New anticancer agents: synthesis of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines)

Temple, Carroll; Wheeler, Glynn P.; Elliott, Robert D.; Rose, J. D.; Kussner, Conrad L.; Comber, Rob

doi:10.1021/jm00351a008

Cited by 23 publications

(15 citation statements)

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“…Chemistry Compounds 15a-d were synthesized starting with the preparation of 2-amino-1-(4-hydroxyphenyl) ethanone hydrochloride 13 by Delépine reaction at low temperature, followed by condensation of carboxylic acids 14a-d in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl) and 1-hydroxybenzotriazole (HOBT) at room temperature 30,31) (Chart 1). 14a and d were converted into 16a and d in the presence of N,N′-carbonyldiimidazole (CDI) under an H 2 S atmosphere, and then 14a, d, 16a, and d were allowed to react with 2-bromo-4′-hydroxyacetophenone 11 in the presence of K 2 CO 3 32,33) (Chart 2).…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 22e-i were synthesized as shown in Chart 3, using a route nearly identical to that in Chart 1. 30,31) The amide 24 was prepared by condensation of carboxylic acid 14d and 1-(tertbutoxycarbonyl) piperazine 23 with EDCI·HCl as a condensation agent and 4-dimethylaminopyridine (DMAP) as a catalyst in CH 2 Cl 2 .…”

Section: Resultsmentioning

confidence: 99%

“…General Procedure for the Synthesis of 15a-d 30,31) To a solution of 2-bromo-4′-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine (20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45°C.…”

Section: Methodsmentioning

confidence: 99%

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Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Nian

Gan

Tan

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC 50 value of 6.4 µM against LXRα and an IC 50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists.Key words liver X receptor α; liver X receptor β; antagonistic activity Nuclear receptors (NRs) are ligand-activated transcription factors that coordinate gene expression in response to the modulation of metabolism, development, proliferation, and inflammation.1,2) Liver X receptors (LXRs) belonging to the NR superfamily are activated by specific oxidized forms of cholesterol and intermediate products of the cholesterol biosynthetic pathway. 1,3,4) There are two LXR isoforms in mammals, termed LXRα and LXRβ. LXRα is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRβ is more ubiquitously expressed, with particularly high levels in the developing brain. [5][6][7][8] Both isoforms share almost 80% homology of their amino acid sequences in their DNA-binding domain and ligand-binding domain. 5,7)The LXR consists of four domains: N-terminal ligandindependent activation function domain (AF-1); DNA-binding domain (DBD); hydrophobic ligand-binding domain (LBD); and C-terminal ligand-dependent transactivation sequence (AF-2).5,9,10) By forming heterodimers with retinoid X receptors (RXRs), LXRs bind to LXR response elements (LXREs) in the promoter or enhancer elements of LXR target genes. The activation of LXR-RXR heterodimers not only induces the expression of a variety of target genes (CYP7A, ABCA1, SREBP-1) that are involved in lipid and glucose metabolism, but also results in the inhibition of genes encoding inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ. 1,[11][12][13][14][15] In the last decade, GlaxoSmithKline and other several pharmaceutical companies have been active in developing synthetic LXR agonists (Fig. 1). T0901317 (1, Tularik) and GW3965 (2, GSK) exhibit nonselectivity for LXRα and LXRβ with high affinity.11,16-18) The first compound to enter the clinic was LXR-623 (3, Wyeth), an LXRα/β partial agonist for the potential treatment of atherosclerosis and dyslipidemia. Unfortunately, the trial was terminated due to adverse central nervous system effects.19-21) LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others 22-28) (Fig. 1).SR-9238 was the first selective synthetic LXR inverse agonist that displays a degree of LXRβ selectivity with an IC 50 value of 214 nM for LXRα and 43 nM for LXRβ, and this compound effectively suppressed hepatic lipogenesis, inflammation, and hepatic lipid...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Nian

Gan

Tan

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…[186] Structure-activity relationship studies indicated that the basic diaminopyridine is an essential structural requirement. [187,188] The fused dihydropyrazine increases the pyridine basicity and tolerates diverse substituents in positions 2 and 3. [189] Clinical trials with mivobulin (CI-980) showed that it lacks sufficient activity in the treatment of disseminated malignant melanoma [190] metastatic colorectal carcinoma [191] progressive malignant gliomas [192] and soft tissue sarcomas.…”

Section: Pyrido[34-b]pyrazinesmentioning

confidence: 99%

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Álvarez¹,

Aramburu²,

Puebla³

et al. 2016

CMC

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Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharmacokinetic and pharmacodynamics properties. CSL have been classified according to their chemical structures and the chemical structures of the pyridine and azine containing antimitotic compounds are described. The designed principles behind the structural modifications and the achieved effect on the biological activity upon inclusion of these heterocycles are also discussed. Lessons from the achievements and failures have been extracted and future perspectives delineated.

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“…In view of the possibility that other benzoylphenyl ureas might possess higher and more selective antitumor activity compared to DFB, a study of analog screening was undertaken using B16 melanoma cells as an in vitro prescreen and B16 melanoma implanted subcutaneously (s.c.) in mice [9][10][11] as secondary screening. Because structure-activity relationships may be successful in designing novel selective inhibitors with improved chemotherapeutic potential [12][13][14][15], we examined the cytostatic activity of substituted 1-benzoyl-3-phenyl ureas with the following structural modifications: 1. Substitutions in the benzoyl ring (R).…”

Section: Introductionmentioning

confidence: 99%

Effects of benzoylphenyl ureas on growth of B16 melanoma cells in vitro and in vivo

Hofs¹,

McVie

1991

Invest New Drugs

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New analogs of diflubenzuron, a benzoylphenyl urea, are tested on their in vitro cytostatic activity against B16 melanoma cells. The following structure-activity relationship was established: substitution by a hydroxylated function at the ortho, meta or para position or by a dimethylamino function at the ortho position of the benzoyl moiety appeared to be necessary for cytostatic activity in vitro. Acetoxy functions at the ortho position or hydroxy functions at the para position of the aniline ring resulted also in active compounds. A number of these benzoylphenyl ureas are selected for in vivo evaluation of antitumor activity on B16 melanoma growing s.c.. Although many of the tested benzoylphenyl ureas delayed tumor growth during the first ten days of drug treatment, only a few increased animal life span. The best results (% T/C) were obtained with compounds 5 (127%), 7 (147%), 13 (135%) and 16 (135%), which all have hydroxylated functions in the benzoyl moiety.

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New anticancer agents: synthesis of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines)

Cited by 23 publications

References 0 publications

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

Effects of benzoylphenyl ureas on growth of B16 melanoma cells in vitro and in vivo

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