dc.contributor.advisor | Buszek, Keith R. | eng |
dc.contributor.author | Maina, Lincoln Wamae | eng |
dc.date.issued | 2014 | eng |
dc.date.submitted | 2014 Fall | eng |
dc.description | Title from title page, viewed on June 4, 2015 | eng |
dc.description | Dissertation advisor: Keith R. Buszek | eng |
dc.description | Vita | eng |
dc.description | Includes bibliographic references (pages 186-201) | eng |
dc.description | Thesis (Ph.D.)--Department of Chemistry and School of Pharmacy. University of Missouri--Kansas City, 2014 | eng |
dc.description.abstract | Dissertation under the direction of Keith R. Buszek, Ph.D., Professor of Chemistry,
University of Missouri-Kansas City.
Heterocyclic chemistry is one of the most valuable sources of novel compounds with
diverse biological activity. The indole nucleus for instance, is an important element of many
natural and synthetic molecules with significant biological activity. Drug discovery and
development processes highly value the utility of the ability to synthesize a diverse library
based on one core scaffold which can be screened against a variety of different receptors and
cell lines, yielding several active compounds. Privileged structures offer an ideal source of
lead compounds for drug discovery due to their inherent affinity for diverse biological
targets. Indole motifs represent one of the most prominent privileged structures and are
ubiquitous in natural products and pharmaceutical compounds. A variety of fused
heterocyclic structures will be designed, resulting in novel polycyclic frameworks with
virtually no representation in the National Institutes of Health PubChem and Molecular
Library of Small Molecule Repository (MLSMR) databases.
These molecular frameworks would be predicted to occupy unoccupied or sparsely
occupied regions of the chemical property space, which increase their chances of finding
applications as new drug leads with different modes of actions. Consequently, efficient
methodologies resulting in polycyclic structures from biologically active heterocyclic
templates are highly desired in the drug discovery and development programs. The synthesis
of such a unique class of polycyclic benzannulated indole scaffolds is described.
The 4,6,7-tribromoindole and the 5,6,7-tribromoindole were synthesized via the
Bartoli and Leimgruber-Batcho and indole synthesis protocols respectively. Both indoles
underwent selective metal-halogen exchange at C-7 and subsequent elimination to give the
6,7-indole aryne which underwent Diels-Alder cycloadditions with cyclopentadiene, furan
and 2,5-dimethyl furan. These cycloadducts were N-alkylated and then subjected to Grubb’s
catalyst ring opening metathesis/ring closing metathesis to afford 12 unique 6,7-
benzannulated with an additional 7 or 8–membered rings fused from the benzenoid ring to
the pyrrole ring of the indole nucleus.
Library development is facilitated by the extra bromine at the 4 or 5 position of the
indole nucleus which serves as a diversity handle which can be subjected to several
palladium catalyzed cross-couplings including but not limited to Suzuki-Miyaura, Negishi
and Buchwald-Hartwig. Diversity of these scaffolds can be further enhanced via olefin
functionalization: cross metathesis, hydroamination and epoxidation among others to afford
pharmaceutically useful functional groups like carbamates, ureas, secondary and tertiary
amines as well as sulfonamides. | eng |
dc.description.tableofcontents | Introduction -- Therapeutics inspired by natural products -- Benzannulated indole alkaloid natural products discovery, isolation and synthesis -- Biological studies and results of a benzannulated indole scaffolds libraries -- Design and synthesis of novel 4-, 5-, 6,7 benzannulated tribromo scaffolds for cross-coupled libraries -- Experimental section -- Conclusions | eng |
dc.format.extent | xviii, 203 pages | eng |
dc.identifier.uri | https://hdl.handle.net/10355/45581 | eng |
dc.subject.lcsh | Indole | eng |
dc.subject.lcsh | Drug development | eng |
dc.subject.other | Dissertation -- University of Missouri--Kansas City -- Chemistry | eng |
dc.subject.other | Dissertation -- University of Missouri--Kansas City -- Pharmacy | eng |
dc.title | Novel Polycyclic Benzannulated Indole Scaffolds via Indole
Aryne Cycloaddition, Pd (0)-Catalyzed Cross-coupling and ROM/RCM methodologies: Their Applications
to Library Development and Drug Discovery | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Chemistry (UMKC) | eng |
thesis.degree.discipline | Pharmacy (UMKC) | eng |
thesis.degree.grantor | University of Missouri--Kansas City | eng |
thesis.degree.level | Doctoral | eng |
thesis.degree.name | Ph.D. | eng |