Syntheses of natural products OSW-1, superstolide A and their derivatives

Abstract

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 different from other well-known anticancer agents. However, its mechanism still remains 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 toxicological 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, simplified analogs and amino analogue were synthesized for the SAR study. 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. This dissertation includes a model study for the construction of the 16-membered macrolactone present in Superstolide A. More specially, there is a focus on the investigation of three crucial carbon-carbon bond-forming reactions in our synthetic strategy including Julia olefination, Suzuki coupling and Horner-Emmons olefination.

Development of novel anticancer agents based on natural products

“…(1.71) containing a simplified steroidal aglycone had a similar cytotoxicity profile as compared to OSW-1 (1.1). 34 However, the deprotection of the C-2'' phthaloyl group was far tougher than it was anticipated. Jin's lab was able to obtain the amine 2.18 on using harsh conditions with very low yields.…”

“…43 Scheme The synthesis of the steroidal aglycone was adapted from Jin's total synthesis of OSW-1. [11][12][13]34 (Figure 3.1). [64][65][66] D' Auria and Zampella reported that they were successfully able to isolate 31.2 mg of Superstolide A and 3.0 mg of Superstolide B as colorless amorphous solids from 1.0 kg of the marine sponge.…”

“…i 1 st generation of OSW-1 analogs by Jin's groupIn this series of compounds, Jin designed and synthesized OSW-1 analogs by modifying both, the sugar and the side chain of OSW-1(Figure 1.7). Compounds 1.30, 1.66 and 1.67 are monosaccharide analogs while compound 1.68 has a modified side chain and compound 1.69 is a 5,6-dihydro analog of OSW-1 with the ratio of 3:1 trans:cis fused AB rings 34. …”

“…st Generation of OSW-1 analogs by Jin's group1.4.5.ii 2 nd Generation of OSW-1 analogs by Jin's groupAfter completing the 1 st generation of OSW-1 analogs, Jin designed two 2 nd generation analogs of OSW-1. These analogs as shown inFigure 1.8,are the 17-deoxy and the 17-deoxy-22-deketo analogs of OSW-1.These analogs were evaluated for their in vitro activities against a panel of malignant cell lines 34. …”

“…Studies performed by Dr. Mei in Jin's lab has explored various synthetic routes to obtain the target ZJ-201 (2.1) 34. His findings are summarized below.Previous total synthesis of OSW-1 typically employed a synthetic strategy where a disaccharide donor was glycosylated to the steroidal aglycone to obtain an OSW-1 precursor 3,6,[10][11][12][13]15,16,28,30.…”