Thesis summary
Design, Synthesis and Biological Evaluation of Novel Quinoline Based
Small Molecules as Anticancer Agents Targeting Topoisomerase I(ࢺࢺ࣏࢖ࢯ࣓࣮ࣛࢮI㜼ᐖ⸆ࢆ┠ᣦࡋࡓ࢟ࣀࣜࣥㄏᑟయࡢタィࠊྜᡂࠊ⏕≀άᛶ)Name: Mostafa Mohamed Mostafa Elbadawi(ࣔࢫࢱࣇ࢓ࣔࣁ࣓ࢻ ࣔࢫࢱࣇ࢓࢚ࣝࣂࢻ࢘࢕)Cancer is considered as a major health obstacle threating the life of millions of people
annually. The incidence and mortality of cancer are increasing rapidly worldwide.
Consequently, enormous efforts are being implemented to develop potential anticancer agents.
Quinoline is considered as one of the most privileged motifs in drug discovery and exertsa crucial and prominent role in anticancer drug discovery. So far, sets of quinoline derivatives
have been developed for cancer treatment. Interestingly, various quinolines provoked theiranticancer influences through inhibition of enzymes essential for proliferation of cancer cell as
Epidermal Growth Factor Receptor (EGFR) and topoisomerase I.
Topoisomerase I (TOP1) is ubiquitous nuclear enzyme and is crucial in vital cellular eventsas transcription and replication. For cancer cells, it was revealed that they displayed
overexpressed levels of TOP1. Therefore, TOP1 is emerged as a validated target for cancer
therapy. Moreover, the medicinal use of TOP1 poisons (topotecan and irinotecan) for cancer
therapy has been hindered owing to several problems like metabolic instability and clinicalresistance.
Herein adopting fragment-based drug design, novel two series of 4-alkoxy-2-arylquinolines
were synthesized as anticancer agents targeting TOP1 enzyme. The anticancer potential of allcompounds have been evaluated. Interestingly, the propoxy-2-phenyl analogs showed good
anticancer activity. Additionally, two morpholinopropoxy-2-phenyl derivatives moderately
stabilized TOP1ccs as the first 4-alkoxy-2-arylquinolines TOP1 poisons lead compounds.
Pursuing of our endeavor to develop quinolines as TOP1 poisons endowed with potential
anticancer activity, we exploited structural modification strategy of our reported TOP1 poison
to design six series of 4-propoxy-2-arylquinolines and 4-propoxy-2,6-diarylquinolines. Despiteof the good anticancer activity of most compounds, they exhibited no or weak TOP1 poisoning1

activity. Based on literature review, the compounds were evaluated against nine kinases todetect the plausible mechanism of anticancer action. The potent anticancer compounds showed
EGFR/FAK potent dual inhibition. The binding interactions of the tested compounds andEGFR/FAK active sites have been rationalized by molecular docking, likewise the stability ofcomplexes of the potent compounds with EGFR/FAK has been investigated by moleculardynamics simulation. As a result, this study reported the first 2-aryquinolines as EGFR/FAK
dual inhibitors with potential anticancer effects.
Furthermore, two novel series of 11-aminopropoxybenzofuro[3,2-b]quinolines and 11aminobenzofuro[3,2-b]quinolines have been designed applying ring fusion and bioisosterism
strategies of our reported TOP1 poison to afford quinoline-benzofuran hybrids merging bothof their characteristics aiming to improve the anticancer and TOP1 poisoning actions of thelead compound. Anticancer activity, TOP1 and TDP1,2 inhibitory actions have been tested forthe synthesized compounds. Some of the investigated compounds exerted good anticancer
activity, but none of them possessed TOP1 inhibitory action. Remarkably, 3,7-dichlorohydroxypiperidine analog emerged as the first reported benzofuroquinoline with TDP1
selective inhibition can be used to enhance the anticancer impact of some drugs as TOP1
poisons.

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