الفهرس | Only 14 pages are availabe for public view |
Abstract The initial computational modeling demonstrated that rescinnamine showed the best cytotoxic activity targeting the MSH2/MSH6 death conformation. When rescinnamine cytotoxicity investigated in animals, the hypotensive action of it prevents applying appropriate concentrations for statistically significant tumor reduction. Therefore, in this thesis a combination of computational molecular modeling, chemical synthesis and cell assays was performed in order to determine how rescinnamine can be modified and what effect these modifications have on cell survival. With this goal in mind, the main objectives of the thesis are including design, synthesis and characterization of the modified novel lead rescinnamine analogues and testing their biological activity as anticancer via inducing the death conformation of MSH2. This dissertation characterizes the molecular modeling study by using the advanced Autodock4 program and then displaying the results in terms of a library concerning the ideal lead rescinnamine analogues along with calculating the Ki constant for each compound even the reserpate intermediates. The modeling study revealed that most of the synthesized rescinnamine derivatives show small Ki except those two rescinnamine analogues 40, 42 and 45. In addition, it extends to describe the chemical reactions required for the synthesis of a series of new rescinnamine derivatives starting from the precursor alkaloid, reserpine, it tells about how the palladium catalyzed Heck reaction conditions is employed to achieve the carbon- carbon coupling between the acryloyl resepate 41 with various appropriate aryl iodides, most of the aryl iodides are prepared by different synthetic pathways. It also shows the importance of using the phosphonium ligand, in case of using an aryl bromide. The newly synthesized compounds were characterized by using various spectrometric tools; NMR (1H NMR, 13C NMR, 1H-1H COSY, HMQC, HMBC and NOESY), IR and mass spectroscopy (LC-MS, HRMS, GS-MS). Moreover, the elemental analysis is used to confirm the proposed structures. Also, it focused on the formation of some surprising products, such as the demethylated compound 69, upon exposure to Heck conditions. Also, the amino-substituted rescinnamine derivatives 63 and 64 are unexpected ones which come from coupling 41 with hydroxamic acid containing aryl iodides that seems as Lossen rearrangement reaction occurred under Heck condition. Interestingly, this work focused on a detailed study of the Lossen rearrangement on various appropriate hydroxamic acids under different condition of base (TEA) and catalyst (Pd(OAc)2) proposing mechanisms to illustrate how Lossen rearrangement occurred under those Heck conditions. Finally, this work goes more to screen the antitumor activity. Most of reserpate intermediate and their rescinnamine analouges exhibited a promising activity as significant cytotoxic compounds but with small MSH2 dependence. Additionally, results revealed that the cell death is largely dependent on specific functional groups, such as 44 and 64, rather than just presence of ring systems, as 41, and small changes to the structure of rescinnamine affect its activity on cell death significantly like 44 vs 48 and 63 vs 64. Thus, to elucidate the exact mechanism of these effects and the structure activity relationship, further computational modeling and cell biology studies are required. The dissertation extends to describe the detailed synthetic experimental procedures along with the physical and spectroscopic properties of the following compounds: 1. Fifteen new final compounds. |