angelmarin

National Institutes of Health

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Review

2020

Review

2020

An insight into the therapeutic applications of coumarin compounds and their mechanisms of action.

S. Garg, J. Gupta, Shikha Sharma, D. Sahu
European journal of pharmaceutical sciences…
2020
Corpus ID: 219637116

2016

Evaluation of synthetic coumarins for antiausterity cytotoxicity against pancreatic cancers.

C. Farley, D. F. Dibwe, Jun-ya Ueda, Eric A. Hall, S. Awale, J. Magolan
Bioorganic & medicinal chemistry letters
2016
Corpus ID: 206268595

2016

Investigation of the Antiproliferative Mechanism of Novel Isoprenylated Coumarin Compounds Against Pancreatic Cancer Cells

Ronghao Zhou
2016
Corpus ID: 85463248

.................................................................................................................................. 4 INTRODUCTION.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1. PANCREATIC CANCER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Statistics and Treatments for Pancreatic Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Pancreatic Cancer Cell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2. NATURAL PRODUCTS IN MEDICINE AND ANGELMARIN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Natural Products as Anticancer Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Discovery of Angelmarin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3. SAR STUDIES OF COUMARIN DERIVATIVES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 SAR Study of Hydroxycoumarin Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 SAR Study of Isoprenylated Coumarins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4. PREFERENTIAL CYTOTOXICITY OF COMPOUND 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Against Other Pancreatic Cancer Cell Lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Medium Component Study of Compound 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 5. INTRODUCTION TO INVESTIGATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 RESULTS AND DISCUSSION.................................................................................................. 24 1. PREPARATION OF COMPOUND 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2. TIME DEPENDENT STUDY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 3. MEDIUM COMPONENT STUDY ON BxPC-3 AND COMPARISON. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 New Reference Validation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Medium Component Study on BxPC-3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Comparison Among Three Pancreatic Cancer Cell Lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4. CYTO-ID KIT STUDY OF AUTOPHAGY IN PANC-1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Fluorescence Microscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Fluorescence Microplate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5. WESTERN BLOTTING ANALYSIS OF AUTOPHAGY IN PANC-1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Effect of 21 and Autophagy Inhibitors on Conversion of LC3-I to II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Conversion of LC3-I to II Dependent on Time of Incubation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 CONCLUSION........................................................................................................................... 46 METHODS AND MATERIALS................................................................................................ 47 1. PREPARATION OF COMPOUND 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 2. TUMOR CELL CULTURE AND MEDIA PREPARATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 3. CYTOTOXCITY ASSAYS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 4. CYTO-ID AUTOPHAGY DETECTION KIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 5. WESTERN BLOTTING ANALYSIS OF AUTOPHAGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 REFERENCES ........................................................................................................................... 55 INDEX OF APPENDICES......................................................................................................... 57

2015

Natural Product Derivatives as Promising Anti-Pancreatic Cancer Agents

Hong Zhang
2015
Corpus ID: 30592690

................................................................................................................................................ 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