5222
Mai Ali Ahmed Khater
Design, synthesis and Molecular Modeling studies of Some Novel rrisubstituted Pyrazole Derivatives as Anticancer Agents
uilsmiers reaction, Pyrazole, Anticancer
In this thesis a new series oftri-substitutedpyrazole derivatives was designed as anticancer agents and synthesized,. starting by the formylation of semicarbazone via Vilsmeier-Haack reaction to give 3-(4-Bromophenyl)-1 H-pyrazole-4-carbaldehyde 36 which was the precursor of compounds I-XIX. All the structures were confirmed by analytical and spectral measurements in addition to a single crystal X-ray study performed on compound VII confirming our proposed molecular structure. The new chemical entities were screened for their anti-cancer activrty on various human cancer cell lines namely: hepatocellular carcinoira HepG2, breast cancer MCF7, lung carcinoma As$g,prostatic cancerPC3 and colon carcinomaHCT1 16 attheNational Research'Centre (NRC, Egypt). Most of the synthesized compounds showed remarkable activity on the tested cell lines. especially compounds VId, WI and IX. The molecular modeling study was used to explain the synthesized compounds' mechanism of action as potential B-Raf kinase inhibitors. The presented thesis comprises the following chapters: 1- Introduction: It contains a survey covering the definition of cancer, its risk factors and etiology. This section also explains cancer therapeutic strategies, with a focus on protein kinases and a review on the B-Raf kinase inhibitory activity of pyrazole derivatives. 2- Rationale and design: In this section a series of novel tri-substituted pyrazole derivatives was designedas potential B-Raf kinase inhibitors. Our design was based on the bioisosteric modifications ofthe reference gompound after exploring the key interactions with the binding site. The different routes adopted for the preparation ofthe target compounds are outlined in schemes (1-3).
2016
M.Sc
Ain Shams
Pharmacy