Conversion of biguanides into substituted s‐Triazines Assayable by GC or Mass Fragmentography

Alkalay, David; Volk, Joseph; Bartlett, M. F.

doi:10.1002/jps.2600650412

Cited by 36 publications

(7 citation statements)

References 4 publications

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“…Following the general procedure, the reaction of 4-methyl-phenylethylamine (compound 20) (135.2 mg, 1.0 mmol) was performed under the irradiation condition (130°C, 10 minutes, 3.0 mL dry CH 3 CN) to afford compound 9 hydrochloride21 (213.0 mg, 83%). The analytical sample was obtained by recrystallization from EtOH as a colorless powder, compound 9 dihydrochloride.…”

Section: Methodsmentioning

confidence: 99%

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Narise

Okuda

Enomoto

et al. 2014

DDDT

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Adaptive cellular responses resulting from multiple microenvironmental stresses, such as hypoxia and nutrient deprivation, are potential novel drug targets for cancer treatment. Accordingly, we focused on developing anticancer agents targeting the tumor microenvironment (TME). In this study, to search for selective antitumor agents blocking adaptive responses in the TME, thirteen new compounds, designed and synthesized on the basis of the arylmethylbiguanide scaffold of phenformin, were used in structure activity relationship studies of inhibition of hypoxia inducible factor (HIF)-1 and unfolded protein response (UPR) activation and of selective cytotoxicity under glucose-deprived stress conditions, using HT29 cells. We conducted luciferase reporter assays using stable cell lines expressing either an HIF-1-responsive reporter gene or a glucose-regulated protein 78 promoter-reporter gene, which were induced by hypoxia and glucose deprivation stress, respectively, to screen for TME-targeting antitumor drugs. The guanidine analog (compound 2), obtained by bioisosteric replacement of the biguanide group, had activities comparable with those of phenformin (compound 1). Introduction of various substituents on the phenyl ring significantly affected the activities. In particular, the o-methylphenyl analog compound 7 and the o-chlorophenyl analog compound 12 showed considerably more potent inhibitory effects on HIF-1 and UPR activation than did phenformin, and excellent selective cytotoxicity under glucose deprivation. These compounds, therefore, represent an improvement over phenformin. They also suppressed HIF-1- and UPR-related protein expression and secretion of vascular endothelial growth factor-A. Moreover, these compounds exhibited significant antiangiogenic effects in the chick chorioallantoic membrane assay. Our structural development studies of biguanide derivatives provided promising candidates for a novel anticancer agent targeting the TME for selective cancer therapy, to be subjected to further in vivo study.

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Section: Methodsmentioning

confidence: 99%

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Narise

Okuda

Enomoto

et al. 2014

DDDT

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“…1;P <0.05; Student's t test) in all samples collected between 2 and 24 hr after the drug was given. In contrast, whereas the metabolite, 4-hydroxy-phenformin could readily be detected in all urine samples from EM, in PM, the excretion of 4-hydroxyphenformin could not be detected in most samples collected, the concentration being below the lower limit of the assay (1 Ag/m1).…”

Section: Resultsmentioning

confidence: 76%

Influence of oxidation polymorphism on phenformin kinetics and dynamics

Oates

Shah

Idle

et al. 1983

Clin Pharmacol Ther

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Plasma and urinary kinetics and responses of blood lactate, pyruvate, and glucose after a single 50-mg phenformin dose were investigated in eight subjects of known debrisoquin oxidation phenotype, four poor metabolizers (PM) and four extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 +/- 12.7 ng/ml; mean +/- SE) and a greater plasma AUC (779 +/- 99 ng X hr X ml-1) were reached in PM than in EM (99.8 +/- 13.7 ng/ml and 549 +/- 47 ng X hr X ml-1). Although the urinary excretion of unchanged phenformin was greater in PM between 2 and 24 hr after dosing than in EM, excretion of 4-hydroxy-phenformin could not be detected in most samples collected from PM but was present in every sample from EM. Blood lactate concentrations increased dramatically in PM but fell in EM after phenformin. There were no changes in either blood pyruvate or glucose levels. The results may help to explain lactic acidosis in patients given phenformin in the absence of other predisposing factors.

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“…Moreover, this protocol required temperature control and showed dependence on the amine nucleophile reactivity [ 27 ]. Another route involved the reaction of substituted biguanidines with acetic anhydrides, chlorides or carboxylates [ 11 , 28 – 31 ]. Liu et al [ 32 ] reported a one-pot synthesis of N 2 ,6-disubstituted-1,3,5-triazine-2,4-diamines in 44–72% yields that employed the reaction of isothiocyanates with sodium hydrogen cyanamide and amidines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and heating at 75 °C for 3 h. Recently, Ma et al [ 33 ] described a one-pot two step procedure for the synthesis of 6-substituted- N 2 -aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines via the reaction of aromatic amines, cyanoguanidine, and ketones which afforded the corresponding 1-aryl-1,6-dihydro-6-substituted-1,3,5-triazine-2,4-diamines in 21–56% yields followed by Dimroth rearrangement utilizing sodium hydroxide (50%) in aqueous ethanol ( Scheme 1 ).…”

Section: Introductionmentioning

confidence: 99%

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

Moustafa

Mekheimer

Al‐Mousawi

et al. 2020

Beilstein J. Org. Chem.

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Conversion of biguanides into substituted s‐Triazines Assayable by GC or Mass Fragmentography

Cited by 36 publications

References 4 publications

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Influence of oxidation polymorphism on phenformin kinetics and dynamics

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

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Conversion of biguanides into substituted s‐Triazines Assayable by GC or Mass Fragmentography

Cited by 36 publications

References 4 publications

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Influence of oxidation polymorphism on phenformin kinetics and dynamics

Microwave-assisted efficient one-pot synthesis of N2-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

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Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines