Dissertation summary Organic chemistry: Synthesis and antiinflammatory, antiproliferative activities of new Coxib–Combretastatin hybrids - Trường Đại học Công nghiệp Thực phẩm Tp. Hồ Chí Minh

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MINISTERY OF EDUCATION 
AND TRAINING

VIETNAM ACADEMY OF 
SCIENCE AND TECHNOLOGY 
GRADUATE UNIVERSITY OF SCIENCE AND TECHNOLOGY

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NGUYEN THI THUY HANG

“SYNTHESIS AND ANTIINFLAMMATORY, ANTIPROLIFERATIVE 
ACTIVITIES OF NEW COXIB–COMBRETASTATIN HYBRIDS’’

Scientific Field: Organic Chemistry 
Classification Code: 9.44.01.14

DISSERTATION SUMMARY

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Institute of Chemistry

Vietnam Academy of Science and Technology
Scientific Supervisors:

1. Assoc. Prof. Dr. Ngo Quoc Anh
2. Assoc. Prof. Dr. Vu Dinh Hoang

1st Reviewer: ...
...
2nd Reviewer: ...
...
3rd Reviewer: ...
...

The dissertation will be defended at Graduate University of Science And
Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc
Viet, Cau Giay District, Ha Noi City.

At ….. hour….. date….. month …..2021.

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INSTRODUCTION

1. The urgency of the thesis

Cancer is a group of diseases that involve disorganized cell division and
cells that have the ability to invade other tissues by either growing directly into
nearby tissue or moving to multiple locations different (metastatic). According
to the Global Cancer Organization GLOBOCAN 2018, there are currently
more than 300,000 people living with cancer nationwide, there are 164,671
new cases, 114,871 people die from this disease. Globally, there are about 23
million people infected, of which more than 14 million people are newly
infected and 8 million 2 hundred thousand people die. The World Health
Organization (WHO) ranked Vietnam in the top 50 countries in the top 2 of
the cancer map.

Researching to find cancer treatment drugs with few side effects is one of
the directions that is always interested in the scientific community. Among
current treatments, chemotherapy is a cancer treatment that uses one or more
anticancer drugs - cytotoxic. One of the anti-cancer drugs, used today in
chemotherapy, influences the cell cycle to inhibit cancer cell growth and
subsequently induce apoptosis (apoptosis).

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practice, it is still necessary to look for new agents that can overcome the
limitations of resistance and the undesirable side effects of these therapies.
current method [3].

2. Objectives of the dissertation

1. Structured design of coxib - combretastatin hybrid compounds
2. Synthesize coxib - combretastatin hybrid compounds

3. Screening for anti-cancer and anti-inflammatory activities of hybrid
compounds

4. Identifying anti-inflammatory and anti-cancer mechanisms of hybrid
compounds

5. Docking of a hybrid coxib - combretastatin compound with two purpose
effect COX2 and tubulin

3. The main research contents of the thesis

- Research on coxib - combretastatin hybrid compounds synthesis

- Determination of the structure of coxib-combretastatin hybrid compounds

- Screening the activity of coxib - combretastatin hybrid substances

- Study on mechanism of action of some coxib - combretastatin hybrid
substances

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DISSERTATION CONTENTS 
CHAPTER 1. LITERATURE REVIEW

General presentation of anticancer compounds by tubulin inhibitory
mechanism, profile of tubulin mechanism. The group of tubulin-based
compounds has always been a topic of concern in the field of anti-cancer drug
research. Combretastatin compounds with rich biological activity have been
used in the treatment of a number of cancers. They are known for their
cytotoxic activity by inhibiting tubulin polymerization at the colchicine site [ 2].
Up to now, these cancer treatment compounds with this mechanism are still
being widely used and always a research direction that receives a lot of
attention.

Overview of combretastatin compounds, which belong to the class of cis
-stilbene, a rich source of pathogens in the search for new drugs, typical
compounds such as resveratrol and combretastatin A-4 phosphate are currently
is clinically tested to treat Alzheimer's disease and cancer. The recently isolated
stilbene has been shown to have a diverse range of biological activities,
including antioxidant, antibacterial, anti-malarial, cytotoxic, liver protective and
anti-inflammatory properties. Combretastatin A-4 (CA4) is also considered to
be a potential cytotoxic agent by strongly inhibiting microtubule polymerization
by binding to the binding point of colchicine on tubulin. CA-4 is highly toxic
on many cancer cell models, making it a very interesting target structure.

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substance known for its potent anti-inflammatory activity, which selectively
inhibits COX2 through its action. Prostaglandins induce inflammation and pain
without effects on prostaglandins COX1 that have a protective effect on the
gastrointestinal tract. Furthermore, Celecoxib inhibits the proliferation of
human breast cancer in vitro models such as MCF7 and MDAMB-231. Some
studies indicate that celecoxib and related compounds can induce cell cycle
arrest at G0 /G1 stage leading to apotosis cyclic apoptosis, inhibition of tumor
growth and prevents tumor angiogenesis in the absence of COX2

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CHAPTER 2. EXPERIMENTS 
2.1. Materials and equipments

2.1.1. Materials 
 2.1.2. Equipments

2.2. Methods

2.2.1. Organic synthesis method 
 2.2.3. Biological activity test method

2.3. Synthesis of coxib- combrestatin hybrid compounds

2.3.1. Synthesis of ester derivatives of coxib - combretastatin hybrid ester 
hybrid

Figure 2.2. Ester derivative synthesis of coxib - combrestatin hybrids

compound

(i) Alkaline: t-BuOLi (3 mmol, 3 eq), refluxe, (ii) Ethyl chlorooxoacetate (1
mmol, 1 eq) (77), 5 ml THF; (iii) HCl (4 mmol); refluxe, 5 ml C2H5OH dry;

phenylhydrazin (1 mmol, 1 eq) (78).

Synthesized 20 hybrids esters of coxib - combretastatin ester form substances
from 79 to 98.

2.3.2. Synthesis of coxib - combrestastatin hybrids compounds containing

groups CF3

Figure 2.5. Synthesis of coxib - combretastatin hybridization containing

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(a) 100 (1.0 mmol), 99 etyl trifluoroacetate (1,2 eq) and NaH (2,5 eq) in THF (5 mL), 6 h. 
(b), EtOH (5 mL), axit (1.0 eq); arylhydrazin hydrochloride 78 (1.0 mmol) is added
consecutively to the residue and restored for 6 hours. Substance 102 was isolated by column
chromatography.

2.3.3. Synthesis of acid derivatives of coxib - combretastatin hybrid

Figure 2.8. Synthesis of coxib - combretastatin hybrids

(i) Alkaline: t-BuOLi (3 mmol, 3 eq), refluxe, (ii) Ethyl chlorooxoacetate (1
mmol, 1 eq) (77), 5 ml THF; (iii) HCl (4 mmol); refluxe, 5 ml C2H5OH dry;

phenylhydrazin (1 mmol, 1 eq) (78). The product obtained after isolation
through column chromatography was dissolved in the solvent system THF /
MeOH / H2O = 3: 1: 1, then NaH (1,2 eq) was added to the mixture. Carry out
the reaction in 3 hours to obtain compounds acid hybrids 103-122.

successful synthesis of 20 acid hybridization of coxib – combretastatin hybrids

103-122

2.5. Biologically active testing of research compounds

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CHAPTER 3. RESULTS AND DISCUSSIONS

The advantages of using a hybrid molecule over co-combination of multiple
drugs at the same time may improve the limitations of adverse effects and
resistance [107]. Despite its outstanding activity, combretastatin still has many
undesirable effects. This is why the team aims to combine combretastatin, an
anticancer compound, and celecoxib, a COX2-engineered anti-inflammatory
agent, as derivatives for new hybrid compounds in hopes of finding new It has
interesting biologically active properties such as the anticancer and
anti-inflammatory properties of the parent substance and has less side effects.

3.1. Design of the structure and biological activity of the hybrids

3.1.1. Design of hybrid molecular structure

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