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ATTEMPTED SYNTHESIS OF (BENZYLIDINE-2-(4-AMINOPHENOXY)2-METHYL PROPIONIC ACID), A POSSIBLE POTENT ANTISICKLING AND ANTITUMOR AGENT
BY
UGIM, SAMUEL UGIM REG. NO: 01/42211
A B.Sc PROJECT SUBMITTED TO
THE DEPARTMENT OF PURE AND APPLIED CHEMISTRY UNIVERSITY OF CALABAR, CALABAR – NIGERIA
IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE AWARD OF THE BACHELOR OF SCIENCE DEGREE IN APPLIED CHEMISTRY
JANUARY, 2006
CERTIFICATION
I certify that this research work on the “Attempted synthesis of (Benzylidine-2-(4-aminophenoxy)-2-methyl propionic acid), a possible potent antisickling and antitumor agent” is an original work done by Ugim, Samuel Ugim, Reg. No: 01/42211, under my supervision.
NAME:
Mr. OROK OYO-ITA (Supervisor)
Signature:……………………… Date:……………………………..
QUALIFICATION: M.Sc. Pharmaceutical chemistry
DEDICATION
I humbly dedicate this research work to God Almighty, my late Mum Mrs. Lucy Ugim, my Dad, Mr. Joseph Ugim and all those who have contributed positively to the development of Science and Technology as well as my other sources of inspiration.
ACKNOWLEDGEMENTS My due acknowledgment goes first with special thanks and gratitude to God Almighty who has seen to the success of this research work. My sincere gratitude goes to my Dad for his constant and undeterred support throughout my stay in the University. My unreserved gratitude also goes to my younger brother master George Ugim, my other siblings Beatrice, Theresa, Francis, John, Emmanuel and to my step grand mum Mrs. Rita Ugim for their constant support and prayers. I remain grateful to my supervisor Mr. Oyo-Ita for his strict guidance in ensuring that through rain and shine this research work was completed successfully, I also will not fail to acknowledge Abigail for computing this work. Finally, I appreciate and acknowledge my Uncle Mr. Ugim Clement for his undeterred assistance, my entire extended and nuclear family, all my friends and well wishers, the school in general and the department of Pure and Applied Chemistry in particular for providing me with the wonderful opportunity of conducting a research of this nature.
ABSTRACT
The potency of the antisickling agent, 2-(4-aminophenoxy)-2-methyl propionic acid has been reported by several researchers. A molecular modification of the amino moiety by its reaction with benzaldehyde
yielded
a
Schiff-base,
benzylidine-2-(4-
aminophenoxy)-2-methyl propionic acid (melting point 80-820C, % yield 50.94), thought to possess an anti-tumor property. Thin layer chromatographic analysis using a solvent system consisting, benzene (20ml), ethyl acetate (50ml) and methanol (30ml) gave a resolution showing the Rf value of 0.92, 0.88 and 0.989 for nitrophenol, 2-(4aminophenoxy)-2-methyl
propionic
acid
and
benzylidine-2-(4-
aminophenoxy)-2-methyl propionic acid respectively.
TABLE OF CONTENTS
Certification
…
…
…
…
…
…
ii
Dedication
…
…
…
…
…
…
iii
Acknowledgement
…
…
…
…
…
…
iv
Abstract
…
…
…
…
…
…
v
Table of Contents
…
…
…
…
…
…
vi
List of Tables
…
…
…
…
…
…
ix
List of Figures
…
…
…
…
…
…
x
…
…
…
…
…
…
1
…
…
2
…
…
4
…
…
6
2.2.1 Sickle cell anemia as a genetic disorder …
…
9
…
…
14
…
…
16
…
…
…
18
…
…
…
20
2.3.1 Pathophysiological considerations …
…
…
22
2.3.2 Symptoms of sickle cell anemia
…
…
24
CHAPTER ONE 1.0
Introduction
1.1
Aim and Objective of the research
CHAPTER TWO: LITERATURE REVIEW 2.1
History of Sickle Cell Anemia
2.2
Hemoglobin and the three faces of sickle cell anemia
…
…
2.2.2 Sickle cell anemia as a disease of the hemoglobin molecule 2.2.3 Sickle cell anemia as a disease of the red blood cells
…
2.2.4 Factors responsible for intracellular polymerization of Hbs 2.3
…
General overview of the disease
…
2.3.3 Sickle cell crisis
…
…
…
…
…
25
…
2.4
Treatment of sickle cell anemia
…
…
27
2.5
Anti sickling agent and their classification
…
30
…
30
2.5.2 Hbs molecule modifiers (anti-gelling agents) …
32
2.5.2 (a)
Non covalent modifiers
…
…
…
33
2.5.2 (b)
Covalent modifiers
…
…
…
36
2.5.3 Erythrocyte membrane modifiers …
…
…
38
…
40
2.7: Schiff-bases and their anti tumor tendencies …
45
2.5.1 The gene modifiers
2.6
…
…
…
…
…
Mechanisms via which emerging therapeutic agent retard the sickling process. …
…
CHAPTER THREE: MATERIALS AND EXPERIMENTAL METHODS 3.1.1 Materials/Reagents
…
…
…
…
…
48
3.1.2 Apparatus
…
…
…
…
…
49
…
3.2.0 Synthesis of benzylidin-2-(4-aminophenoxy)-2methyl propionic acid …
…
…
…
…
50
…
50
2-(4-aminophenoxy)-2-methyl propionic acid …
54
3.2.1 Synthesis of 2-(4-Nitrophenoxy)-2-methyl propionic acid
..
…
…
…
3.2.2 Reduction of synthesized compound to
3.2.3 Condensation of 2-(4-aminophenoxy)-2-
3.3
methyl propionic acid with benzaldehyde
…
57
Determination of purity
…
…
…
…
57
3.3.1 Melting point determination …
…
…
…
58
3.3.2 Thin layer chromatography …
…
…
…
59
CHAPTER FOUR: RESULTS AND DISCUSSION
4.1
Results
…
…
…
…
…
…
61
4.2
Discussion
…
…
…
…
…
…
66
5.0
Summary and Conclusion
…
…
…
…
73
5.1
Suggestion for further studies
…
…
…
74
Reference
…
…
…
…
…
…
76
Appendix
…
…
…
…
…
…
79
CHAPTER FIVE
LIST OF TABLES
Table 2.1: Emerging therapeutic agents in sickle cell disease … …
…
…
45
Table 4.1: Melting point determination …
…
…
61
Table 4.2: TLC Resolution results …
…
…
62
…
LIST OF FIGURES
FIG 2.1(a): Structure of the heme group …
…
…
7
FIG 2.1(b): Structure of Hemoglobin A showing binding nature … … … …
…
8
…
32
FIG 2.2:
Structure of some drugs that act via the gene modification mechanism
FIG 2.3:
Structures of some non-covalent modifiers… 35
FIG 2.4:
Structures of some covalent modifiers …
38
FIG 2.5:
Structures of some Erythrocyte membrane modifiers … …
…
40
Schematic representation of Fetal Hemoglobin induction by hydroxyurea
…
41
Structures of some Schiff bases with anti tumor tendencies … … …
…
47
FIG 2.6
FIG 2.7:
FIG 3.1(a): Reflux set up
…
…
…
53
FIG 3.1(b): Setup for reduction process …
…
…
56
FIG 4.1:
…
…
…
TLC Plate showing resolution of components…61
BY
UGIM, SAMUEL UGIM REG. NO: 01/42211
A B.Sc PROJECT SUBMITTED TO
THE DEPARTMENT OF PURE AND APPLIED CHEMISTRY UNIVERSITY OF CALABAR, CALABAR – NIGERIA
IN PARTIAL FULFILMENT OF THE REQUIREMENT FOR THE AWARD OF THE BACHELOR OF SCIENCE DEGREE IN APPLIED CHEMISTRY
JANUARY, 2006
CERTIFICATION
I certify that this research work on the “Attempted synthesis of (Benzylidine-2-(4-aminophenoxy)-2-methyl propionic acid), a possible potent antisickling and antitumor agent” is an original work done by Ugim, Samuel Ugim, Reg. No: 01/42211, under my supervision.
NAME:
Mr. OROK OYO-ITA (Supervisor)
Signature:……………………… Date:……………………………..
QUALIFICATION: M.Sc. Pharmaceutical chemistry
DEDICATION
I humbly dedicate this research work to God Almighty, my late Mum Mrs. Lucy Ugim, my Dad, Mr. Joseph Ugim and all those who have contributed positively to the development of Science and Technology as well as my other sources of inspiration.
ACKNOWLEDGEMENTS My due acknowledgment goes first with special thanks and gratitude to God Almighty who has seen to the success of this research work. My sincere gratitude goes to my Dad for his constant and undeterred support throughout my stay in the University. My unreserved gratitude also goes to my younger brother master George Ugim, my other siblings Beatrice, Theresa, Francis, John, Emmanuel and to my step grand mum Mrs. Rita Ugim for their constant support and prayers. I remain grateful to my supervisor Mr. Oyo-Ita for his strict guidance in ensuring that through rain and shine this research work was completed successfully, I also will not fail to acknowledge Abigail for computing this work. Finally, I appreciate and acknowledge my Uncle Mr. Ugim Clement for his undeterred assistance, my entire extended and nuclear family, all my friends and well wishers, the school in general and the department of Pure and Applied Chemistry in particular for providing me with the wonderful opportunity of conducting a research of this nature.
ABSTRACT
The potency of the antisickling agent, 2-(4-aminophenoxy)-2-methyl propionic acid has been reported by several researchers. A molecular modification of the amino moiety by its reaction with benzaldehyde
yielded
a
Schiff-base,
benzylidine-2-(4-
aminophenoxy)-2-methyl propionic acid (melting point 80-820C, % yield 50.94), thought to possess an anti-tumor property. Thin layer chromatographic analysis using a solvent system consisting, benzene (20ml), ethyl acetate (50ml) and methanol (30ml) gave a resolution showing the Rf value of 0.92, 0.88 and 0.989 for nitrophenol, 2-(4aminophenoxy)-2-methyl
propionic
acid
and
benzylidine-2-(4-
aminophenoxy)-2-methyl propionic acid respectively.
TABLE OF CONTENTS
Certification
…
…
…
…
…
…
ii
Dedication
…
…
…
…
…
…
iii
Acknowledgement
…
…
…
…
…
…
iv
Abstract
…
…
…
…
…
…
v
Table of Contents
…
…
…
…
…
…
vi
List of Tables
…
…
…
…
…
…
ix
List of Figures
…
…
…
…
…
…
x
…
…
…
…
…
…
1
…
…
2
…
…
4
…
…
6
2.2.1 Sickle cell anemia as a genetic disorder …
…
9
…
…
14
…
…
16
…
…
…
18
…
…
…
20
2.3.1 Pathophysiological considerations …
…
…
22
2.3.2 Symptoms of sickle cell anemia
…
…
24
CHAPTER ONE 1.0
Introduction
1.1
Aim and Objective of the research
CHAPTER TWO: LITERATURE REVIEW 2.1
History of Sickle Cell Anemia
2.2
Hemoglobin and the three faces of sickle cell anemia
…
…
2.2.2 Sickle cell anemia as a disease of the hemoglobin molecule 2.2.3 Sickle cell anemia as a disease of the red blood cells
…
2.2.4 Factors responsible for intracellular polymerization of Hbs 2.3
…
General overview of the disease
…
2.3.3 Sickle cell crisis
…
…
…
…
…
25
…
2.4
Treatment of sickle cell anemia
…
…
27
2.5
Anti sickling agent and their classification
…
30
…
30
2.5.2 Hbs molecule modifiers (anti-gelling agents) …
32
2.5.2 (a)
Non covalent modifiers
…
…
…
33
2.5.2 (b)
Covalent modifiers
…
…
…
36
2.5.3 Erythrocyte membrane modifiers …
…
…
38
…
40
2.7: Schiff-bases and their anti tumor tendencies …
45
2.5.1 The gene modifiers
2.6
…
…
…
…
…
Mechanisms via which emerging therapeutic agent retard the sickling process. …
…
CHAPTER THREE: MATERIALS AND EXPERIMENTAL METHODS 3.1.1 Materials/Reagents
…
…
…
…
…
48
3.1.2 Apparatus
…
…
…
…
…
49
…
3.2.0 Synthesis of benzylidin-2-(4-aminophenoxy)-2methyl propionic acid …
…
…
…
…
50
…
50
2-(4-aminophenoxy)-2-methyl propionic acid …
54
3.2.1 Synthesis of 2-(4-Nitrophenoxy)-2-methyl propionic acid
..
…
…
…
3.2.2 Reduction of synthesized compound to
3.2.3 Condensation of 2-(4-aminophenoxy)-2-
3.3
methyl propionic acid with benzaldehyde
…
57
Determination of purity
…
…
…
…
57
3.3.1 Melting point determination …
…
…
…
58
3.3.2 Thin layer chromatography …
…
…
…
59
CHAPTER FOUR: RESULTS AND DISCUSSION
4.1
Results
…
…
…
…
…
…
61
4.2
Discussion
…
…
…
…
…
…
66
5.0
Summary and Conclusion
…
…
…
…
73
5.1
Suggestion for further studies
…
…
…
74
Reference
…
…
…
…
…
…
76
Appendix
…
…
…
…
…
…
79
CHAPTER FIVE
LIST OF TABLES
Table 2.1: Emerging therapeutic agents in sickle cell disease … …
…
…
45
Table 4.1: Melting point determination …
…
…
61
Table 4.2: TLC Resolution results …
…
…
62
…
LIST OF FIGURES
FIG 2.1(a): Structure of the heme group …
…
…
7
FIG 2.1(b): Structure of Hemoglobin A showing binding nature … … … …
…
8
…
32
FIG 2.2:
Structure of some drugs that act via the gene modification mechanism
FIG 2.3:
Structures of some non-covalent modifiers… 35
FIG 2.4:
Structures of some covalent modifiers …
38
FIG 2.5:
Structures of some Erythrocyte membrane modifiers … …
…
40
Schematic representation of Fetal Hemoglobin induction by hydroxyurea
…
41
Structures of some Schiff bases with anti tumor tendencies … … …
…
47
FIG 2.6
FIG 2.7:
FIG 3.1(a): Reflux set up
…
…
…
53
FIG 3.1(b): Setup for reduction process …
…
…
56
FIG 4.1:
…
…
…
TLC Plate showing resolution of components…61
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