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

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

  • Eur J Med Chem. 2018 May 10:151:723-739. doi: 10.1016/j.ejmech.2018.04.014.
Tamer Nasr 1,  Samir Bondock 2,  Hassan M Rashed 3,  Walid Fayad 4,  Mahmoud Youns 5,  Tamer M Sakr 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Modern University for Technology and Information, Egypt. Electronic address: tamerhefni@yahoo.com.
  • 2 Department of Chemistry, Faculty of Science, Mansoura University, ET-35516, Mansoura, Egypt; Department of Chemistry, Faculty of Science, King Khalid University, 9004, Abha, Saudi Arabia.
  • 3 Labeled Compounds Department, Hot Labs Center, Egyptian Atomic Energy Authority, P.O. Code 13759, Cairo, Egypt.
  • 4 Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza, 12622, Egypt.
  • 5 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Egypt. Electronic address: dr.mahmoudyouns@yahoo.com.
  • 6 Radioactive Isotopes and Generators Department, Hot Laboratories Centre, Atomic Energy Authority, P.O. Code 13759, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts (MSA), Giza, Egypt. Electronic address: Tamer_sakr78@yahoo.com.
PMID: 29665526 DOI: 10.1016/j.ejmech.2018.04.014
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.

Keywords

Apoptosis; CYP3A4; Caspases 3/7; Coumarin hydrazide-hydrazone; GST; Microarray; Radiolabeling.

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