الفهرس 
Aim of the workOnly 14 pages are availabe for public view
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Abstract
This thesis aims to synthesize novel heterocyclic compounds via conventional, and click reactions. Biological activities of some of the obtained products were investigated.
The thesis is divided into three parts:
Part 1:
In this part, we report rapid, and effective procedures for the synthesis of dibenzofuran derivatives by the reaction of dimedone (1) with some selected electrophiles such as 2,3,5,6-tetrachloro-1,4-benzoquinone (p-chloranil, 255), 3,4,5,6-tetrachloro-1,2-benzoquinone (o-chloranil, 257) and 1,4-naphthoquinone (NQ, 259) (Scheme 89). We have found that on refluxing 1 with the electron -acceptor 255 in ethanol in the presence of sodium hydroxide as a catalyst, dibenzo[b,d]furan derivative 256 was formed in good yield (Scheme 89).
Additionally, We examine the reactivity of dimedone (1) towards both of TCNE 266 and/or 2-(bis(methylthio)methylene)malononitrile (captodative, 268). We have found that, on heating equimolar ratios of their alcoholic solutions for 4-6 hrs under reflux conditions in the presence of NaOH as a catalyst, the reaction proceeds to give 2-amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3,4,4-tricarbonitrile (267) and 6,6-dimethyl-4-oxo-5,6-dihydrobenzofuran-2,2(4H)-dicarbonitrile (269), respectively (Scheme 91).
The previous results encouraged us to study of the reactivity of the electron rich benzene-1,2dithiol (276) with 2,3-dichloronaphthalene-1,4-dione (DCHNQ, 277), 2,3,5,6-tetrachloro-1,4benzoquinone (p-chloranil, 255), 5,6-dichloro-2,3-dicyano-1,4-benzoquinone (DDQ, 279) and tetracyanoethylene (TCNE, 266). These reactions led to synthesize of thianthrene derivatives 278, 280 and 281as well as thianapthalene derivative 282 in good yields.
Part 2:
In this part we have explored click approach for the rapid synthesis and discovery of important classes of organic compounds containing quinolone and triazole heterocycles. We expected that the method described in this context will find wide spread applications in the emerging field molecular architectures.
Schemes 94 and 95 depict the synthesis of compounds 286a-e and 289a-e via cycloaddition reaction of the obtained 1,8-bis(prop-2-yn-1-yloxy)naphthalene (284), or 1,5-bis(prop-2-yn-1-yloxy)naphthalene (288) with different readily prepared azides of quinolones 285a-e. The cycloaddition reaction of azide-alkyne was performed in DMF via click conditions to afford a series of five different Syn-like and anti-like quinolone-dioxo-naphthalene hybrids via triazole linker 286a-e and 289a-e, respectively.
Biology:
The newly synthesized compounds were tested for antiproliferative activity against four different types of cancer cells: A-549 (epithelial cancer cell line), MCF-7 (breast cancer cell line), Panc-1 (pancreas cancer cell line), and HT-29 (colon cancer cell line). Erlotinib was used as the reference, and displayed good results compared to the reference.
Antiproliferative assay:
Three compounds with the highest antiproliferative activity were identified: 286a and 289b with a Syn quinoline backbone structure (Scaffold A) and 289d with an Anti-quinoline backbone structure (Scaffold B), with GI50 values ranging from 34 nM to 54 nM. Compound 286a inhibited the MCF-7 (breast cancer) cell line more effectively than compounds 286e Syn quinoline backbone) and compound 289d, Anti quinoline backbone because the free NH group in compound 286a was replaced with a methyl group.
EGFR inhibitory assay:
Compounds 286a, 286b, and 289d significantly inhibited the activity of the EGFR enzyme, with IC50 values ranging from 64 nM to 97 nM. Compound 286a, the most effective antiproliferative of all synthetic derivatives. Compounds 286b and 289d significantly inhibited EGFR with IC50 values of 93 and 97 nM, respectively, which were roughly 1.3-fold less effective than erlotinib. The outcomes of this assay supplemented cancer cell-based assay results, suggesting that EGFR-TK may be a viable target for these drugs’ antiproliferative effects.
Effect of compounds 286a, 286b, and 289d on Caspases Cascade:
The effects of derivatives 286a, 286b, and 289d on caspase-3 were studied and compared to the reference drug doxorubicin. The results showed that 286a, 286b, and 289d increased the level of active caspase-3 by 7-9 folds when compared to control untreated cells and that 286a, 286b, and 289d had remarkable overexpression of caspase-3 protein level (587.50±4.50, 535.50±4.50, and 485.50±4.25 pg/mL, respectively) when compared to the reference doxorubicin (503.2±4.50 pg/mL).
Effect of compounds 286a, 286b, and 289d on Cytochrome C level:
In the A-549 epithelial cancer cell line, hybrids 286a and 286b result in a 16- and 14-fold overexpression of Cytochrome c compared to control.
Effect of compounds 286a, 286b, and 289d on BaX and Bcl2 levels:
The most effective hybrids 286a and 286b were further investigated for their impact on Bax and Bcl-2 levels against the A-549 epithelial cancer cell line.
Docking studies:
Docking studies proved that the compound 286a is the most active EGFR inhibitor among the investigated compounds, also had a most significant docking score of -7.20 kcal/mol and a ΔG Bind of -75.62 kcal/mol when contrasted to Erlotinib (-9.07 and -84.86 kcal/mol, respectively). The binding interaction showed that compound 286a formed one hydrogen bond with Arg817 at a 2.21 A° bond length, while the central naphthyl ring formed π-cation interaction with Lys721(4.08 A°) in the EGFR kinase domain (Fig.7A). The quinolin-2(1H)-one and triazole portions of compound 286a were shown to have substantial van der Waals contacts with Gly772 (-3.09 kcal/mol), Val702 (-3.95 kcal/mol), and Leu694 (-4.14 kcal/mol) which demonstrated that the molecule is entrenched within the active site.
Part 3:
Based on the previous research results we use several selected derivatives of aldehydes and ketones together with p-chloroaniline (17) for the synthesis of the β-amino ketone 290a-e following the typical one-pot Mannich reaction (Scheme 96). We have found that, β-amino ketone derivatives 290a-e were formed on good yields with short reaction time on mixing acetophenone derivatives 38a,b and aromatic aldehyde derivatives 2a-e with p-chloroaniline in presence of zirconium oxychloride (ZrOCl2.8H2O) as an inexpensive and commercially available catalyst (Scheme 96).