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VIETNAM ACADEMY OF SCIENCE AND
TECHNOLOGY
INSTITUTE OF CHEMISTRY
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RESEARCH ON THE SYNTHESIS AND EVALUATION
OF CYTOTOXIC ACTIVITY OF QUINAZOLINE
COMPOUNDS
Speciality : Organic Chemistry
Code : 9.44.27.01
Students : Đinh Thuy Van
DISSERTATION SUMMARY
Ha Noi – 2019
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The work was completed at the Vietnam academy of Science
and Technology
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Supervisors:
Supervisor 1: Pro.Doc. Nguyen Van Tuyen
Supervisor 2: Doc. Dang Thi Tuyet Anh
Reviewer 1:
Reviewer 2:
Reviewer 3:
The thesis will be defended before the Doctoral Dissertation Council,
at the Academy of Science and Technology - Vietnam Academy of
Science and Technology. No. 18 - Hoang Quoc Viet, Cau Giay,
Hanoi. At ... time ... .. … 2019
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A. INTRODUCTION
1. The urgency, scientific and practical significance of the thesis
Quinazoline is a potential class in the design of synthetic anti-cancer
drugs according to the kinase enzyme inhibition mechanism [1-4]. Gefitinib
(Iressa), erlotinib (Tarceva), lapatinib (Tykerb) and vandetanib (Caprelsa)
are typical quinazoline compounds that have been introduced into the
production of cancer drugs. Among them Gefitinib and Erlotinib are the first
epidermal growth factor receptor(EGFR) chemotherapy drugs used to treat
non-small cell lung cancer. Erlotinb is a derivative of quinazoline with the
trade name Tarceva, produced by Hoffmann pharmaceutical company - La
Roche. The drug is highly effective for the treatment of non-small cell lung
cancer (NSCLC) with EGFR activating mutation. This is a breakthrough
method in treating NSCLC that creates an opportunity to prolong life time
with higher quality of life. In Vietnam, erlotinib hydrochloride Tarceva drug
has not been widely used; first of all because the cost of treatment with
Tarceva is very high, 2,000 USD per treatment cycle (one cycle = 1 month), price
in Vietnam market is about 42 million VND per bottle of 30 150mg tablets.
Therefore, the thesis "Research on synthesis and evaluation of cytotoxic
activity of quinazoline compounds" is a scientifically and practically
significant research direction.
2. Objectives of the dissertation
1. Research to improve the synthesis process of erlotinib hydrochloride drugs.
2. Research on the synthesis and determination of quinazoline derivative structure.
3. Research on the synthesis and determination of the structure of hybrid
compounds of quinazoline derivatives and azides via triazole bridges.
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4. Research on cytotoxic activity of hybrid compounds synthesized on three
human cancer cell lines including KB (carcinoma, Hep-G2 (liver cancer) and
Lu (non-small cell lung cancer).
3. New points of the dissertation
a. Successfully synthesized erlotinib hidrocloride according to the new
improvement process
b. Synthesis of 23 new quinazoline derivatives in which there were 19
derivatives containing triazole rings:
* 4 derivatives of erlotinib and different azides via triazole bridges
* 4 derivatives of quinazoline-4- amine containing crown ether group in
position C-6, C-7 following a completely new path. These derivatives are used to
hybridize with other active azides via triazole bridges by click reaction.
* 15 hybrid compounds of quinazoline crown ether and azides via triazole bridges
c. The structure of new hybrid compounds has been confirmed from the
results of analysis of infrared spectral data (IR), nuclear magnetic resonance
spectroscopy (1H-NMR and 13C-NMR, HMBC, HSQC) and mass
spectroscopy (HRMS).
d. Evaluation of activity of 19 new quinazoline derivatives on three human
cancer cell lines including KB (carcinoma, Hep-G2 (liver cancer) and Lu
(non-small cell lung cancer) in which there are 13 substances that can cause
investigated cancer cell toxicity. Among them there are 8 substances exhibiting
strong anti-cancer cell activity with the value of IC50 from 2 to 6 µM.
e. Using protein docking simulation to predict the target activity of
compounds 120d, 122a, 122b, 123c
f. Synthesized Compound 122a which has the strongest inhibitory activity
for all three KB cell lines, Hep-G2 and Lu with IC50 values of 0.04 µM, 0.14
µM and 1.03 µM, respectively, 100 times higher than erlotinib. The 123c
compound has IC50 value (1.49; 1.61; 1.81 µM) equivalent to the Ellipticine
standard (IC50 is 1.95; 2.72; 1.38 µM, respectively).
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4. Structure of the dissertation
The dissertation consists of 129 pages including:
Introduction: 2 pages.
Chapter 1. Literature review: 31 pages
Chapter 2. Experiment: 25 pages.
Chapter 3. Results and discussion: 56 pages.
The reference section has 122 documents on the relevant areas of the
dissertation, updated to 2018.
The appendix consists of 62 pages, including the spectroscopy of
synthesized substances.
5. Research methodology
The substances were synthesized according to known modern organic
synthesis methods, improved and applied appropriately in specific cases.
Reaction products were cleaned by column chromatography and
recrystallization. The structure of the product was determined by modern
spectral methods such as IR, HRMS, ESI-MS, 1H-NMR, 13C-NMR,
HMBC, HSQC, DEPT. Biological activity was explored according to the
method of Mossman on three cancer cell lines, KB, Hep-G2 and Lu.
Protein docking simulation was used to predict the target activity of
synthesized compounds.
B. CONTENTS OF THE DISSERTATION
CHAPTER 1. LITERATURE REVIEW
This chapter presents the following contents:
- The quinazoline synthesis methods
- The erlotinib synthesis methods
- Anti-cancer activity of quinazoline derivatives
- Click reaction
- Protein docking technique