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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Development of novel anticancer agents based on natural products

Shah, Aashay Kirit 15 December 2015 (has links)
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.

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