Dissertation summary Organic chemistry: Synthesis and antiinflammatory, antiproliferative activities of new Coxib–Combretastatin hybrids

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MINISTERY OF EDUCATION AND TRAINING VIETNAM ACADEMY OF SCIENCE AND TECHNOLOGY GRADUATE UNIVERSITY OF SCIENCE AND TECHNOLOGY ------------- 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 HA NOI - 2021 The dissertation was completed at: 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. The dissertation can be found in National Library of Vietnam and the library of Graduate University of Science And Technology, Vietnam Academy of Science and Technology. 1 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). Prospective treatment guidelines often recommend a combination of anticancer drugs acting on a variety of mechanisms. Nowadays, research discovering drugs targeting multiple targets is gaining attention, with a desire to combine different molecular targets on a single chemical agent. The advantages of a hybrid molecule over a combination of many drugs can improve the technical limitations, side effects and resistance of a single target [1]. One of the most important groups of anticancer agents are tubulin-binding molecules. Although some drugs that target microtubule have been used in clinical 2 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 - Research docking of typical hybrid compounds with target effects of colchicine and COX2 3 Figure 31: Simulation of coxib - combretastatin hybrid compound according to set target 4 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 cisstilbene, 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. Overview of Pyrazole are pentagonal heterocyclics that form a group of compounds that are particularly useful in organic synthesis. They are one of the most studied groups of compounds in the azol family. Pyrazole is reported through the available literature and SAR shows that it is necessary for the design of selective COX2 inhibitors. One of the most important and commonly used compounds in commercially applied pyrazole compounds is celecoxib, a 5 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 Thereby, it can be seen that combretastatin celecoxib hybrid compounds are promising classes that are still new in terms of structural development as well as bioactivity, contributing to the construction of new research projects looking for different types anticancer drugs in the pharmaceutical industry. 6 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 groups CF3 7 (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 The synthetic compounds were screened for anti-breast cancer activity MCF7, colon cancer HT-29, hepatic carcinoma Hep-G2 and inhibited NO production. 8 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 antiinflammatory 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 In this study, we adopted the hybridization strategy to incorporate the important pharmacophoric groups of two original compounds celecoxib and CA-4 in a single molecule. We utilized 1,2-diphenyl substituted pyrazole ring of celecoxib as a scaffold to mimic the cis-1,2-diphenylethylene motif in CA-4. Replacement of the double bond with heterocyclic five membered rings was demonstrated to retain both cytotoxic and antitubulin activities of the compounds [108]. Indeed, these cis-locked analogues provide several advantages: preventing of isomerization from cis to trans; increasing specificity of these drugs to cellular targets; and improving the therapeutic potential of these drugs. The presence of the trimethoxybenzene moiety of CA-4 is also crucial to obtain relevant cytotoxic and antitubulin responses. [76]. We were particularly interested in maintaining the sulfonamid group or related bioisosteres of celecoxib which seems to result in its COX-2 selectivity [109]. The COX-2 inhibitory effect, if any, will contribute to the overall anti-tumor activity of new molecules.
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