My thesis includes the development of two novel anticancer agents based on natural products; OSW-1 analog (ZJ-201) and truncated Superstolide A analog (ZJ-102).
OSW-1 is isolated from the bulbs of Ornithogalum saundersiae. It exhibits an extremely potent anticancer activity against a wide spectrum of cancer cells. Relatively, its anticancer activities are about 10-100 times more potent than many well-known anticancer drugs in clinical use. However, the promise of OSW-1 is dampened by its relatively weak in vivo anticancer activity. We hypothesize that the loss of two ester groups on OSW-1 in mouse causes a discrepancy in its in vivo efficacy. Therefore, replacing both ester groups in the disaccharide portion of OSW-1 with bioisosteric amides should significantly reduce the rate of metabolism and greatly improve its in vivo anticancer activity. This dissertation includes the synthesis of amide analog of OSW-1, ZJ-201. The synthetic route described in this thesis is characterized by its flexibility to synthesize multiple amino analogs of OSW-1. ZJ-201 will be evaluated for its in vitro cytotoxicity, metabolic stability and pharmacokinetic properties. The biological data obtained will enable us to get insights into the SAR of OSW-1 and assist in transforming OSW-1 into a clinically agent.
Superstolide A is a highly potent anticancer agent isolated from marine sponge Neosiphonia superstes. In 2013, Jin’s lab reported the design and synthesis of truncated Superstolide A (ZJ-101) in 15 steps with a yield of 6.2%. In vitro cytotoxicity studies showed that ZJ-101 maintains and sometimes exceeds the potent anticancer activity of the parent natural product. As this is the first active analog of Superstolide A reported, there is a need to develop additional analogs of ZJ-101 to probe into the SAR of this anticancer agent. This dissertation includes the synthesis of aromatic analog of truncated Superstolide A, ZJ-102. In vitro cytotoxicity studies showed that ZJ-201 demonstrated poor antiproliferative properties in comparison to ZJ-101. Hence, we can conclude that the cyclohexene ring of ZJ-101 cannot be simplified to an aromatic core as it significantly affects anticancer activity.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7474 |
| Date | 15 December 2015 |
| Creators | Shah, Aashay Kirit |
| Contributors | Jin, Zhendong |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2015 Aashay Kirit Shah |
Page generated in 0.0015 seconds