الفهرس 
Pathology and SurgeryOnly 14 pages are availabe for public view
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Abstract
Cancer is one of the leading diseases that cause millions of deaths worldwide per year. The number of affected persons and deaths are in steadily increase. The development of new chemotherapeutic agents for the treatment of cancer is still urgently needed to ensure the availability of new drug candidates to feed the preclinical pipeline. This will help the surmount current issues arising from the drawbacks of current drugs such as low efficacy, significant side effects and drug resistance. In this context, plants are still an important resource for the discovery of new drugs. Natural products have recently drawn renewed interests and attentions as a seed of novel medicines. However, the availability of such natural products from nature tends to be severely limited. In order to develop novel medicines from natural products, sufficient amounts of compounds need to be provided for derivatization and biological testing. One of the goals of our thesis is to establish synthetic route for the natural products of medicinal importance. In addition, a variety of derivatives of the natural products will be synthesized for biological testing. Many naturally occurring compounds, including the major alkaloid cryptolepine I and the minor alkaloid neocryptolepine II, were isolated from the roots of the West African climbing shrub Cryptolepis sanguinolenta (Figure 1), a traditional herb used in folk medicine for the treatment of malaria. Both of the two tetracyclic heteroaromatic compounds are linearly fused indoloquinolines and exhibit a wide scope of biological activity. Therefore, we selected neocryptolepine II as the lead compound for the development of new drugs because of its lower cytotoxic activity compared to cryptolepine I towards the DNA intercalation. In addition, alkaloids are known for their broad spectrum of pharmacological activity.
This thesis includes three chapters. The first chapter is the introduction which comprises an updated literature survey of the chemistry of indoloquinolines especially cryptolepine , isocryptolepine and neocryptolepine (indoloquinoline alkaloids from Cryptolepis sanguinolenta). This review included the most important methods of total synthesis of this alkaloid as well as their reactions and biological activities are considered.
The second chapter is devoted to results and discussion which includes the preparation of 11chloroneocryptolepine 5 that was achieved by chlorination of 1H-methylindole-3-carboxylate 1 with N-chlorosuccinimide in the presence of 1,4-dimethylpiperazine, followed by the addition of Nmethylaniline 2 as a trichloroacetate salt. The resulting intermediates 3 were cyclized in boiling diphenyl ether to give the required tetracyclic indoloquinolinone 4 core structure of the neocryptolepine nucleus, which upon reaction with phosphorus oxychloride give the corresponding key intermediate 11-chloroneocryptolepine 5. This three-step approach, starting from easily accessible intermediates, was employed for the preparation of new analogues with varied substitution patterns in good yields, and high degree of purity. The key intermediate 5 was used for the diversification of the neocryptolepine core at the C-11 position. Thus, 11-aminoalkylaminoneocryptoepines 7a-f / 9 were synthesized after reaction of 5 with an excess of appropriate diamines 6a-f / 8 via a nucleophilic substitution reaction with release of chloride at the C-11 position as depicted in Scheme 5, 6 and 7 (cf. R&D section). The key compound 5 reacted with glycine methyl ester 10 in DMF in presence of TEA as a base to afford 11. Using the same conditions 5 also react with 12 to liberate 13 which react with heterocyclic/aryl amines 14a-c / 16a-c to afford 11-heterocyclic/aryl aminoneocryptolepines 15a-c / 17a-c respectively.
Neocryptolepine-quinoline hybrids 19a,b / 21a,b were synthesized by reaction of 7b,c,e with dichloroquinoine 18 /20 respectively in DMF in presence of TEA.
Reaction of 9/7b,d,e with Cholesterylchloroformate 22 / Carbethoxyethylidenetriphenyl phosphorane 25 in ethanol and TEA as a base yielded 23, 24a,b and 26a,b respectively.
The reaction of appropriate amines 7b,d, carbon disulfide and ethylbromoacetate 27 in acetonitrile provided cyclized intermediates 28a-b. Furthermore, structures bearing neocryptolepine - rohadanine surrogates 30a-b were obtained via Knoevenagel condensation reaction of 28b with appropriate aldehydes 29a-b in presence of sodium acetate and glacial acetic acid. Finally, Compound 5 was refluxed with 3-amino rhodanine 31 (New Class of neocryptolepineRhodanine Hybrids) in presence of DMF and TEA as a base to afford 32. Structures bearing neocryptolepine-rohadanine surrogates 34a-b were obtained via Knoevenagel condensation reaction of 32 with appropriate aldehydes 33a-b in presence of sodium acetate and glacial acetic acid. Moreover, the structures of all key intermediates and final compounds have been established on the basis of IR, 1H NMR, 13C NMR and mass spectral analysis and the analytical data of all compounds are in agreement with their proposed structure.
The final part displays the potency of these synthetic analogues to inhibit cancer cell proliferation. Twenty-five compounds were examined in vitro for their activities against MDA-MB-231(hormoneindependent human breast adenocarcinoma) and Hep-G2 (human hepatocellular carcinoma) human cancer cells using the MTT assay and 5-Flurouracil (5-FU) as a reference drug. Two compounds 21a and 21b are potent anticancer candidate drugs against both human breast and liver cancer types. However, fifteen compounds (32, 34a, 26b, 19b, 17c, 30b, 34b, 26a, 11, 17b, 17a, 15c, 28a, 19a and 15b, respectively) are selectively active on only human liver cancer type and not active on human breast cancer type. Investigation of the inhibitory action of the tested compounds on DNA-topoisomerase I activity as one of most important targets for cancer chemotherapy was investigated by using the molecular docking technique. The molecular modeling allowed us to understand the interaction of the tested compounds with DNA-topoisomerase I at the molecular level. Therefore, molecuar docking was carried out for the 25 tested compounds. All of 25 inhibitors showed Match2 of range 0.69 -0.84, so the hydrophobic interactions are the main forces that stabilize such compounds, while hydrogen bonds which represent hydrophilic interactions are few. The third chapter of the thesis is devoted to the experimental section. It includes the description of the methods of preparation of the organic compounds under investigation. The techniques of their characterization are also give the analytical data used to prove and elucidate the structure of compounds.
The thesis is ended with a bibliography (appendix, reference and Arabic summary).
In conclusion, our initial goal is to prepare synthetic neocryptolepine analogues with higher anticancer activity comparing with 5FU, as reference drug resulting in some compounds with good in vitro activity. The side chain proved to be critical for biological activity.