Natural Product Derivatives as Promising Anti-Pancreatic Cancer Agents

................................................................................................................................................ 5 INTRODUCTION ....................................................................................................................................... 6 NATURAL PRODUCTS IN MEDICINAL CHEMISTRY .................................................................................... 6 PANCREATIC CANCER ............................................................................................................................... 7 DISCOVERY AND SYNTHETIC HISTORY OF THE SPIROXINS ...................................................................... 9 MEDICINAL SIGNIFICANCE OF SPIROXIN A ............................................................................................ 12 SYNTHESIS OF THE CORE STRUCTURE OF SPIROXIN A ........................................................................... 13 STRUCTURE-ACTIVITY RELATIONSHIP (SAR) STUDY ........................................................................... 15 DISCOVERY OF ANGELMARIN ................................................................................................................. 16 NOVEL ISOPRENYLATED COUMARINS AND THEIR ANTITUMOR ACTIVITY ............................................ 16 INTRODUCTION TO INVESTIGATION ........................................................................................................ 19 1. Validation of Initial Lead Structure ............................................................................................... 19 2. SAR Study based on (S)-34 ............................................................................................................. 20 3. Effect of Medium Components on Cytotoxicity of 50 ..................................................................... 25 RESULTS AND DISCUSSION ............................................................................................................... 27 VALIDATION OF INITIAL LEAD STRUCTURE ........................................................................................... 27 SAR STUDY BASED ON (S)-34 ................................................................................................................ 28 1. Preparation of the SAR Library ..................................................................................................... 29 2. Biological Evaluations of SAR Analogs ......................................................................................... 39 EFFECT OF MEDIUM COMPONENTS ON CYTOTOXICITY OF 50 ............................................................... 44 FUTURE DIRECTIONS .............................................................................................................................. 48 CONCLUSION .......................................................................................................................................... 52 EXPERIMENTAL .................................................................................................................................... 53 GENERAL PROTOCOL .............................................................................................................................. 53 SYNTHESIS OF (R)-1,2-DIHYDRONAPHTHALEN-1-OL ((R)-33) ................................................................ 54 SYNTHESIS OF (R)-TERT-BUTYL((1,2-DIHYDRONAPHTHALEN-1-YL)OXY)DIPHENYLSILANE ((R)-34) ... 56 PREPARATION OF TERT-BUTYL((1,2-DIHYDRONAPHTHALEN-1-YL)OXY)DIPHENYLSILANE (34) ........... 57 SYNTHESIS OF TERT-BUTYLDIPHENYLSILANOL (55) ............................................................................... 58 SYNTHESIS OF (S)-1-(TRITYLOXY)-1,2-DIHYDRONAPHTHALENE ((S)-60) .............................................. 59 SYNTHESIS OF TERT-BUTYLDIMETHYLSILANOL (75) .............................................................................. 61 PREPARATION OF COMPLETE DULBECCO MODIFIED EAGLE’S MEDIUM (DMEM) ................................ 61 PREPARATION OF NUTRIENT-DEPRIVED MEDIUM, NUTRIENT-RICH MEDIUM AND MEDIA 1-6 ........... 62 TUMOR CELL CULTURE PROCEDURES .................................................................................................... 62 GENERAL PROCEDURES OF CYTOTOXICITY ASSAYS ............................................................................. 62 Cytotoxicity Assays of Spiroxin A Derivatives against PANC-1 ........................................................ 63 Cytotoxicity Assays of 50 against PANC-1 ........................................................................................ 63 Cytotoxicity Assays of 50 against BxPc-3 and Capan-2 .................................................................... 64 REFERENCES AND NOTES .................................................................................................................. 65 INDEX OF APPENDICES ....................................................................................................................... 68