The potential of human 20S proteasome inhibitors continues to be of interest for
anticancer chemotherapy and the recent FDA approval of bortezomib (Velcade)
validates the proteasome as a target for cancer chemotherapy. Salinosporamide A, a
marine unique bicycle [3.2.0] Beta-lactone-containing natural product, is not only a potent
nanomolar inhibitor of the human proteasome but also active against bortezomibresistant
multiple myeloma cells. The racemic and asymmetric syntheses of
salinosporamide A and derivatives were targeted.
In this dissertation, we successfully accomplished the shortest route to date with
only a 9-step total synthesis of (–)-salinosporamide A. The conciseness of this strategy
arises from the key bis-cyclization of a Beta-keto tertiary amide, amenable to gram scale,
constructs both the Gamma-lactam and the fused-Beta-lactone in one operation with high
enantiopurity, which was enabled by A^1,3-strain. Several derivatives were synthesized and their inhibition activity toward chymotripsin-like, caspase-like, and trypsin-like of
the human 20S proteasome was evaluated.
This dissertation also included a successfully optimized Organic Syntheses
procedure for asymmetric synthesis of (1S,5R)-6-oxaspiro[bicyclo[3.2.0]heptane-3,2'-
[1,3]dioxolan]-7-one via the nucleophile-catalyzed aldol-lactonization.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/148462 |
| Date | 14 March 2013 |
| Creators | Nguyen, Henry |
| Contributors | Romo, Daniel |
| Source Sets | Texas A and M University |
| Detected Language | English |
| Type | Thesis, text |
| Format | application/pdf |
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