Advisor(s)

Graham B. Jones

Contributor(s)

Alexandros Makriyannis, Robert N. Hanson, Zhaohui S. Zhou

Date of Award

2010

Date Accepted

3-2010

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

College of Arts and Sciences. Department of Chemistry and Chemical Biology.

Keywords

Cannabinoid, DNA, Enediyne, Microwave, Radiolabels, RNA

Subject Categories

Bioconjugates, Nucleic acids, Chemotherapy

Disciplines

Biochemistry | Macromolecular Substances | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

As researchers continue to unveil the role between structure and function, the potential use of nucleic acids as a therapeutic target grows.1 Nucleic acids can have richly diverse structures2 and are of general biological significance3 being suggested as binding motifs for regulatory proteins involved with viral replication, including the TAR region of HIV-1.4 Additionally, the etiology of at least 12 human neurodegenerative genetic diseases has been attributed to genetic variations in the lengths of triplet repeats in genomic DNA. The unstable expansion of triplet repeats has been attributed to reiterative synthesis due to slippage and bulge formation in the newly formed DNA strand.5 As such, compounds capable of binding to bulges could have significant therapeutic potential. Despite these obvious ramifications, few previous attempts have been made to prepare compounds with affinity for bulged sequences. The most promising bulgespecific agent discovered to date originated from work on the enediyne natural product NCSchrom.6 Based on this finding we have designed libraries of compounds and have achieved nanomolar affinity for specific bulged sequences.7 A schematic route towards the next generation of synthetic bulge binders has been developed. In addition, we have developed synthetic routes to a series of photoactivated enediyne pharmacophores which target duplex DNA. The designed agents were functionalized through PEGylation and derivatized to improve water solubility. These enediynes undergo photo activation to produce cytotoxic diradicals on demand.8

Despite an increased interest in nucleic acid targeting, proteins still remain a focus for small molecule drug design. The discovery of the cannabinoid 1 (CB1) receptor in the 1990’s bolstered an interest in the development of novel ligans capable of antagonizing the receptor.9 Symmetric and asymmetric schemes based off the Sanofi-Aventis lead compound AVE16254 have been developed. A library of over 40 novel CB1selective receptor ligands has been constructed with affinity in the low nanomolar range.

In another area of work, new methods for the rapid incorporation of radio labels using microwave chemistry has been developed. The introduction of fluorine into drugs is not only important to medicinal chemistry for its physiochemical and metabolic impact,10 but also for its use as an imaging agent using positron emission tomography (PET).11 Microwave accelerate fluorodenitration12 and Negishi-fluoroalkylation reactions are described.

References:

1. (a) Borman, S. Chem. Eng. News 2009, 87, 63. (b) Gallego, J.; Varani, G. Acc. Chem. Res. 2001, 34, 843. (c) Sucheck, S. J.; Wong, C.-H. Curr. Op. Chem. Bio. 2000, 4, 678.

2. Sanger, W. Principles of Nucleic Acid Structure, Springer, New York, 1994.

3. (a)Turner, D. H. Curr. Opin. Struct. Biol. 1992, 2, 334. (b) Chastain, M.; Tinoco, I. In Progress in Nucleic Acid Research and Molecular Biology, Cohn, W. E.; Moldave, D.eds., Academic, New York, 1991, 41, 131-177.

4. (a) Lilley, D. M. S. Proc. Natl. Acad. Sci. USA 1995, 92, 7140. (b) Cullen, B. R. Cell 1990, 63, 655. (c) Greenblatt, J; Nodwell, J. R.; Mason, S. W. Nature 1993, 364, 401.

5. Wells, R. D. J. Biol. Chem. 1996, 271, 2875.

6. Xi, Z.; Goldberg, I. H. In Comprehensive Natural Products Chemistry, Barton, D. H. R.; Nakanishi, K. eds., Pergamon, Oxford, 1999, 7, 553.

7. (a) Xi, Z.; Hwang, G.-S.; Goldberg, I. H.; Harris, J. L.; Pennington, W. T.; Fouad, F. S.; Qabaja, G.; Wright, J. M.; Jones, G. B. Chem. Biol. 2002, 9, 925. (b) Ma, D.; Lin, Y.; Xiao, Z.; Kappen, L.; Goldberg, I. H.; Kallmerten, A. E.; Jones, G. B. Bioorg. Med.Chem. 2009, 17, 2428.

8. LaBeaume, P.; Wager, K.; Falcone, D.; Li, J.; Torchilin, V.; Castro, C.; Holewa, C.; Kallmerten, A. E.; Jones, G. B. Bioorg. Med. Chem. 2009, 17, 6292.

9. Bergman, J.; Delatte, M. S.; Paronis, C. A.; Vemuri, K.; Thakur, G. A.; Makriyannis, A. Physio. Behav. 2008, 93, 666-670.

10. (a) Chambers, R. D. Fluorine in Organic Chemistry, Blackwell, Oxford, 2005. (b) Ojima,T. Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell Inc.; Chichester, 2009.

11. Moon, B. S.; Lee, T. S.; Lee, K. C.; An, G. I.; Cheon, G. J.; Lim, S. M.; Choi, C. W.; Chi, d. Y.; Chun, D. S. Bioog. Med. Chem. Lett. 2007, 17, 200.Mukherjee, J; Head, E.; Pichika, R.; Easwaramoorthy, B.; Collins, D.; Chen, I.; Wang, C. S.; Saigal, N.; Trinidad, P.; Kim, D.; Nguyen, V. L. J. Label. Compd. Radiopharm. 2007, 50, 375.

12. LaBeaume, P.; Placzek, M.; Daniels, M.; Kendrick, I.; Ng, P.; McNeel, M.; Afroze, R.; Alexander, A.; Thomas, R.; Kallmerten, A. E.; Jones, G. B. Tetrahedron Lett. 2010, 51, 1906-1909.

Document Type

Dissertation

Rights Holder

Paul LaBeaume

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