Synthesis and Evaluation of Diphyllin β‐Hydroxyl Amino Derivatives as Novel V‐ATPase Inhibitors

Background & Objective:New diaryl-substituted pyrimidinedione compounds, their thioxo derivatives as well as their bicyclic thiazole compounds were synthesized and characterized.Methods:The glycosylamino derivatives of the synthesized disubstituted derivatives of the pyrimidine scaffold were also prepared via reaction of the N3-amino derivatives with a number of monosaccharides followed by acetylation.Results:The anticancer activity of the synthesized compounds was studied against human liver cancer (HepG2) and RPE-1cell lines. Compounds 2a, 2b, 3a and 12 showed potent activities with IC50 results comparable to that of doxorubicin.Conclusion:Docking investigations into Cyclin-dependent kinase 2 (CDK-2) enzyme, a potential target for cancer medication, were also reported showing the possible binding interaction into the enzyme active site to support their activity behavior.

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Thermal cyclocondensations of 3-N(4- and 5-benzimidazolyl and benztriazolyl)amino derivatives of 2-propenoic acid

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19872918 ◽

1987 ◽

Vol 52 (12) ◽

pp. 2918-2925 ◽

Cited By ~ 10

Author(s):

Viktor Milata ◽

Dušan Ilavský

Keyword(s):

Uv Spectra ◽

Propenoic Acid ◽

Amino Derivatives ◽

Derivatives Of ◽

C Nmr ◽

Ir And Uv Spectra

The cyclization of 3-N(4- and 5-benzimidazolyl and benztriazolyl)amino-2-cyano- and 2-ethoxycarbonyl-2-propenoate esters Ia, b-IVa, b under the conditions of the Gould-Jacobs reaction leads to angularly ring-fused substituted imidazo or triazolo[4,5-f] (V, VI) and [4,5-h] (VII, VIII) quinolines, respectively. The esters Vb-VIIIb have been transformed into the corresponding chloroderivatives Vc-VIIIc. 3-N(5-Benzimidazolyl and 5-benztriazolyl)amino-2-cyano-2-propenenitriles are cyclized in the presence of aluminium(III) chloride to give the aminoquinolines Vd, VId. The structure of the products has been characterized by their 1H, 13C NMR, IR, and UV spectra.

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The preparation of 3-amino-3-deoxy-1,2-O-isopropylidene-α-L-erythrofuranose, 3-amino-3-deoxy-1,2-O-isopropylidene-β-D-threofuranose and their derivatives

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19803378 ◽

1980 ◽

Vol 45 (12) ◽

pp. 3378-3390 ◽

Cited By ~ 3

Author(s):

Jiří Jarý ◽

Milena Masojídková ◽

Ivan Kozák ◽

Miroslav Marek ◽

Jan Staněk

Keyword(s):

Nucleophilic Substitution ◽

Sodium Azide ◽

Sodium Benzoate ◽

Nmr Spectra ◽

Subsequent Reduction ◽

H Nmr ◽

Amino Derivatives

The title amino derivatives VI and XIV were prepared by nucleophilic substitution of p-toluenesulfonyl derivatives II and XVII with sodium azide or hydrazine and subsequent reduction. Nucleophilic substitution of compounds II and XVII with sodium benzoate was also investigated. The 1H NMR spectra of the substances prepared are discussed.

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Synthesis of isomeric 1,1'-phenylene-bis(6-azauracil-5-carbonitriles)

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19902967 ◽

1990 ◽

Vol 55 (12) ◽

pp. 2967-2976 ◽

Cited By ~ 6

Author(s):

Jan Slouka

Keyword(s):

General Formula ◽

Mutual Distance ◽

Planar Molecules ◽

Amino Derivatives

The described synthesis of all three isomeric 1,1'-phenylene-bis(6-azauracil-5-carbonitriles) IVa-IVc starts from the respective 1-nitrophenyl-6-azauracil-5-carbonitriles Ia-Ic which were reduced to the corresponding amino derivatives IIa-IIc, diazotized, and coupled with ethyl cyanoacetylcarbamate to give the isomeric hydrazones IIIa-IIIc which were finally cyclized to the title compounds containing two 6-azauracil rings. A general formula is presented for calculation of mutual distance of arbitrary atoms in any planar molecules.

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Synthesis of 3-Amino- and 3-Acylamino-1-cyclopropylquinolin-4(1H)-ones

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19942123 ◽

1994 ◽

Vol 59 (9) ◽

pp. 2123-2126 ◽

Cited By ~ 2

Author(s):

Stanislav Rádl

Keyword(s):

Carboxylic Group ◽

Amino Derivatives

Antibacterial quinolones have attracted an increasing attention as a source of clinically useful drugs. During our research into antibacterial quinolones we were also interested in compounds having at the position 3 various groups that could mimic the carboxylic group present in these drugs. Having our own procedure for the preparation of 3-nitroquinolones, we decided to investigate the question of possible activity of 3-amino derivatives and 3-acylamino derivatives.

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Kinetics and Mechanism of Decomposition of 1,3-Bis(4-methylphenyl)triazene Catalyzed with Substituted Benzoic Acids in 25% Aqueous Methanol-General or Specific Catalysis?

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19942029 ◽

1994 ◽

Vol 59 (9) ◽

pp. 2029-2041

Author(s):

Oldřich Pytela ◽

Taťjana Nevěčná

Keyword(s):

Benzoic Acids ◽

Hammett Equation ◽

Aqueous Methanol ◽

Mechanism Of Decomposition ◽

Kinetics Of Decomposition ◽

Independent Variable ◽

Amino Derivatives ◽

Substituted Benzoic Acids ◽

The Individual ◽

Kinetics Of

The kinetics of decomposition of 1,3-bis(4-methylphenyl)triazene catalyzed with 13 substituted benzoic acids of various concentrations have been measured in 25 vol.% aqueous methanol at 25.0 °C. The rate constants observed (297 data) have be used as values of independent variable in a series of models of the catalyzed decomposition. For the catalytic particles were considered the undissociated acid, its conjugated base, and the proton in both the specific and general catalyses. Some models presumed formation of reactive or nonreactive complexes of the individual reactants. The substituent effect is described by the Hammett equation. The statistically best model in which the observed rate constant is a superposition of a term describing the dependence on proton concentration and a term describing the dependence on the product of concentrations of proton and conjugated base is valid with the presumption of complete proton transfer from the catalyst acid to substrate, which has been proved. The behaviour of 4-dimethylamino, 4-amino, and 3-amino derivatives is anomalous (lower catalytic activity as compared with benzoic acid). This supports the presumed participation of conjugated base in the title process.

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Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽

10.3390/molecules26061637 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1637

Author(s):

Solida Long ◽

Joana B. Loureiro ◽

Carla Carvalho ◽

Luís Gales ◽

Lucília Saraiva ◽

...

Keyword(s):

Growth Inhibition ◽

Small Molecules ◽

Tumor Cells ◽

Mutant P53 ◽

Wild Type ◽

Naturally Occurring ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Amino Derivatives ◽

Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

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Differential regulation of AMP-activated protein kinase in healthy and cancer cells explains why V-ATPase inhibition selectively kills cancer cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010243 ◽

2019 ◽

Vol 294 (46) ◽

pp. 17239-17248

Author(s):

Karin Bartel ◽

Rolf Müller ◽

Karin von Schwarzenberg

Keyword(s):

Reactive Oxygen Species ◽

Protein Kinase ◽

Cancer Cells ◽

Reactive Oxygen Species Production ◽

Differential Regulation ◽

Oxygen Species ◽

Atpase Inhibitors ◽

Species Production ◽

Amp Activated Protein Kinase ◽

Atpase Inhibition

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic hub regulating various pathways involved in tumor metabolism. Here we report that vacuolar H+-ATPase (V-ATPase) inhibition differentially affects regulation of AMPK in tumor and nontumor cells and that this differential regulation contributes to the selectivity of V-ATPase inhibitors for tumor cells. In nonmalignant cells, the V-ATPase inhibitor archazolid increased phosphorylation and lysosomal localization of AMPK. We noted that AMPK localization has a prosurvival role, as AMPK silencing decreased cellular growth rates. In contrast, in cancer cells, we found that AMPK is constitutively active and that archazolid does not affect its phosphorylation and localization. Moreover, V-ATPase–independent AMPK induction in tumor cells protected them from archazolid-induced cytotoxicity, further underlining the role of AMPK as a prosurvival mediator. These observations indicate that AMPK regulation is uncoupled from V-ATPase activity in cancer cells and that this makes them more susceptible to cell death induction by V-ATPase inhibitors. In both tumor and healthy cells, V-ATPase inhibition induced a distinct metabolic regulatory cascade downstream of AMPK, affecting ATP and NADPH levels, glucose uptake, and reactive oxygen species production. We could attribute the prosurvival effects to AMPK's ability to maintain redox homeostasis by inhibiting reactive oxygen species production and maintaining NADPH levels. In summary, the results of our work indicate that V-ATPase inhibition has differential effects on AMPK-mediated metabolic regulation in cancer and healthy cells and explain the tumor-specific cytotoxicity of V-ATPase inhibition.

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ChemInform Abstract: SYNTHESIS AND ANTITUMOR ACTIVITY OF 6-OXO-7-AMINO DERIVATIVES OF 5H-PYRIDO(2,3B)- AND 5H-PYRIMIDO(4,5B)(1,4)THIAZINES

Chemischer Informationsdienst ◽

10.1002/chin.198515259 ◽

1985 ◽

Vol 16 (15) ◽

Author(s):

N. I. TRAVEN' ◽

YU. A. ERSHOVA ◽

A. S. SOKOLOVA ◽

V. A. CHERNOV ◽

T. S. SAFONOVA

Keyword(s):

Antitumor Activity ◽

Amino Derivatives ◽

Derivatives Of

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