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Studies on the Total Synthesis of a New Largazole Analogue as a Potential Histone Deacetylase Inhibitor

Farrell, Robert Liam
http://rave.ohiolink.edu/etdc/view?acc_num=mco1440071080

Abstract Details

2015, Master of Science in Pharmaceutical Science (MSP), University of Toledo, Medicinal Chemistry.
Cancer is a general term used to describe a group of over 100 different diseases all of which have a similar characteristic about them; the out of control abnormal growing of cells. Cancer kills over half a million people every year in the United States and is on the rise. Thus the need for new cancer therapies is also on the rise. It has been shown that histone deacetylases (HDACs) are over expressed in cancer tissues and therefore, inhibiting them is considered to be a way to slow down the progression or stop the spread of cancer in the body. However HDACs are involved in many other cellular functions in the body and indiscriminately inhibiting them would be undesirable. Isoform or class selective HDAC inhibitors targeted to specific HDAC proteins are therefore required. Natural products are known for being an excellent source of bioactive agents with diverse structure and varying biological activity. They constitute one of the most useful sources of lead molecules for treating a variety of human diseases and disorders. From 1940s to most recent data collected in 2012, of the 175 small molecule drugs approved for treating cancer, 131 or 75% are either natural products or directly derived from them. To date, there are four HDAC inhibitors approved for treating cancer, but most are non-specific pan-inhibitors. Vorinostat (SAHA) and romidepsin are two HDAC inhibitors that have been approved for the treatment of CTCL. SAHA binds to the Zn2+ ion of the HDAC protein without having much interaction with the surface of the protein, while romidepsin has a large surface binding group along with the Zn2+ binding moiety, which may account for its higher class I selectivity. Largazole is a potent HDAC inhibitor that has both a Zn2+ binding group and a large surface recognition group which may account for its class I selectivity. Taking largazole as a lead structure, our lab is interested in the synthesis of analogues as potentially more selective HDAC inhibitors by modifying the cyclic group of the molecule. The synthetic approach for one of the analogues RF1 was successfully developed in the lab. In this molecule the thiazole ring is replaced with a pyridine and the thiazoline ring is replaced with a 4-methylbenzyl amine group. This approach provides a means to synthesize larger quantities of the compound for biological studies.
Viranga Tillekeratne, Dr. (Advisor)
Amanda Bryant-Friedrich, Dr. (Committee Member)
Zahoor Shah, Dr. (Committee Member)
76 p.
Chemistry; Organic Chemistry
Largazole, Synthesis

Recommended Citations

Citations

  • Farrell, R. L. (2015). Studies on the Total Synthesis of a New Largazole Analogue as a Potential Histone Deacetylase Inhibitor [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1440071080

    APA Style (7th edition)

  • Farrell, Robert. Studies on the Total Synthesis of a New Largazole Analogue as a Potential Histone Deacetylase Inhibitor. 2015. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1440071080.

    MLA Style (8th edition)

  • Farrell, Robert. "Studies on the Total Synthesis of a New Largazole Analogue as a Potential Histone Deacetylase Inhibitor." Master's thesis, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1440071080

    Chicago Manual of Style (17th edition)

mco1440071080
511
© 2015, some rights reserved.Creative Commons License Studies on the Total Synthesis of a New Largazole Analogue as a Potential Histone Deacetylase Inhibitor by Robert Liam Farrell is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.