الفهرس 
CancerOnly 14 pages are availabe for public view
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Abstract
Cancer is a multicellular disease that can arise from any cell types and organs with a multi-factorial etiology. In 2008, World health organization (WHO) considered it as the leading cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths).
Anticancer agents consisting of hybrid molecules are used to improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized heterocyclic steroids of promising anticancer effects which are loaded in polyethylene glycol (PEG( based nanoparticles form.
In this study several heterocyclic steroids (I-IX) were synthesized via multicomponant reactions (MCRs) using 5α-cholestan-3-one as starting material. The analytical and spectral data (IR, 1HNMR, 13CNMR, and mass spectrum) of all new compounds are compatible with the proposed structures.
The study involved the synthesis and the characterization of the following new- targeted compounds:
8-Amino-10-(4-methoxyphenyl)-11a,13a-dimethyl-1-octyl2,3,3a,3b,4,5,5a,-6,6a,7,11,11a,11b,12,13,-13a-hexadecahydro-1H-cyclopenta[5,6]naphtha-[1,2-g]quinoline-9-carbonitrile (I).
8-Amino-10-(4-methoxyphenyl)-11a,13a-dimethyl-1-octyl-1,2,3,3a,3b,4,5,-5a,6,6a,11,11a,11b,12,13,-13a-hexadecahydro-cyclopenta[5,6]naphtha-[1,2g]chromene-9-carbonitrile (II).
12-(4-Methoxyphenyl)-13a,15a-dimethyl-1-octyl-10-phenyl-1,2,3,3a,3b,4-,5,5a,6,6a,7-,10,13,13a,13b,14,15,15a-octadecahydro-11H-cyclopenta[5,6]-naphtho[1,2-g]pyrimido[4,5-b]quinolin-11-imine (III).
11-(4-Methoxyphenyl)-12a,14a-dimethyl-1-octyl-1,2,3,3a,3b-,4,5,5a,6,6a,-8,9,12,-12a,12b,13,14,14a-octadecahydrocyclopenta-[5,6]naphtho[1,2-g]-pyrazolo[3,4-b]quinolin-10(10aH)-imine (IV).
11-(4-Methoxyphenyl)-12a,14a-dimethyl-1-octyl-9-phenyl1,2,3,-3a,3b,4,5,5a,6,6a,8,9,12,12a,12b,13,-14,14aocta-decahydrocyclopenta-[5,6]naphtha-[1,2-g]pyrazolo-[3,4-b]quinolin-10(10aH)-imine (V).
11-Imino-12-(4-methoxyphenyl)-13a,15a-dimethyl-1-octyl-3,3a,3b,4,5,-5a,6,6a,8,10,11,11a,13,13a,13b,14,15,15a-octadecahydro-1H-cyclopenta-[5,6]naphtho[1,2-g]pyrimido-[4,5-b]quinoline-9(2H)-thione (VI).
11-Imino-12-(4-methoxyphenyl)-13a,15a-dimethyl-1-octyl-3,3a,-3b,4,5,-5a-,6,6a,8,10,11,-11a,13,13a,13b,14,15,15a-octadecahydro-1H-cyclopenta-[5,6]naphtho[1,2-g]pyrimido[4,5-b]quinolin-9(2H)-one (VII).
12-(4-Methoxyphenyl)-13a,15a-dimethyl-1-octyl-9-thioxo3,3a,-3b,4,5,5a,-6,6a,8,9,10,11a,13,13a,13b,14,15,15a-octadecahydro-1H-cyclopenta[5,6]-naphtho[1,2-g]pyrimido[4,5-b]quinolin-11(2H)-one (VIII).
12-(4-Methoxyphenyl)-13a,15a-dimethyl-1-octyl-3,3a,3b,4,5,-5a,6,6a,10-,11a,13,13a,13b,-14,15,15a-hexadecahydro-1H-cyclopenta-[5,6]naphtho[-1,2-g]pyrimido[4,5-b]quinoline-9,11(2H,8H)-dithione (IX).
The newly synthesized compounds were converted into PEG based nanoparticles via precipitation method, particle size distribution and zeta potential of the synthesized nanosized cholestane heterocyclic derivatives (NI-NIX) was measured by Malvern Zetasizer system, in addition to the morphology and particle size were evaluated by Transmission Electron Microscope (TEM).
Compounds ( I, II, III, IV,V,VI, VII and IX), were investigated individually in their free and PEG based nano size form as anticancer agents against three human cell lines hepatocellular carcinoma cells (HepG2), breast cancer cells (MCF-7) and colon cancer cells (HCT116) using neutral red supravital dye uptake assay. The enzymatic assay was performed in BPS Bioscience Corporation; USA. The enzymatic activity of the synthesized compounds was evaluated against cKit Protein tyrosine kinase at 10 μM concentration.Compound (NVI) in its PEG based nano size revealed the best cytotoxic effect against HepG2 and HCT116 cell lines with IC50 2.44 µmol/L and 2.59 µmol/L, respectively. Besides it showed a considerable low IC50 value against MCF-7 (3.46 µmol/L). This study introduced promising anticancer agents acting through converting them into PEG-based nanoparticles.
These results were further explained in the molecular docking studies using C-DOCKER protocol in Discovery Studio 2.5 Soft WSoftware, it was attempted to investigate the binding mode of the targeted compounds and interpret their variable inhibitory activity. It revealed the ability of the steroidal derivatives to form a network of key interactions, known to be essential for inhibitors.
This thesis includes 142 references covering the time period from 1934 to 2017.