MINISTRY OF EDUCATION VIETNAM ACADEMY
AND TRAINING OF SCIENCES AND TECHNOLOGY
GRADUATE UNIVERSITY OF SCIENCE AND TECHNOLOGY
-----------------------------
LE VAN HAI
SYNTHESIS AND EVALUATION OF ANTICANCER ACTIVITY
OF TUBULYSIN DERIVATIVES
Major: Organic Chemistry
Code: 9.44.01.14
SUMMARY OF CHEMISTRY DOCTORAL THESIS
HA NOI, 2020
The thesis was completed at:
Institute of Chemistry
Vietnam Academy of Science and Technology
Supervisor:
1. Asso. Prof. Dr. Tran Van Loc
Institute of Chemistry-Vietnam Academy of Science and Technology
2. Dr. Tran Van Chien
Institute of Chemistry-Vietnam Academy of Science and Technology
Reviewer 1:
Reviewer 2:
Reviewer 3:
The thesis will be presented in front of the doctoral thesis council at:
Graduate University of Science and Technology - Vietnam Academy of
Science and Technology- 18 Hoang Quoc Viet Road, Cau Giay, Hanoi.
At time ........, ……………………
The thesis can be found at:
- Library of Academy of Science and Technology
- National Library of Vietnam
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OPENING
1. The essential of the thesis
The natural compounds have considered infinite supplies of
bioactive substances for research and medical application. The
abundance and diversity of the substance-frames had highly bioactive.
Especially, the mechanism of action of each layer of these frames
attracted of researchers so far. For the purpose of research on drug
development, compounds from microbial sources are often achieved by
total synthesis or will be modified in chemical structure to create large
quantities of products as well as new derivatives.
Tubulysins are the tetrapeptide class (figure 1.8) isolated from two
myxobacteria strains Angiococcus disciformis An d48 and Archangium
gephyra Ar 315. Studies have shown that tubulysins are the best class of
anticytokines known to nowaday. The cancer cell inhibitory of
tubulysins are show a wide range of human cancer cell lines such as
ovarian cancer, breast cancer, prostate cancer, colon, lung and blood
cancer.
In vitro and in vivo studies have shown that tubulysins inhibit the
growth of cancer cells higher than anticancer drugs in use such as
vinblastine, epothilone or taxol by approximately 20- to 1000 fold.
Figure 1.8. Chemical formula of the tubulysins
From the point of view of pharmaceutists, natural tubulysins are a
leading class for research and development of new anticancer drugs.
However, their content in bacteria are very low, which were not enough
for intensive research. Thus, the total synthesis of tubulysins and their
derivatives are very necessary and scientific significance.
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2. Aim of the thesis
Synthesis of several derivatives and tubulysin analogues with the
replacement of the amino acid methylpipecolic (Mep) at the N-terminal,
replacing N,O-acetyl group by methyl group, and researching the role of
tubuphenylalanine (Tup) group at the C-terminal .
Evaluation of cytotoxic activity on a number of cancer cell lines in
order to further clarify the correlation between the activity and the
structure of the tubulysins, and to find new compounds with remarkable
activity.
3. The main research content of the thesis
+ Overview of the myxobacteria. Overview of tubulysin: Biological
activity, active-structure correlation.
+ Overview of synthesis of ɤ-amino acid tubuphenylalanine (Tup) and
tubuvaline (Tuv).
+ Synthesize Tuv
+ Synthesize Tup
+ Synthesize dipeptides.
+ Synthesize tripeptides.
+ Synthesize tetrapeptides (derivatives and analogues of tubulysin)
+ Evaluation of cytotoxic activity of tetrapeptides
Layout of the Thesis
The thesis includes 133 pages: Opening (2 pages), Chapter 1:
Overview (28 pages), Chapter 2: Research Methods and Experimental
(37 pages), Chapter 3: Results and discussions (55 pages), conclusions
(1 page), The list of published related to thesis (1 page).
The reference contains of thesis have 96 documents, which were
updated until the year 2020.
The appendix 81 pages have composed the spectrum of synthetic
substances.
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CHAPTER 1. OVERVIEW
1.1. Myxobacteria, substances and biological activity
1.2. Microtube in drug research
1.3. Tubulysin: Isolation, determination of structure, biosynthesis
and biological activity.
Figure 1.10. Chemical formulas of natural tubulysins