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Ismail Abdel Karim Mousa El Haty
Department of Chemistry
College of Science
Dissertation
Title
Molecular Recognition of Duplex and Quadruplex DNA by Small Molecules and its Applica-
tion for Developing New Anticancer Therapies
Faculty Advisor
Prof. Alaa Eldin Salem
Defense Date
20 May 2015
Abstract
Human telomeres are the end caps of linear chromosomes. Under physiological conditions, telomere folds up into four
stranded intramolecular structure called G-quadruplex. Formation of G-quadruplex has been associated with inhibiting
telomerase enzyme found enriched in cancer cells and involved in cells’ replications. Subsequently, G-quadruplex has
become an active target for the development of anticancer agents. Small molecules stabilize G-quadruplex are
potential for developing anticancer therapeutic agents acting by inhibiting telomerase.
In this work, several new benzoquinone derivatives were synthesized and their structures were elucidated using
elemental analyses, IR, NMR and MS. Benzoquinone and its synthesized analogues were studied for their binding
affinity and selectivity towards telomeric G-quadruplex DNA using UV-Vis absorption, fluorescence, circular dichroism,
melting temperature and NMR. The results indicated that G-quadruplex DNA interacted with synthesized compounds
in stoichiometric ratios ranged in 1:1 to 1:4. Binding affinities ranged between 5.60x104 - 1.33x107 M-1. Compounds TQ8
and TQ6 showed the best stabilizing effects on G-quadruplex with changes in melting temperature (ΔTm) of 21 and 10
αC, respectively. In addition, synthesized analogues showed good selectivity towards G-quadruplex DNA over duplex
DNA.
Synthesized compounds were also tested against lung, breast, colorectal, prostate, pancreatic, colon and lymphoma
cancer cell lines. Loss in cells’ viabilities in the range of 25-100 % with IC50’s between 6.18 and 100.0 μM were reported
for synthesized analogues after 24 h relative to the control. These results revealed compounds of high potential for
further processing as anticancer therapeutic agents.
Research Relevance and Potential Impact
Cancer is the third cause of death in UAE and worldwide. Therefore searching for new effective and selective anticancer drugs con-tinued over
decays as a topic of high importance in science. This work revealed compounds of high potential for further pro-cessing as anticancer agents. The
study combined molecular recognition of G-quadruplex DNA and the effect of synthesized com-pounds on cancer cells in-vitro.
Relevant Publications
• Alaa A. Salem, Ismail M. El Haty, Ibrahim M. Abdou and Yaguang Mu, Interaction of human telomeric G-quadruplex DNA with thymoquinone: A
possible mechanism for thymoquinone anticancer effect. Biochimica Biophysica Acta (BBA), 2015. 1850 (2): p 329-342.Career
Career Aspirations
My dream is to be an active team player within an academic institution to contribute in the education development. On the other hand, I would
like to use the experience and skills that I have gained during PhD and Post doctorate to synthesize new compounds that may help in developing
anticancer therapies.