OSW-1, a Naturally Occurring Antiproliferative Steroidal Saponin

          OSW-1, a cholestane glycoside isolated from the bulbs of the garden plant, Ornithogalum saudersiae, exhibits potent in vitro cytotoxicity against several malignant tumor cell lines. For example, the IC₅₀ against human leukemia (HL-60) cells ranges from 0.1-0.3 nM. However, the mode of action (more on this in a subsequent post: stay tuned) that elicits this very promising anticancer activity is poorly understood. It has been noted that the cytotoxicity pattern of OSW-1 against the NCI-60, a collection of human cancer cell lines, resembles that of ritterazine B, a complex antiproliferative dimeric steroid. This suggests that the two steroid derivatives share a similar mechanism. In an effort to elucidate the precise cellular target and MOA of OSW-1, organic chemists have developed efficient strategies to synthesize the complex steroidal saponin, recently on multigram scale. A selection of this research effort is highlighted below.

          The structure of OSW-1 suggests a logical retrosynthetic disconnection into two hemispheres, the cholestane aglycone and the beta-disaccharide moiety. The synthesis of the disaccharide from L-arabinose and D-xylose, is relatively straight-forward, involving Schmidt glycosylation methodology to control stereochemistry at the anomeric positions. We will focus instead on expedient methods to assemble the aglycone portion from commercially available steroids.

          The first synthesis of OSW-1 was completed in 1999 by the laboratory of Biao Yu at the Shanghai Institute of Organic Chemistry. Yu’s method generates the steroidal aglycone in 12 synthetic operations from dehydroisoandrosterone. Zhongwu Guo's group has recently (JOC 2008) adapted and optimized Yu’s route in the disclosure of a 10 step synthesis of OSW-1 (6.4% overall yield) that has generated gram quantities of the precious lead compound for the development of novel anti-tumor drugs. According to the Guo protocol, the side chain is introduced to C17 of dehydroisoandrosterone in a modified fashion. An initial aldol condensation of the 17-oxo steroid functionality with propanenitrile delivers an excellent yield of epimeric beta-hydroxy (C20-) nitrile products that are conveniently isolated by recrystallization. The side chain is then elongated by addition of a Grignard reagent to the C20 nitrile, and this procedure is accompanied by elimination of water and isomerization of the resultant olefin to the endocyclic (delta^16,17) D-ring position. Silylation of the C3 beta-hydroxyl followed by protection of the C22 carbonyl as the cyclic ketal then secures Yu’s advanced intermediate in only four scalable operations. Finally, regio- and stereoselective dihydroxylation of the D-ring double bond with stoichiometric osmium tetroxide followed by inversion of C16 stereochemistry provides the OSW-1 aglycone that was successfully advanced by Yu and Guo to the natural product OSW-1.

          Zhendong Jin’s group at the University of Iowa has described, arguably, the most innovative and efficient preparation of OSW-1. The route proceeds in ten linear synthetic steps with 28% overall yield. An inventive initial transformation developed by Jin and co-workers is a regio- and stereoselective SeO₂-mediated allylic oxidation that provides access to a key enone intermediate. Jin's olefination/allylic oxidation protocol offers a facile entry into C16-oxygenated steroid systems and may be of broad utility to the synthetic community.  In a subsequent operation, a stereoselective 1,4-addition of an alpha-alkoxy vinyl cuprate (acyl anion equivalent) to the aforementioned enone incorporates the cholestane side chain with outstanding control of C20 stereochemistry. Enolate oxidation with Davis’ reagent then affords an alpa-hydroxy C16 ketone that is stereospecifically reduced from the alpha-face due to the directing effect of the C17 hydroxyl group. The synthetic technologies described Jin and the other outstanding organic chemists mentioned above will facilitate the semisynthetic construction of designed non-naturally occurring analogues of OSW-1 that may eventually inspire the invention of novel, effective and relatively nontoxic anticancer agents.