Search In this Thesis
   Search In this Thesis  
العنوان
Design, Synthesis and Biological Investigation of Some New Quinoxaline Derivatives as Potential Anticancer Agents /
المؤلف
ElAttar, Maryam Ali Zakaria.
هيئة الاعداد
باحث / مريم على زكريا العطار
مشرف / أ . د . نرجس صموئيل حبيب
مشرف / أ . د . إبراهيم محمد لعبوظة
مشرف / أ . د . سعاد عبدالحميد الحواش
الموضوع
Potential Anticancer. Quinoxaline Derivatives. Pharmaceutical Chemistry.
تاريخ النشر
2020.
عدد الصفحات
201 p. :
اللغة
الإنجليزية
الدرجة
الدكتوراه
التخصص
العلوم الصيدلية
تاريخ الإجازة
14/4/2019
مكان الإجازة
جامعة الاسكندريه - كلية الصيدلة - الكيمياء الصيدلية
الفهرس
Only 14 pages are availabe for public view

from 227

from 227

Abstract

Aim: Cancer is a multifaceted and multi-mechanistic disease with serious threat across the globe.
Despite significant achievements in therapeutic and diagnostic tools for cancer management, the successful treatment of cancer remains a challenge. Using highly selective or specific blocking of only one of the cancer’s signaling pathways has been associated with the development of drug resistance and limited responses.
Hence, the discovery and development of multi-targeted agents able to interact simultaneously with multiple altered pathogenic pathways have emerged as a new paradigm for anticancer treatment.
Over the past decades, inflammation has become an important hallmark of cancer.
In addition to tumor initiation, inflammation plays a decisive role in tumor promotion, malignant conversion, and metastatic dissemination.
Moreover, several epidemiological and clinical studies have reported the relation between COX-2, 15-LOX and PGE2 over expression and carcinogenesis.
On the other hand, quinoxaline derivatives are acknowledged as attractive bioactive scaffolds in the area of medicinal chemistry, owing to its wide spectrum of biological activities including anticancer activity. Moreover, several quinoxaline derivatives have been recently reported as promising epidermal growth factor receptor (EGFR) inhibitors.
Consequently, the present study was directed towards the design and synthesis of some new hybrid molecules comprising quinoxaline scaffold attached to various substituted bioactive triazole moieties through different linkers and at different positions as potential multi-target anticancer agents.
The synthesized compounds were tested in vitro for their ability to inhibit different molecular cancer targets (COX-2, 15-LOX, mPGES1 and EGFR).
The most active compounds were then evaluated for their in vitro cytotoxic activity against human breast (MCF-7) and colorectal cancer (HCT-116) cell lines, in addition to their cytotoxic activity against normal lung cell line (WI-38) to predict their safety profiles.
Results:
Eight compounds (3c, 9c, 10d, 15c, 17b, 18d and 27b,c) showed significant COX-2, 15-LOX, mPGES1 and EGFR inhibitory activity.
Compounds 3c, 18d and 27b showed COX-2 inhibitory activity (IC50= 0.039-0.043 μM) higher than the reference celecoxib (IC50= 0.045 μM), while compounds 9c, 10d, 15c, 17b and 27c (IC50= 0.045-0.068 μM) were of comparable inhibitoy activity to celecoxib.
In addition, these compounds demonstrated 15-LOX inhibitory activity (IC50= 1.63-3.29 μM) higher than the reference quercetin (IC50= 3.34 μM). Moreover, they displayed mPGES1 inhibitory activity (IC50= 2.4-3.5 μM) higher than the reference celecoxib (IC50= 4.1 μM). Furthermore, compounds 10d and 15c exhibited significant EGFR inhibitory activity (IC50= 0.107 and 0.081 μM, respectively) higher than the reference erlotinib (IC50= 0.115 μM).
Compounds 17b and 27b exerted comparable activity (IC50= 0.144 and 0.131 μM, respectively), while compounds 3c, 9c, 18d and 27c showed half the activity of erlotinib (IC50= 0.227-0.267 μM).
On the other hand, the results of in vitro cytotoxic activities against breast and colorectal cancer cell lines revealed that compound 27b displayed significant cytotoxic activity against MCF-7 and HCT-116 cell lines (IC50= 1.77 and 4.53 μM, respectively) higher than erlotinib (IC50= 7.29 and 6.16 μM, respectively).
While, compound 18d exhibited higher inhibitory activity against MCF-7 cell line (IC50= 0.95 μM) than erlotinib and exerted half the activity of erlotinib against HCT-116 cell line (IC50= 11.82 μM). As well, compound 3c was more potent than erlotinib towards MCF-7 cell line (IC50= 2.83 μM) and almost equipotent against HCT-116 cell line (IC50= 6.65 μM).
<However, compound 15c demonstrated significant cytotoxic activity against HCT-116 cell line (IC50= 4.97 μM) higher than erlotinib and comparable activity to erlotinib against MCF-7 cell line (IC50= 9.72 μM).
Besides, all tested compounds exhibited safety profiles towards normal WI-38 cell line (IC50= 15.56-41.89 μM) higher than erlotinib (IC50= 15.01 μM).
xvi Molecular docking studies of the most active compounds into active sites of the four studied targets underlined favorable binding patterns.
Additionally, the results of in silico prediction of physicochemical properties and ADMET profile as well as ligand efficiency metrics calculations proved their suitability as lead-like structures and/or drug-like candidates.
Conclusion:
The series of newly synthesized compounds represents plentiful leads and promising scaffolds that might be of value in the development of new multi-targeted anticancer agents effective against breast and colorectal cancer.