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Synthesis and Radiolabeling of Modified Peptides Attached to Heterocyclic Rings and Their Possible Medical Applications

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Synthesis and Radiolabeling of Modified Peptides Attached to Heterocyclic Rings and Their Possible Medical Applications Menoufiya University Faculty of Science Chemistry Department Synthesis and Radiolabeling of Modified Peptides Attached to Heterocyclic Rings and Their Possible Medical Applications A thesis Submitted in Partial Fulfillment of the Requirements for the Master Degree in Science (Organic Chemistry) By Hesham Abd El-Aal Abd El-Moaty Shams El-Din B.Sc. in Chemistry (May 2007) Demonstrator in Labeled Compounds Department, Hot Laboratories Center, Atomic Energy Authority Supervised by Prof. Dr. Hamed Mohammed Prof. Dr. Kamel Abd El-Hameed Abd El-Bary Moustafa Professor of Organic Chemistry, Professor of Radiobiochemistry, Chemistry Department, Labeled Compounds Department, Faculty of Science, Hot Laboratories Center, Menoufiya University Atomic Energy Authority Dr. Ibrahem Youssef Abd El-Ghaney Ass. Professor of Radiobiochemistry, Labeled Compounds Department, Hot Laboratories Center, Atomic Energy Authority 2012 ﴿ ﴾ رة اء / ١١٣ Contents Contents Dedication I Acknowledgment II Notes III List of Figures IV List of Tables VI Abbreviations VII Aim of the Work IX Summary X Chapter I 1. Introduction 1 1.1 Peptide Synthesis 2 1.1.1 Protection of Functional Groups 3 1.1.2 Peptide Bond Formation: Methods and Strategies 4 1.2 1,2,4-Triazoles 10 1.2.1 Synthesis of 1,2,4-Triazoles 10 1.2.2 Reactions of 1, 2, 4-Triazoles 14 1.3 Tetrazoles 16 1.3.1 Synthesis of Tetrazoles 16 1.3.2 Reactions of Tetrazoles 19 1.4 1,3,4-Oxadiazoles 22 1.4.1 Synthesis of 1,3,4-Oxadiazoles 22 1.4.2 Reactions of 1,3,4-Oxadiazoles 23 Contents 1.5 Radiolabeled compounds 24 1.5.1 Types of labeling 25 1.5.2 Radioiodination 26 2. Results and Discussion 34 Chapter II 2.2 Synthesis of compounds 34 2.2 Radioiodination of dipeptide derivatives 8 and 15 50 3. Experimental 62 Chapter III 3.1 Synthesis of compounds 62 3.2 Radioiodination of dipeptide derivatives 8 and 15 82 4. Biological Evaluation 89 Antimicrobial activity of the newly synthesized 4.1 89 Chapter IV Compounds Biodistribution studies of radiolabeled derivatives 4.2 91 in normal mice References 95 Published papers Arabic summary أ ا ا Dedication To the spirit of my mother To my father & my brothers I Acknowledgements Acknowledgements First of all, limitless gratitude to God, Most Merciful, who blesses my effort, shows me the way and enables me to present this work in an acceptable style. On the top my Parent and my brothersbrothers, none of the things I have done would be done if it was not for your endless support, patience and encouragement throughout my years of study. Thanks for pretending to be interested in what I do. I would like to express my deeply heart thanks to Prof.Prof. Dr. Hamed Abd ElEl----BaryBary (Prof. of Organic Chemistry, Menoufiya University),, Prof. Dr. Kamel Abd ElEl----HameedHameed (Prof. of Radio-biochemistry, Atomic Energy Authority), Dr. Ibrahem Youssef (Ass. Prof. of Radio biochemistry, Atomic Energy Authority) and Dr. Khaled Sallam Salem (Ass. Prof. of Radiochemistry, Atomic Energy Authority) for giving me the honor of working under their supervision, formulating the objectives, supplying the equipments and facilities required to accomplish the work and above all for their unforgettable sincere encouragement. I would like to express my sincere appreciation, regards and gratitude to ProfProf.. Dr. Adel Nassar ( (professor of Organic Chemistry, faculty of science, Menoufiya University) for his help, continuous advice and encouragement. I wish for him a great success and a good health all his life. I would like to express my deepest thanks to Dr. SSShimaShima Basher (Botany department, faculty of science, Menoufiya University) for her help and support in the antimicrobial study. I wish for her great success and good health all her life. I wish also to express my deep thanks to all who supporting me during the study and the investigations of all the stages of the thesis specially Prof. Dr. Mohamed Abd ElElEl-El ---MotalMotalMotaleeeeb,b, Dr. Wael Sh Sheeeendy,ndy, HHHassanHassan Medhat, Mangoud ElElEl-El ---WakeWakeWakeeeeellll,, Mohammed El El----GGGGiiiizawy,zawy, Heba Raslan, Samar Ramadan, Maram ZahraZahra,, Tayseer Zidan, Walaa Gado, Walaa Diab, Eman Mansour, Shaban Abd ElEl----Satar,Satar, Mohamed Fawzy, Ibrahim Katan, SSSayedSayed Gamal, Mostafa Ataf and Ahmed Galhoum for their real help, moral support and continuous encouragement. Finally, I would like to express my thanks and gratitude to all staff members of the Atomic Energy Authority. Also, my deepest thanks all my friends and colleagues at the Faculty of Science, Menoufiya University for their notes and additions which made this work more valuable. I would like to express my hearty thanks and gratitude to all my friends for their help and moral support. I really would like to thank those who helped me even with a word of support, those who really affected and still affecting my life everywhere. With my best regards Hesham Abdel-Aal Shamsel-Din II Notes Notes The present thesis is submitted to the Faculty of Science, Menoufiya University in partial fulfillment for the requirements of Master Degree of Science in Organic Chemistry. Besides the work carried out in this thesis, the candidate Hesham Abd El-Aal Abd El-Moaty Shams El-Din passed post graduate courses for one year in Organic Chemistry, these cover the following topics: 1- Advanced Physical Organic Chemistry. 2- Organo-Metallic Chemistry. 3- Nature Products Chemistry. 4- Polymer Chemistry. 5- Biochemistry. 6- Chromatography. 7- Dyes. 8- Electro-Organic Chemistry. 9- Carbohydrates. 10- Spectroscopy. 11- Statistics. 12- English language. 13- Computer Science. 14- Photochemistry. Head of Chemistry Department Prof. Dr. Ahmed Abd El-Mageed III List of Figure List of Figures Figure No. label Page Fig.(2.1) Variation of the labeling yield of 125 I-EHPIP as a function of different EHPIP amounts; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, (x µg) EHPIP, 100 µg of CAT, at pH 7, the reaction mixtures were kept at room temperature for 15 min…………………………………………………………. 51 Fig. (2.2) Variation of the labeling yield of 125 I-EHPIP as a function of CAT amount; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, (x µg) of CAT, 100 µg of EHPIP, at pH 7, the reaction mixtures were kept at room temperature for 15 min…………………………………………………………. 52 Fig. (2.3) Variation of the labeling yield of 125 I-EHPIP as a function of reaction time; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 100 µg of EHPIP, 150 µg of CAT, at pH 8, the reaction mixtures were kept at room temperature for different intervals of time………………………………….. 53 Fig.(2.4) Variation of the labeling yield of 125 I-EHPIP as a function of pH; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 100 µg of EHPIP, 150 µg of CAT, at different pH, the reaction mixtures were kept at room temperature for 15 min………………………………………………………… 54 Fig. (2.5) Variation of the labeling yield of 125 I-EHPIP as a function of reaction temperature; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 100 µg of EHPIP, 150 µg of CAT, at pH 8, the reaction mixtures were kept at different temperatures for 15 min…………………………………………………. 54 Fig.(2.6) In vitro stability of 125 I-EHPIP in refrigerator…………… 55 Fig.( 2.7) In vitro stability of 125 I-EHPIP at room temperature……... 55 Fig. (2.8) Variation of the labeling yield of 125 I-EHPTIP as a function of different EHPTIP amounts; reaction conditions: 10 µL (~7.2 MBq) Na 125 I, (x µg) EHPTIP, 100 µg of CAT, at pH 7, the reaction mixtures were kept at room temperature for 15 min……………………………………………………… 57 Fig. (2.9) Variation of the labeling yield of 125 I-EHPTIP as a function of CAT amount; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, (x µg) of CAT, 10 µg of EHPTIP, at pH 7,the reaction mixtures were kept at room temperature for 15 min………………………………………………………….. 58 IV List of Figure Figure No. label Page Fig.(2.10) Variation of the labeling yield of 125 I-EHPTIP as a function of pH; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 10 µg of EHPTIP, 150 µg of CAT, at different pH, the reaction mixtures were kept at room temperature for 15 min………. 59 Fig. (2.11) Variation of the labeling yield of 125 I-EHPTIP as a function of reaction time; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 10 µg of EHPTIP, 150 µg of CAT, at pH 7, the reaction mixtures were kept at room temperature for different intervals of time………………………………….. 60 Fig. (2.12) Variation of the labeling yield of 125 I-EHPTIP as a function of reaction temperature; Reaction conditions: 10 µL (~7.2 MBq) Na 125 I, 10 µg of EHPTIP, 150 µg of CAT, at pH 7,the reaction mixtures were kept at different temperatures for 45 min………………………………………………….. 60 Fig. (2.13) In vitro stability of 125 I-EHPTIP…………………………… 61 Fig. (3.1) Paper electrophoresis for 125 I-EHPIP, 125 I-EHPTIP and free iodide………………………………………………………. 85 V List of Tables List of Tables Table No. label Page Table (1.1) Examples of radiolabeled compounds used as therapeutic agents………………………………………………………. 24 Table (1.2) Examples of radiolabeled compounds used as diagnostic agents...................................................................................... 25 Table (1.3) Production methods and radioactive properties of 123 I, 125 I and 131 I………………………………………………………. 27 Table (3.1) Radio-chromatographic behavior of different radiochemical 125 125 species and their R f values for of I-EHPIP and I- EHPTIP in paper chromatography………………………….. 84 Table (3.2) Radio-chromatographic behavior of different radiochemical species for 125 I-EHPIP and 125 I-EHPTIP in paper electrophoresis……………………………………………… 85 Table (4.1) In vitro antimicrobial activity of the newly synthesized compounds (at 50 µg / mL of test solutions)……………….
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