Computer Based Design and Synthesis of Some Novel Thiazole Derivatives Bearing a Sulfonamide Moiety and Studying Their Potential Synergistic Anticancer Effect With γ-Irradiation Thesis presented by Aiten Mahmoud Mohamed Soliman Bachelor Degree in Pharmaceutical Sciences Faculty of Pharmacy Ain Shams University (2006) Submitted for the partial fulfillment of M.Sc. Degree in Pharmaceutical Sciences (Pharmaceutical Chemistry) Prof. Dr. Dalal Abdel-Rahman Prof. Dr. Mostafa Mohamed Ghorab Abou El Ella Professor of Pharmaceutical Chemistry Professor of Applied Organic Chemistry Head of Pharmaceutical Chemistry Department Drug Radiation Research Department, Faculty of Pharmacy National Centre for Radiation Research and Ain Shams University Technology, Atomic Energy Authority Prof. Dr. Helmy Ismail Heiba Assoc. Professor of Applied Organic Chemistry, Drug Radiation Research Department National Centre for Radiation Research and Technology Atomic Energy Authority Faculty of Pharmacy Ain Shams University (2011) Acknowledgement Firstly, I want to thank Allah who gave me the patience and support to achieve my goal. I wish to express my unlimited thanks and gratitude to Prof. Dr. Dalal Abdel-Rahman Abou El-Ella, Prof. of Pharmaceutical chemistry, Faculty of Pharmacy, Ain Shams University, for her support, kind supervision and encouragement throughout the work. I am also deeply grateful to Prof. Dr. Mostafa Mohamed Soliman Ghorab, Prof. of Applied Organic Chemistry, National Center for Radiation Research and Technology(NCRRT), for suggesting the research subject, kind supervision, valuable advices and continuous support and guidance which helped me to complete this work. I would like to express my deep thanks and appreciation to Dr. Helmy Ismail Heiba, Assist. Prof. of Applied Organic Chemistry(NCRRT), for his continuous support and supervision, valuable advices and fruitful opinions through the whole work. I would like to give my special thanks to my whole family for the patience and moral support they provided throughout my research work. Finally, my deep thanks to my colleagues in Drug Chemistry Lab (NCRRT), and to all who gave me help and support for the fulfillment of this work. Contents Abstract……………………………………...…………………... i - v 1. Introduction…………………………………………...……….. 1 1.1. Cancer ……………………………………………….…….…. 2 1.2. Rationale for combining chemotherapy and radiotherapy........ 6 1.3. Sulfonamides …..……………………………………………. 12 1.4. Thiazoles and fused thiazoles as anticancer agents …...….…. 24 1.5. Synthesis of thiazoles and fused thiazoles.…………..………. 31 2. Aim of the present investigation……………………...…......... 38 3. Theoretical Discussion……………………………...……........ 49 4. Experimental…………………………………………………... 68 5. Biological Activity………………………………...………….... 95 5.1. In-vitro anticancer activity………………………………….... 96 5.2. Radiosensitizing evaluation……………...…….…………...... 104 6. Molecular Modeling………………………………….....…..... 110 7. References…………………………………...……………......... 120 أ …………………..………………………………Arabic summary List of Figures Figure (1): Schematic representation of the catalytic mechanism for the α- CA catalysed CO2 hydration………………………………………………14 Figure (2): Zinc binding groups…………………………………….…….15 Figure (3): The cell cycle…………………………………………………20 Figure (4): Tiazofurin and its analogues………………………………….25 Figure (5): Chemical structure of six hybrid compounds (MSt)……….…26 Figure (6): Polar interactions of the inhibitor 45 docked into MMP-9-A16 model……………………………………………………………………....27 Figure (7): Structural elements of CA inhibitors in the CA enzymatic active site………………………………………………………………….………40 Figure (8): Survival curve for HEPG2 cell line for compound III………..98 Figure (9): Survival curve for HEPG2 cell line for compound IVa………98 Figure (10): Survival curve for HEPG2 cell line for compound IVb…….98 Figure (11): Survival curve for HEPG2 cell line for compound VI…...…98 Figure (12): Survival curve for HEPG2 cell line for compound VII..……99 Figure (13): Survival curve for HEPG2 cell line for compound IXa….....99 Figure (14): Survival curve for HEPG2 cell line for compound IXb….....99 Figure (15): Survival curve for HEPG2 cell line for compound IXc…......99 Figure (16): Survival curve for HEPG2 cell line for compound IXd……..99 Figure (17): Survival curve for HEPG2 cell line for compound IXe……...99 Figure (18): Survival curve for HEPG2 cell line for compound IXf.........100 Figure (19): Survival curve for HEPG2 cell line for compound IXg…....100 Figure (20): Survival curve for HEPG2 cell line for compound IXh…....100 Figure (21): Survival curve for HEPG2 cell line for compound XIa…....100 Figure (22): Survival curve for HEPG2 cell line for compound XIb……100 Figure (23): Survival curve for HEPG2 cell line for compound XIc….....100 Figure (24): Survival curve for HEPG2 cell line for compound XId……101 Figure (25): Survival curve for HEPG2 cell line for compound XII…....101 Figure (26): Survival curve for HEPG2 cell line for compound XIIIa.…101 Figure (27): Survival curve for HEPG2 cell line for compound XIIIb….101 Figure (28): Survival curve for HEPG2 cell line for compound XIVa.....101 Figure (29): Survival curve for HEPG2 cell line for compound XIVb….101 Figure (30): Survival curve for HEPG2 cell line for compound XV…….102 Figure (31): Survival curve for HEPG2 cell line for compound XVI…...102 Figure (32): Survival curve for HEPG2 cell line for compound XVII…..102 Figure (33): Survival curve for HEPG2 cell line for compound XVIII....102 Figure (34): Survival curve for HEPG2 cell line for compound XIX…...102 Figure (35): Survival curve for HEPG2 cell line for compound XX…….102 Figure (36): Survival curve for HEPG2 cell line for compound III alone and in combination with γ-irradiation (8 Gy)…………………………………106 Figure (37): Survival curve for HEPG2 cell line for compound IVb alone and in combination with γ-irradiation (8Gy)….………………………….106 Figure (38): Survival curve for HEPG2 cell line for compound IXb alone and in combination with γ-irradiation (8Gy)…………………………..…107 Figure (39): Survival curve for HEPG2 cell line for compound XIIIa alone and in combination with γ-irradiation (8 Gy)…………………………….107 Figure (40): Survival curve for HEPG2 cell line for compound XIVb alone and in combination with γ-irradiation (8 Gy)……………….…………....108 Figure (41): Survival curve for HEPG2 cell line for compound XVII alone and in combination with γ-irradiation (8 Gy)……………………………108 Figure (42): Survival curve for HEPG2 cell line for compound XX alone and in combination with γ-irradiation (8 Gy)……………………………109 Figure (43): Superimposition of hCA II-inhibitor adducts………………111 Figure (44): CA inhibition mechanism by sulfonamides………………...112 Figure(45): Interaction map of N-(2,3,4,5,6-pentafluorobenzyl)-4 sulfamoylbenzamide with hCA II………………………………………...114 Figure (46): Interaction map of E7070 with the active site of hCA II…...115 Figure (47): 2D and 3D Interaction map of compound IVb with hCA II .116 Figure (48): 2D and 3D Interaction map of compound XIVb with hCA II……………..……………………………………………………………116 Figure (49): 2D and 3D Interaction map of compound XVII with hCA II……………………………………………………………………..……117 Figure (50): 2D and 3D Interaction map of compound XX with hCA II ..117 Figure (51): Superimposition of E7070 and compound XIVb in the active site of hCA II……………………………………………………..……….118 Figure (52): Superimposition of E7070 and compound XIc in the active site of hCA II……………………………………………………….…….…...119 List of Tables Table 1, Physico-chemical and analytical data for compounds IVa,b …....72 Table 2, Spectral data for compounds IVa,b………..………………..……73 Table 3, Physico-chemical and analytical data for compound VI……..…..75 Table 4, Spectral data for compound VI……………………………..…....75 Table 5, Physico-chemical and analytical data for compound VII………..76 Table 6, Spectral data for compound VII…………………….…………....76 Table 7, Physico-chemical and analytical data for compounds IX(a-h).….78 Table 8, Spectral data for compounds IX(a-h)……………………….……79 Table 9, Physico-chemical and analytical data for compounds XI(a-d)…..82 Table 10, Spectral data for compounds XI(a-d)…………………….….…83 Table 11, Physico-chemical and analytical data for compound XII...….…84 Table 12, Spectral data for compound XII……………..……………….....84 Table 13, Physico-chemical and analytical data for compound XIIIa,b….85 Table 14, Spectral data for compound XIIIa,b……………………….…...86 Table 15, Physico-chemical and analytical data for compound XIVa,b….87 Table 16, Spectral data for compound XIVa,b…………….……………..88 Table 17, Physico-chemical and analytical data for compound XV……...89 Table 18, Spectral data for compound XV……..…………………………89 Table 19, Physico-chemical and analytical data for compound XVI…......90 Table 20, Spectral data for compound XVI…………………………….…90 Table 21, Physico-chemical and analytical data for compound XVII…….91 Table 22, Spectral data for compound XVII…………………………….. 91 Table 23, Physico-chemical and analytical data for compound XVIII…... 92 Table 24, Spectral data for compound XVIII…………..………………... 92 Table 25, Physico-chemical and analytical data for compound XIX.….... 93 Table 26, Spectral data for compound XIX……….……………….…….. 93 Table 27, Physico-chemical and analytical data for compound XX…...….94 Table 28, Spectral data for compound XX………………...…………..….94 Table 29, In vitro anticancer screening of the synthesized compounds against (HEPG2)………………………………………………………….103 Table 30, In vitro anticancer screening of compounds against (HEPG2) in combination with radiation……………………………………………….105 Abbreviations AMP: Ammonium salt of heteropoly acid. ANOVA: