الفهرس 
1.IntroductionOnly 14 pages are availabe for public view
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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 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, I was interested in
studying the effect of incorporation of metal ions into biologically active ligand with natural origin such as neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline).
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 been reported in the literature and showed improved biological activity after metal chelation. However, till now have taken less concern. With the aim of improving the biological activity and reduce the cytotoxicity 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(II) and palladium(II) complexes with 11- substituted diamino aromatic neocryptolepine ligand L1 , its Schiff base HL2 and Schiff base of aminoalkyl substituted neocryptolepine ligand HL3.
The synthetic methodology for the construction of neocryptolepine 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 intermediate was 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 e was used further for the diversification of the neocryptolepine core at the C-11 diamine L1 side chain was prepared in good yield by the reaction with 1,2 diaminobenzene in DMF at 150 оC for 24 h in the presence of triethylamine (10 equivalent) as a catalyst . In addition the L1 was further transformed to the Schiff base HL2 by reaction with salicyaldehyde by refluxing a hot ethanolic for one hour. Then, few drops of DMF were added to the resulting solution, and the reaction mixture was further stirred under reflux for 12 h. On the other hand, the reaction of e with 1,3-diamino propane give the corresponding 11-aminopropylamino neocryptolepine f which was reacted further with salicyaldehyde to give the corresponding Schiff base HL3. The structure of ligands L1, HL2 and HL3 were confirmed by spectroscopic tools and showed analytical data consistence with the structures. The new generation of the metal complexes 1-6 of the bidentate ligands bearing copper(II), cobalt(II), nickel(II) and palladium(II) as a complexed ions have been synthesized through the reaction of L1 ligand with MX2 salts (X= OAc, Cl, Br and ClO4) in the (1:1) molar ratio and refluxed in ethanolic solution for 4-6 h. On the other hand, the Schiff base HL2 derived from L1 was complexed with different metal salts to yield metal complexes 7 and 8. Moreover, the complexation of different Cu(II) salts or Pd(II) with HL3 afford the corresponding metal complexes 9-13. All complexes were comprehensively characterized by elemental analyses, spectroscopic tools (IR, UV-Vis, 1H NMR, ESR and X-ray diffraction), magnetic, thermal and molecular modeling studies are also performed 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 ligand L1 which behaves as a neutral bidentate moieties with M(II) ions. On the other hand the coordination mode for ligands HL2 and HL3 behave as tridentate moieties with M(II) ions.
2. According to UV-Vis., ESR, and magnetic studies, all metal(II) complexes obtained from L1, HL2 and HL3 ligands are separated in (1L:1M) molar ratio (2,3,5-7), whereas, complex (1) is isolated in (2L:1M) ratio. On the other hand, the binuclear (4, 8-12) and trinuclear metal complexes (13) are formed in (1L:2M) and (1L:3M), respectively.
3. Based on the UV-Vis., ESR, and magnetic studies series of square planar complexes containing Cu(II) salts, PdCl2(3, 4, 5, 6, 8, 9, 10, 11, 12, 13) and octahedral chelates containing NiCl2, CoCl2 salts (2 and 7) have been isolated. Also, the pentacoordinated Co(II) complex (1) has been prepared.
4. According to conductance measurements, nonelectrolyte nature for (3, 4, 6-8 and 11) with recorded values of 32, 20, 40, 0.41, 18 and 22 Ω-1cm2mol-1, respectively. Furthermore, the values recorded for molar conductance are 70, 60, 69, 63, 66 and 50 Ω-1cm2mol-1 for complexes (1, 2, 5, 9, 10 and 13) typified of 1:1 electrolytes. The molar conductance value of complex (12) is found to be 95 Ω-1cm2mol-1indicating 2:1 electrolytic natures for this complex.
5. The presence of lattice and coordinated water was elucidated by TG/DTG and DTA analysis. In general, and based on the energies of activation of desolvation stage for Cu(II) acetate complex (11) is greater than that observed for Cu(II) perchlorate complex (12). This is due to nature and the number of solvent of crystallization in addition to the strong interaction of copper(II) ion with N2O2 and O4 chromophores.
6. The thermal data showed the solvents of crystallization were removed initially at higher temperature for complex (9) than that for complex (10). This is indicating that these solvent molecules are involved in bonding with chloride ion. Also, the higher thermal stability of complex (9) than complex (10) is due to the small size of Cl– ion than Br– ion.
7. The metal-free ligands and their corresponding metal(II) 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 most of the synthesized M(II) complexes exhibited significantly anticaner activity than their free ligands. Of all the studied M(II) complexes, the cobalt complex (1) with ligand L1 exhibited the highest anticancer activity( 86.10%) against colon carcinoma cell (HT-29) when compared to the other complexes and the free ligands. On the other hand, the complexation of HL2 ligand with CoCl2 showed inhibitory activity of 83.22% which is higher than the free ligand (70.57%). While the complexation of CuCl2 with the same ligand exhibits a higher activity with inhibition of (86.34%) which is greater than the free ligand (70.57%). It should be noted that both Schiff base ligand and its metal complexes showed a higher anticancer activity when compared with its corresponding free amine (L1). The complexation of different copper(II) salts such as CuCl2, CuBr2, Cu(OAc)2 and Cu(ClO4)2 with HL3 gave an inhibitory activity of 84.4, 87.5, 87.9 and 82.70%, respectively which exhibit more potency than the free ligand (HL3). While the complexation of PdCl2 with HL3 gave inhibitory activity of (36.4%) which is lower than the free ligand (73.30%).
In conclusion, our initial goal to prepare metal complexes based on neocryptolepine core structure with higher anticancer activity could be achieved, resulting in some compounds with good in vitro activity. The side chain proved to be critical for the activity. Thus, the introduction of nitrogen containing side-chain into the neocryptolepine core structure at the C-11 position resulted in a significant increase in anticancer activities.