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.
- 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: [email protected].
- 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: [email protected].
- 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: [email protected].
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.