الفهرس 
IntroductionOnly 14 pages are availabe for public view
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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.