الفهرس 
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Abstract
Cancer is one of the leading causes of death in the world. Though advances in cancer therapy and diagnosis have considerably improved life expectancy, the overall survival rate of patients still remains poor. Disseminated cancer at the time of diagnosis and acquisition of tumour resistance are two main reasons. The growing knowledge of the biochemical pathways involved in a disease process increases the possibility to develop new approaches to treat this disease. An extremely promising strategy for cancer prevention today is chemotherapy, which is defined as the use of synthetic or natural agents (alone or combination) to block the development of cancer in humans. A major obstacle for the successful use of chemotherapy in cancer treatment is tumour cell resistance. Therefore, the need to find a safe and highly effective cure for cancer remains a major challenge for modern science. The inclusion of biologically active ligands into organometallic complexes offers much scope for the design of novel drugs with enhanced, targeted activity. 1 neocryptolepine The structure of neocryptolepine and its atom numbering It is expected that the combination of metals with biologically active ligands can improve the anticancer profile, e.g. by an increase of drug uptake or a decrease of side effects. In this thesis, we were interested in studying the effect of incorporation of metal ions into biologically active ligand with natural origin such as neocryptolepine (5-methyl-5Hindolo [2,3 -b] quinoline). In this thesis, a range of complexes of copper(II), cobalt(II), nickel(I1) and palladium(I1) with aminoalkylamino neocryptolepine analogues 4 as biologically active ligands were synthesized and tested for their anticancer activity. At the moment, platinum(I1) complexes are the only metal-based drugs in cancer chemotherapy, but also other complexes with a different metal center have a high potential as anticancer agents, such as copper that plays an important role in biological systems. In this work, a range of complexes of copper(II), cobalt(II), nickel(I1) and palladium(I1) with neocryptolepine core as biologically active ligands were synthesized and tested for their anticancer activity. The pharmacological importance of neocryptolepine is demonstrated by the fact that it is a natural product alkaloid isolated from the roots of Cryptolepis sanguinolenta, an African plant used in traditional medicine . The medicinal applicability of neocryptolepine as antimalarial, antischistosomal and anticancer active compounds has been confirmed. However, metal complexes with neocryptolepine containing ligand have never been reported in the literature. With the aim of improving the biological activity and reduce the cyctotoxcity of the neocryptolepine core herein we report on the synthesis and in vitro anticancer activity of the first generation of cobalt(II), nickel(II), copper(I1) and palladium(I1) complexes with aminoalkylamino substituted neocryptolepine ligand. The formal total synthesis of the natural product skeleton of the neocryptolepine 1 was achieved by a three-step approach starting from easily accessible intermediates, this approach allowed us to synthesize the key intermediate 2 with a chloride at the C-1 1 position of the B ring. The synthetic methodology for the construction of neo cryptolepine nucleus was achieved by chlorination of methyl indole-3-carboxylate with N-chloro succinimide in the presence of 1,4-dimethylpiperazine, followed by addition of N-methylaniline as a trichloro acetate salts, the resulting intermediates were cyclised in boiling diphenyl ether to give the required tetracyclic indoloquinolinone core structure of neocryptolepine nucleus I, which upon reaction with phosphorus oxychloride give the corresponding key intermediates 11 -chloroneocryptolepine derivative in good yield, short reaction time and high degree of purity. The key intermediate 11- chloroneocryptolepine derivative 1 was used further for the diversification of the neocryptolepine core at the C-11 position. Thus, the neocryptolepine derivatives with C11-alkyldiamine side chains 4 and two or three carbon spacers between the two nitrogen were synthesized after reaction of the key intermediates, 1 1 -chloroneocryptolepine lwith excess of appropriate alkyldiamine 3, through a nucleophilic aromatic substitution reaction with release of chloride at C-11 position. The new generation of the metal complexes 5 of the bidentate ligands bearing copper(II), cobalt(II), nickel(I1) and palladium(I1) as a complexed ions have been synthesized through the reaction of L1 and L2 ligands with MXz salts (X= OAc, C1, Br and C104) in the (1 : 1) molar ratio according to the following Scheme: 1 M(I1) salts Three stereo types of metal(1I) complexes 5 M = Cu(II), Co(II), Ni(II), Pd(I1) All complexes were comprehensively characterized by elemental analyses, spectra (IR, UV-Vis, ’H NMR and ESR), magnetic and thermal studies and are consistent with the proposed structures for all compounds. The obtained results showed the following trend: 1. The IR data suggest the coordination modes for ligands which behaves as a neutral bidentate moieties with M(I1) ions. The binding of ligands with metals occurred through the two nitrogen atoms of side chain of the neocryptolepine core. 2. Based on the UV-Vis., ESR, and magnetic studies all complexes having octahedral geometry except copper(I1) acetate, and palladium(I1) complexes, possessing a square planner. On the other hand, copper(I1) bromide complexes 9a, 9b of L’ and L2 ligands having square pyramidal geometry and nickel(I1) bromide complex of L2 ligand 14b has a tetrahedral structure respectivly. 3. The presence of lattice and coordinated water was illucidated by TGIDTG and DTA analysis. In general, and based on the energies of activation, the chelate compounds of L1 ligand are thermally more stable than the L2 complexes, this is may be attributed to the difference in the size of the chelate ring formed upon coordination. 4. The thermal data showed that the chloro complexes of cobalt(I1) and nickel(I1) have higher thermal stability than the corresponding bromo complexes. The metal-free ligands and their corresponding metal(I1) complexes were tested for their in vitro anticancer activity against human colon carcinoma (HT-29) by colorimetric MTT assay using cisplatin as a reference drug.. The results showed that the most of the synthesized M(I1) complexes exhibited significantly anticaner activity than their free ligands. Of all the studied M(I1) complexes, the chloro-substituted complexes with cobalt of L2 and palladium chloride of L2 exhibited the highest anticancer activity against colon carcinoma cell (HT-29) at lower micromolar inhibitory concentrations (ICS0= 0.069, 0.07yM respectively) when compared to the other complexes and the free ligands.