الفهرس 
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Abstract
The present study deals with the synthesis and the biological evaluation of new HDAC inhibitors as potential antiproliferative agents. The target compounds were evaluated for their anticancer activity. A molecular mechanism was investigated for selected target compounds as traditional HDAC or SIRT2 inhibitors. Additionally, in silico studies of synthesized derivatives were studied.
This thesis consists of five major parts: introduction, scope of investigation, results and discussion, experimental section and references.
1- Introduction
The introduction is the first part of the thesis that gives an overview of the role of HDAC inhibitors in cancer. Classification of HDAC enzymes to traditional HDAC: class 1, 2, and 4 inhibitors. Pyrimidine-bearing compounds as traditional HDAC inhibitors. The other is class 3 inhibitors. One of these is pyridine-containing compounds, as examples of this group.
2- Scope of investigation
This part represents the aim of the work, including the rational for design and synthesis of novel pyrimidine containing HDAC inhibitors and pyridine containing SIRT2 inhibitors with anticancer activity.
3- Results and discussion
This part includes details of all results obtained, from different stages of study from the synthesis and structural elucidation to biological evaluation of the final target compounds 7a-e, 8a-e, 9a-e, 12a,b, 15a-e, and 19a-g plus their key starting compounds and intermediates.
This part is subdivided into four main sections:
The first one is the chemistry section which includes a description of the methods to synthesize the intermediate compounds 2a-e, 4a-e, 5a-e, and 6a-e as well as target final compounds 7a-e, 8a-e, and 9a-e. In addition, intermediates 11a,b, 13a-b, 17a-g, and 18a-g and final compounds 12a,b, 15a-e, and 19a-g and structural elucidations of the synthesized derivatives by different spectroscopic techniques, including 1H NMR, 13C NMR, and MS spectroscopy, in addition to elemental analyses. The synthesis of the novel compounds was sketched in Schemes 1, 3, 4 and 5 in the present study.
The second section is the biology section that demonstrates different methods and results obtained from different biological investigations of the target compounds. It includes the following parts:
1- Cytotoxicity of the target compounds 7a-e, 8a-e, and 9a-e against four cell lines. These cell lines are MCF7 breast cell lines, PANC1 pancreatic cell lines, A549 lung cell line, and HT-29.
2- HDAC inhibitory activity for the potent cytotoxic derivatives 9b-e.
3- HDAC selectivity against HDACs 1,2, and 8 for the most potent compound 9d.
4- NCI one dose evaluation of in vitro antiproliferative activity for compounds 12a,b, 15a-e, 18b-g, and 19a-g.
5- NCI five dose evaluation of in vitro antiproliferative activity for 12a,b, 15a-e, 18b-g, and final compounds 19b-g.
6- SIRT2 inhibition assay of the final compounds 12a,b, 15a-e, and 19a-g.
The third section is the molecular modelling studies using MOE software(version2019). Docking simulation of target compounds was performed with co-crystalized HDLP protein with SAHA (PDB: lZZ1). Target compounds showed similar fitness to SAHA in the active site of the enzyme. In addition, docking of SIRT2 inhibitors designed compounds within the SIRT2 active site (PDB: 4RMG), taking sireal2 as a reference.
4- Experimental
The experimental part demonstrates the details of the methods and experiments used in this research, and it includes the following three sections:
The first is chemistry section which describes in detail the procedures used to synthesize the intermediates and target compounds. Additionally, it includes all physical, spectroscopic, and elemental analyses data of the synthesized compounds.
The second part is the biology one which illustrates the methodology of anticancer screening of synthesized compounds against different cancer cell lines in addition to the procedures of HDAC and SIRT2 enzyme inhibition evaluation.
The third section is the method of molecular modelling studies by using MOE software (version2019).
Preface
Two articles were published from this thesis:
1- Badran MM, Abbas SH, Fujita M, et al. Harnessing pyrimidine as a building block for histone deacetylase inhibitors. Archiv der Pharmazie e2300208 https://doi.org/10.1002/ardp.202300208
2- Derivatives contain dimethylaminopyridine as SIRT2 inhibitors: A mini review. JABPS.