A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles 4 is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide 2 and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides 3. The 6-azaisocytosines 4 were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-c]-[1,2,4]triazine 8 and the 1,2,4-triazino[2,3-a]quinazolines 9-12.
Skripta
1. vyd. ^^^sv. : il. ; 29 cm
- MeSH
- organická chemie MeSH
- Konspekt
- Organická chemie
- Učební osnovy. Vyučovací předměty. Učebnice
- NLK Obory
- chemie, klinická chemie
- NLK Publikační typ
- učebnice vysokých škol
A series of the 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines have been synthesized in five steps. The cytotoxic activity of all of the newly synthesized compounds has been tested in vitro against five cancer cell lines. Several compounds demonstrated significant broad cytotoxic activity in low micromolar range, while others were selectively active against lung adenocarcinoma cell line A549.
In this paper we describe the preparation of some derivatives of 1,2,4-triazino[4,5-a]benzimidazol-1-ones (5 and 6), containing additional benzimidazole ring. These compounds were prepared using coupling reactions of diazonium salts with 1,1-bis(1-ethoxycarbonyl-benzimidazol-2-yl)methane (2) to obtain unstable hydrazones 4, which readily undergo cyclization. Interestingly, the selected compounds demonstrated preferential cytotoxic activities against human carcinoma and glioma cell lines compared with leukemic cells. They showed significant activity against multidrug-resistant P-glycoprotein expressing cell lines but had less effect on multidrug-resistance protein 1 positive and topoisomerase IIalpha negative leukemias.
- MeSH
- benzimidazoly farmakologie chemická syntéza chemie toxicita MeSH
- financování organizované MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakologie chemická syntéza chemie toxicita MeSH
- racionální návrh léčiv MeSH
- senzitivita a specificita MeSH
- Check Tag
- lidé MeSH
In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
- MeSH
- antimetabolity diagnostické užití MeSH
- azosloučeniny farmakologie chemická syntéza MeSH
- bromodeoxyuridin diagnostické užití MeSH
- buněčný cyklus účinky léků MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- financování organizované MeSH
- imunoblotting MeSH
- inhibitory enzymů farmakologie chemická syntéza MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk účinky léků MeSH
- pyrazoly farmakologie chemická syntéza MeSH
- reverzní transkripce účinky léků MeSH
- RNA biosyntéza izolace a purifikace MeSH
- substrátová specifita MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- MeSH
- finanční podpora výzkumu jako téma MeSH
- Publikační typ
- abstrakty MeSH
- MeSH
- finanční podpora výzkumu jako téma MeSH
- Publikační typ
- abstrakty MeSH
- MeSH
- finanční podpora výzkumu jako téma MeSH
- Publikační typ
- abstrakty MeSH
