Novel hydrazide-hydrazone and amide substituted coumarin derivatives: Synthesis, cytotoxicity screening, microarray, radiolabeling and in vivo pharmacokinetic studies

Nasr T.; Bondock S.; Rashed H.M.; Fayad W.; Youns M.; Sakr T.M.

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Novel hydrazide-hydrazone and amide substituted coumarin derivatives: Synthesis, cytotoxicity screening, microarray, radiolabeling and in vivo pharmacokinetic studies

Nasr T.; Bondock S.; Rashed H.M.; Fayad W.; Youns M.; Sakr T.M.

Full Text link: https://t.ly/52MAY

Date issued: 2018

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Doi: https://doi.org/10.1016/j.ejmech.2018.04.014 PubMed ID 29665526

Publisher: Pharmacologyonline , Elsevier Masson SAS

Series Info: European Journal of Medicinal Chemistry
151

Type: Article

Keywords: October University for Modern Sciences and Arts , جامعة أكتوبر للعلوم الحديثة والآداب , University of Modern Sciences and Arts , MSA University , Apoptosis , Caspases 3/7 , Coumarin hydrazide-hydrazone , CYP3A4 , GST , Microarray , Radiolabeling , 2 chloro 6 ethoxy 3 formylquinoline , 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide , 2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide , 6 bromo 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide , 6 bromo 2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide , 6 bromo n (4 ethoxyphenyl) 2 oxo 2h chromene 3 carboxamide , 6 bromo n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 oxo 2h chromene 3 carbohydrazide , 6 nitro 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide , 6 nitro 2 oxo n' [(pyridin 4 yl)methylene] 2h chromene 3 carbohydrazide , 7 hydroxy 2 oxo n' [(pyridin 3 yl)methylene] 2h chromene 3 carbohydrazide , amide , antineoplastic agent , caspase 3 , caspase 7 , coumarin derivative , cytochrome P450 3A4 , doxorubicin , hydrazide derivative , hydrazone derivative , n (4 ethoxyphenyl) 2 oxo 2h chromene 3 carboxamide , n (4 ethoxyphenyl) 6 nitro 2 oxo 2h chromene 3 carboxamide , n (4 ethoxyphenyl) 7 hydroxy 2 oxo 2h chromene 3 carboxamide , n (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 2 oxo chromene 3 carboxamide , n (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 6 bromo 2 oxo chromene 3 carboxamide , n (4 {[(3,4 dimethylisoxazol 4 yl)amino]sulfonyl}phenyl) 6 nitro 2 oxo chromene 3 carboxamide , n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 cyanoacetohydrazide , n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 2 oxo 2h chromene 3 carbohydrazide , n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 6 nitro 2 oxo 2h chromene 3 carbohydrazide , n' [(2 chloro 6 ethoxyquinolin 3 yl)methylene] 7 hydroxy 2 oxo 2h chromene 3 carbohydrazide , unclassified drug , unindexed drug , antineoplastic agent , coumarin derivative , cytochrome P450 3A , cytochrome P450 3A inhibitor , hydrazone derivative , antiproliferative activity , apoptosis , Article , cell cycle , controlled study , down regulation , drug bioavailability , drug cytotoxicity , drug screening , drug synthesis , enzyme activation , enzyme assay , Hep-G2 cell line , human , human cell , in vitro study , in vivo study , isotope labeling , Knoevenagel condensation , leukemia , liver cell carcinoma , metabolic inhibition , microarray analysis , PANC-1 cell line , pancreas carcinoma , pharmacokinetic parameters , proton nuclear magnetic resonance , structure activity relation , tumor growth , tumor suppressor gene , upregulation , animal , chemistry , drug effect , halogenation , metabolism , mouse , neoplasm , pathology , synthesis , tissue distribution , tumor cell line , Animals , Antineoplastic Agents , Apoptosis , Cell Line, Tumor , Coumarins , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Halogenation , Humans , Hydrazones , Mice , Neoplasms , Tissue Distribution

Abstract:

The current work presents the synthesis and biological evaluation of new series of coumarin hydrazide-hydrazone derivatives that showed in vitro broad spectrum antitumor activities against resistant pancreatic carcinoma (Panc-1), hepatocellular carcinoma (HepG2) and leukemia (CCRF) cell lines using doxorubicin as reference standard. Bromocoumarin hydrazide-hydrazone derivative (BCHHD) 11b showed excellent anticancer activity against all tested cancer cell lines. Enzyme assays showed that BCHHD 11b induced apoptosis due to activation of caspases 3/7. Moreover, 11b inhibited GST and CYP3A4 in a dose dependent manner and the induced cell death could be attributed to metabolic inhibition. Moreover, 11b microarray analysis showed significant up- and down-regulation of many genes in the treated cells related to apoptosis, cell cycle, tumor growth and suppressor genes. All of the above presents BCHHD 11b as a potent anticancer agent able to overcome drug resistance. In addition, compound 11b was able to serve as a chemical carrier for 99mTc and the in vivo biodistribution study of 99mTc-11b complex revealed a remarkable targeting ability of 99mTc into solid tumor showing that 99mTc-11b might be used as a promising radiopharmaceutical imaging agent for cancer. � 2018 Elsevier Masson SAS