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. 2010 Jan 13;132(1):371-83.
doi: 10.1021/ja908626k.

Chemical and biological studies of nakiterpiosin and nakiterpiosinone

Shuanhu Gao  1 , Qiaoling Wang, Lily Jun-Shen Huang, Lawrence Lum, Chuo Chen
Affiliations

Chemical and biological studies of nakiterpiosin and nakiterpiosinone

Shuanhu Gao et al. J Am Chem Soc. .

Abstract

Nakiterpiosin and nakiterpiosinone are two related C-nor-D-homosteroids isolated from the sponge Terpios hoshinota that show promise as anticancer agents. We have previously described the asymmetric synthesis and revision of the relative configuration of nakiterpiosin. We now provide detailed information on the stereochemical analysis that supports our structure revision and the synthesis of the originally proposed and revised nakiterpiosin. In addition, we herein describe a refined approach for the synthesis of nakiterpiosin, the first synthesis of nakiterpiosinone, and preliminary mechanistic studies of nakiterpiosin's action in mammalian cells. Cells treated with nakiterpiosin exhibit compromised formation of the primary cilium, an organelle that functions as an assembly point for components of the Hedgehog signal transduction pathway. We provide evidence that the biological effects exhibited by nakiterpiosin are mechanistically distinct from those of well-established antimitotic agents such as taxol. Nakiterpiosin may be useful as an anticancer agent in those tumors resistant to existing antimitotic agents and those dependent on Hedgehog pathway responses for growth.

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Figures

Figure 1
Figure 1
The structures of C-nor-D-homosteroids 1–6.
Figure 2
Figure 2
Probing the C-20/C-22/C-23 configurations of nakiterpiosin and nakiterpiosinone.
Figure 3
Figure 3
Probing the C-25 configurations of nakiterpiosin and nakiterpiosinone.
Figure 4
Figure 4
Biogenetic analysis of nakiterpiosin.
Figure 5
Figure 5
The retrosynthetic analysis of nakiterpiosin.
Scheme 1
Scheme 1
Synthesis of the electrophilic coupling component 30.
Scheme 2
Scheme 2
Synthesis of the nucleophilic coupling component 47.
Scheme 3
Scheme 3
Model studies for the carbonylative coupling/Nazarov cyclization strategy.
Scheme 4
Scheme 4
Completion of the synthesis of nakiterpiosin (1).
Scheme 5
Scheme 5
An improved synthesis of nakiterpiosin (1).
Scheme 6
Scheme 6
Synthesis of 64 (6-epi-30).
Scheme 7
Scheme 7
Synthesis of the 6,20,25-epi-nakiterpiosin (3).
Figure 6
Figure 6
Difference in the chemical shifts of the 1H NMR spectra of 1, 3 and the natural product.
Figure 7
Figure 7
Difference in the chemical shifts of the 13C NMR spectra of 1, 3 and the natural product.
Scheme 8
Scheme 8
Rearrangement of the [2.2.1] bicyclic system.
Scheme 9
Scheme 9
Synthesis of nakiterpiosinone (2).
Figure 8
Figure 8
Effects of nakiterpiosin on Hh signaling and primary cilia. (A) The Hh pathway response of Light2 cells (NIH3T3 cells with a Hh-specific firefly luciferase reporter) in the presence of nakiterpiosin. (B) NIH3T3 cells treated with nakiterpiosin showing a compromised ability to form primary cilia, as detected by anti-acetylated tubulin antibody.
Figure 9
Figure 9
The DNA profiles of nakiterpiosin treated HeLa cells.
Figure 10
Figure 10
The in vitro tubulin polymerization assays.
See this image and copyright information in PMC

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