OSW-1 is a natural saponin and its anticancer activities are 10- to 100-fold more potent than many well-known anticancer agents in clinical use. Its cytotoxicity profile suggests that it may have a unique mode of action that is different from other well-known anticancer agents. However, its mechanism still remains as a mystery after years of study, and no paper has ever been published in this area. Extensive in vitro and in vivo testing has been conducted and toxicology experiments have also been carried out by our collaborator Prof. Huang's laboratory at MD Anderson Cancer Center. In order to identify the pharmacophore and mechanism of OSW-1 and increase its in vivo activity and selectivity, amino analogues are synthesized for the SAR study employing the chemistry developed in our lab. Superstolide A (1) is a highly potent anti-tumor reagent that was isolated from deep water marine sponge in 1996. The potent anticancer activity, molecular complexity (11 chiral centers) and scarcity in natural resources make this molecule an attractive synthetic target. Currently I am working on the model study for the construction of the 16-membered macrolactone present in Superstolide A. Specifically I am focusing on the investigation of three crucial carbon-carbon bond-forming reactions in our synthetic strategy including Julia olefination, Suzuki coupling and Horner-Emmons olefination.

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.