting the cytochrome P450-dependent lanosterol 14α-demethylase (Erg11p, CYP51), encoded by the ERG11 gene, resulting in accumulation of toxic methylsterols in membranes that may culminate in fungistatic effect or fungal death. 2 Most azoles are orally active, show a broad-spectrum against most yeasts and filamentous fungi, and are relatively nontoxic. Unfortunately, the increasing number of fungal infections, coupled with emerging resistance, has resulted in a need to develop new, more effective agents. Among these molecules, albaconazole (UR-9825, Palau Pharma S.A., Figure 1) 3 is a new oral triazole antifungal agent with broad-spectrum antifungal activity against resistant and emerging pathogens as compared with fluconazole and itraconazole, good pharmacokinetics, and excellent oral bioavailability. 4 It has demonstrated high in vitro activities against pathogenic yeasts, dermatophytes, and other filamentous fungi and has been shown to be effective in animal models of systemic aspergillosis, candidiasis, cryptococcosis, and scedosporiosis. 4 Albaconazole has been assayed in several clinical trials, including phase I/II studies in candidal vulvovaginitis, tinea pedis, and onychomycosis (clinicaltrials.gov: NCT00199264, NCT00509275, and NCT00730405). However, phase III studies are not available until now, and the lack of an intravenous form makes studies in the acute infection setting very difficult. 5 As part of our research program focused on the synthesis and SAR studies of novel broad-spectrum antifungal agents, 6−10 we aimed to develop a strict structural analogue of albaconazole in which the quinazolinone ring will be replaced by a thiazoloquinazolinone scaffold (compounds I and II, Figure 1) via Appel salt chemistry. Our goal was to slightly increase the size of the inhibitor to cover a larger area within the active site of fungal

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Tyrosine Kinase Inhibitors. 9. Synthesis and Evaluation of Fused Tricyclic Quinazoline Analogues as ATP Site Inhibitors of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor

Cited by 171 publications

References 21 publications

Acid-Base Transport by the Renal Proximal Tubule

Acid-Base Transport by the Renal Proximal Tubule

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

Discovery of a Novel Broad-Spectrum Antifungal Agent Derived from Albaconazole

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