- Activity of 2,6,9-trisubstituted purines as potent PDGFRα kinase inhibitors with antileukaemic activity
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Receptor tyrosine kinase PDGFRα is often constitutively activated in various tumours and is regarded as a drug target. Here, we present a collection of 2,6,9-trisubstituted purines with nanomolar potency against PDGFRα and strong and selective cytotoxicity in the human eosinophilic leukaemia cell line EOL-1 that expresses the FIP1L1-PDGFRA oncogene. In treated EOL-1 cells, the example compound 14q inhibited the autophosphorylation of PDGFRα and the phosphorylation of STAT3 and ERK1/2. Interestingly, we observed pronounced and even increased effects of 14q on PDGFRα and some of its downstream signalling pathways after drug washout. In accordance with suppressed PDGFRα signalling, treated cells were arrested in the G1 phase of the cell cycle and eventually underwent apoptosis. Our results show that substituted purines can be used as specific modulators of eosinophilic leukaemia.
- ?ezní?ková, Eva,Gucky, Tomá?,Ková?ová, Veronika,Ajani, Haresh,Jorda, Radek,Kry?tof, Vladimír
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- New phenylaniline derivatives as modulators of amyloid protein precursor metabolism
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The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7-chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2-aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3–10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100 μM.
- Gay, Marion,Carato, Pascal,Coevoet, Mathilde,Renault, Nicolas,Larchanché, Paul-Emmanuel,Barczyk, Amélie,Yous, Sa?d,Buée, Luc,Sergeant, Nicolas,Melnyk, Patricia
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p. 2151 - 2164
(2018/03/23)
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- AMIDINE DERIVATIVES WITH NITRIC OXIDE SYNTHETASE ACTIVITIES
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Amidine derivative compounds of formula I as defined in the Specification having nitric oxide synthetase inhibitory activity as well as processes for the preparation of and compositions containing said compounds are described
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- Nitrobenzyl Derivatives as Bioreductive Alkylating Agents: Evidence for the Reductive Formation of a Reactive Intermediate
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o- and p-nitrobenzyl chlorides and carbamates were chemically and electrochemically reduced in the presence and absence of the nucleophile morpholine; activation of these compounds by reduction was required to produce an intermediate capable of alkylation.The reduction products formed by the catalytic hydrogenation of each compound were examined by gas chromatography-mass spectrometry.In addition, the products generated by controlled-potential electrolysis were examined by ESR and NMR spectrometry.After a one-electron reduction, o- and p-nitrobenzyl chlorides were activated to the nitrobenzyl radicals, which subsequently dimerized to the dinitrobibenzyl derivatives or reacted with morpholine when present in the reaction medium to form the (nitrobenzyl)morpholine adducts.The nitrobenzyl carbamates were not activated after a one-electron reduction; however, the morpholine and the ether adducts of these agents were observed after catalytic hydrogenation.It was assumed that an intermediate or intermediates formed after the one-electron reduction product, or the full reduction product of the carbamates, were capable of alkylating various nucleophiles.Chemical reduction of the potential bioreductive alkylating agent (o-nitrobenzyl)-6-thioguanine produced (o-aminobenzyl)-6-thioguanine, indicating a lack of formation of a reactive electrophile by reduction. (o-, (m-, and (p-nitrobenzyl)-6-thioguanine analogues were also examined for cytotoxic activity toward EMT6 tumor cells under aerobic and hypoxic conditions.In agreement with the inability of (o-nitrobenzyl)-6-thioguanine to form a reactive species after chemical reduction, no decrease in the survival of neoplastic cells exposed to 10-4 M drug occurred under either aerobic or hypoxic conditions.
- Kirkpatrick, D. L.,Johnson, K. E.,Sartorelli, A. C.
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p. 2048 - 2052
(2007/10/02)
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