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Design and Synthesis of Bile Acid Based Conjugates, Dimers, Oligomers and Their Pharmacological and Supramolecular Applications

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Design and Synthesis of Bile Acid Based Conjugates, Dimers, Oligomers and Their Pharmacological and Supramolecular Applications DESIGN AND SYNTHESIS OF BILE ACID BASED CONJUGATES, DIMERS, OLIGOMERS AND THEIR PHARMACOLOGICAL AND SUPRAMOLECULAR APPLICATIONS Mr. NILKANTH G. AHER (RESEARCH STUDENT) Dr. Mrs. VANDANA S. PORE (RESEARCH SUPERVISOR) ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY PUNE 411 008, INDIA JANUARY 2009 DESIGN AND SYNTHESIS OF BILE ACID BASED CONJUGATES, DIMERS, OLIGOMERS AND THEIR PHARMACOLOGICAL AND SUPRAMOLECULAR APPLICATIONS THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY Mr. NILKANTH GANPAT AHER ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY PUNE 411 008, INDIA Dedicated To My Family… Dr. (Mrs.) Vandana S. Pore Phone: +91-20-25902320 Scientist-EII Fax: +91-20-25902624 Organic Chemistry Division E-mail: [email protected] Website: http://www.ncl-india.org January 20, 2009 CERTIFICATE This is to certify that the work incorporated in the thesis entitled “Design and Synthesis of Bile Acid Based Conjugates, Dimers, Oligomers and Their Pharmacological and Supramolecular Applications” which is being submitted to the University of Pune for the award of Doctor of Philosophy in Chemistry by Mr. Nilkanth Ganpat Aher was carried out by him under my supervision at the National Chemical Laboratory, Pune. Such material as has been obtained from other sources has been duly acknowledged in the thesis. Dr. Mrs. Vandana S. Pore Research Guide Organic Chemistry Division National Chemical Laboratory Pune 411008, India National Chemical Laboratory, Pune (India) CANDIDATE’S DECLARATION I hereby declare that the thesis entitled “Design and Synthesis of Bile Acid Based Conjugates, Dimers, Oligomers and Their Pharmacological and Supramolecular Applications” submitted by me for the degree of Doctor of Philosophy in Chemistry to the University of Pune is the record of work carried out by me during the period April, 2004 to December, 2008 and has not been submitted by me for a degree to any other University or Institution. This work was carried out at Organic Chemistry Division, National Chemical Laboratory, Pune, India. Nilkanth G. Aher January 2009 Organic Chemistry Division National Chemical Laboratory Pune 411008, India ACKNOWLEDGEMENTS It gives me great pleasure to express my deep sense of gratitude to my mentor and guide Dr. Mrs. Vandana S. Pore for her constant and generous support and guidance. I am grateful to her for giving me a great opportunity to flow in such an ocean of chemistry and motivating me in steroid chemistry and appreciate her able guidance, wholeheartedly. Working with her was really a great pleasure and fetched me a lot of learning experience. It is really a great help and guidance rendered by Dr. P. K. Shukla, and his group at Division of Fermentation Technology, Central Drug Research Institute, Lucknow, Dr. M. K. Bhat and his group at National Centre for Cell Science, Pune University Campus, Pune for biological activity of new molecules, without their help it would be an incomplete research. I express my gratitude to all of them. I am grateful to Dr. B. G. Hazra, and Dr. Mrs. V. A. Kumar, for their advice, guidance, support and encouragements during every stage of this research work. My thanks are due to Dr. K. N. Ganesh, Director Indian Institute of Science Education and Research, Pune (former Head, OCS Division) for his constant support. It is my privilege to thank Dr. Ganesh Pandey, Head, OCD, Dr. S. Sivaram (Director, NCL) for permitting me to work in NCL, UGC-CSIR, New Delhi for fellowship. I am also grateful to Dr. H. B. Borate, Dr. P. L. Joshi, Dr. D. D. Dhavale, Dr. N. P. Argade, Dr. S. P. Chavan, Dr. U. R. Kalkote, Dr. Mrs. R. D. Wakharkar, Dr. R. A. Joshi, Dr. Mrs. R. R. Joshi, for their help and encouragement. I would also like to acknowledge all the staff members of GC, HPLC, IR, NMR, Mass, Microanalysis, X-ray analysis, Library, Administration and technical divisions of NCL for their assistance during the course of my work. I feel great sense of gratitude for Dr. V. B. Gaikwad (Dean of Science faculty, University of Pune and Principal K.T.H.M. college Nashik) for his inspirational teaching, ethics and discipline. He has introduced me to this fascinating subject and inspired me to move towards the research. I take this opportunity to thank my teachers, Prof. S. R. Ahire, Dr. G. H. Jain, D. D. Kajale, Y. R. Baste, P. Kulkarni, Art. Comm & Sci, College Nandgaon (Nashik), Dr. Awachat, Dr. Bhagwat,Dr. Mrs. Deshpande (S. P. College, Pune) for their encouragements and motivation during my B. Sc. and M. Sc.studies. Most importantly, I am very much thankful to my lab-friends Namdev, Bapu, Deepak, Sudhir, Sachin, and Khandekar for helping me in various capacities throughout my work and maintaining cheerful atmosphere with humor in the lab. Thanks are due to Sheetal, Minakshi, Anurag, and Richa for the help during their project tenure in our laboratory. I take this opportunity to thank to my present labmates Dr. Moneesha, D’costa, Mrs. Anita Gunjal, Khirud, Sachin, Madhuri, Seema, Namrata, Venu, Kiran, Parmeshwar, Harshid, Mrs. Mane and Bhumkar. They made working in the lab enjoyable. No words will be sufficient to express my thanks to my friends Arun, Navnath, Rajabhau, Amit, Mahesh, Manoj, Motikar, Sachin, Vinayak, Shekhar, Prashant, Nagendra (NB), Kulbhushan, Sachin Narute, Lalit, Pankaj, Patwa, Mahesh, Awadhut, Pandurang, Amol, Shriram, Ganesh, Sharad, Abasaheb, Suleman, Manmat,Ravi,Kishor, Prasanna, Ramesh, Vishal Mahajan, Vilas, Lakxman, Sanjay, Taterao, Shafi, Kiran, Kishan, Mrs. Ajit Malwade, Pawar, Umesh, Dr. Sada, Dr. Anil, Dr. Modani and Milind Dumbare all my friends of NCL as well as out of NCL during my long stay in NCL, who helped me whenever it was needed; be it personal or research related. I owe my deepest gratitude and affection to my parents Nana and Tai. No word would suffice to express my gratitude and love to Yogesh (brother), Minakshi, Shidhi, Aruna (sister), Mahendra, Lalit, Satish, Chhaya, Shivali, Surekha, Harshali,Yogesh, Bhushan, Rani, father in law, mother in law, Savita Shingote, Sandhya, Sonali, Sphurti, Sheetal,Prerna, Alka, Kalpana, Arnav, Tanu, Anushka, Sonu, all other relatives and friends for their continuous showering of boundless affection on me and supporting me in whatever I chose or did. The warmth and moral value of my parents have stood me in good stead throughout my life and I would always look up to them for strength no matter what I have to go through. This Ph. D. thesis is a result of the extraordinary wills, efforts and sacrifices of my parents. My successes are dedicated to them now and always. The love and support from my wife MANISHA who walked along with me, sharing every ups and downs and I am highly indebted to them for their sacrifice, help and encouragement for the healthy and inspiring environment with out whom I would not been able to stand out as a person and my deep sense of gratitude remains forever. The thesis is a form to pay respect to their attributes. I thank my son OM (Sharvil) for making my life more beautiful than it was. I dedicate this achievement to my parents and wife Manisha and son Om. Finally, my acknowledgement would not be completed without thanking the God Shiva, for giving me the strength and the determination to overcome the hardship faced in my life. Nilkanth CONTENTS General remarks i Abbreviations iii Abstract vi Chapter 1 Synthesis of bile acid based dimers, oligomers to study their micelle like properties and studies towards the synthesis of cholaphanes. 1.1 Abstract 1 1.2 Introduction 2 1.3 Review of literature 2 1.4 Present work 14 1.4.1 Objective 14 1.4.2 Results and discussion 16 1.5 Conclusion 28 1.6 Experimental section 28 1.7 Selected spectra 47 1.8 References 77 Chapter 2 Synthesis of bile acid-fluconazole conjugates, new fluconazole analogues using click reaction, bile acid based amino alcohols and their bioevaluation. Section I Synthesis of bile acid-fluconazole conjugates and new fluconazole analogues using click reaction and their bioevaluation. 2.1.1 Abstract 86 2.1.2 Introduction 87 2.1.3 Review of literature 87 2.1.4 Present work 99 2.1.4.1 Objective 99 2.1.4.2 Result and discussion 100 2.1.5 Conclusion 107 2.1.6 Experimental section 108 2.1.7 Selected spectra 119 2.1.8 References 132 Section II Synthesis and bioevaluation of bile acid based amino alcohols. 2.2.1 Abstract 137 2.2.2 Introduction 138 2.2.3 Review of literature 138 2.2.4 Present work 143 2.2.4.1 Objective 143 2.2.4.2 Results and discussion 143 2.2.5 Conclusion 148 2.2.6 Experimental section 149 2.2.7 Selected spectra 159 2.2.8 References 174 Chapter 3 Stereoselective synthesis of steroidal side chain from 16- dehydropregnalone acetate. 3.1 Abstract 177 3.2 Introduction 178 3.3 Review of literature 180 3.4 Present work 193 3.4.1 Objective 193 3.4.2 Results and discussion 193 3.5 Conclusion 200 3.6 Experimental section 200 3.7 Selected spectra 207 3.8 References 221 List of Publications 226 Erratum 228 GENERAL REMARKS • Independent reference and compound numbering have been employed for abstract, as well as each chapter (Chapter 1-3). • All the solvents used were purified using the known literature procedures. • Petroleum ether used in the experiments was of 60-80 °C boiling range. • Column chromatographic separations were carried out by gradient elution using silica gel (60-120 mesh/230-400 mesh) or neutral deactivated alumina with light petroleum ether-ethyl acetate mixture, unless otherwise mentioned. • TLC was performed on E-Merck pre-coated silica gel 60 F254 plates and the spots were rendered visible by exposing to UV light, iodine, charring or staining with ninhydrin, p-anisaldehyde or phosphomolybdic acid solutions in ethanol.
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