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Page history last edited by PBworks 12 years, 6 months ago
Pladienolide B:

In 2004, researchers from Tsukuba Research Laboratories and Bioresource Laboratories reported the discovery of seven compounds isolated from the bacteria Streptomyces platensis (1).  These seven compounds, which have been termed pladienolides, were discovered while screening for inhibitors of the vascular endothelial growth factor (VEGF) promoter.  The VEGF promoter induces gene expression in hypoxic environments.  Because many human tumors proliferate under hypoxic conditions, many anti-tumor drugs target VEGF-controlled gene expression.  Of the seven pladienolides discovered in this study, six inhibited expression of a reporter gene controlled by human VEGF promoter.  These six compounds also inhibited proliferation of U251 human glioma cells in vitro.  The most potent of these six compounds, Pladienolide B, inhibited VEGF-promoted gene expression with an IC50 of 1.8 nM, and inhibited glioma cell proliferation with an IC50 of 3.5 nM.  The structure of Pladienolide B was elucidated in a subsequent publication.

 Pladienolide B


The structure of Pladienolide B was elucidated utilizing proton and Carbon-13 NMR, mass spectrometry, IR spectroscopy, and two-dimensional NMR studies including HMQC, HMBC, and NOESY spectra (2).  The seven pladienolide derivatives discovered all contain the twelve-membered lactone ring and a linear twelve carbon chain containing an epoxide funcitonality.  The pladienolides are polyketide compounds, and the biosynthesis of these compounds are therefore highly analogous to the biosynthsis of fatty acids.  Starting with propionyl-CoA, successive condensation reactions with malonyl-Coa or methyl-malonyl-CoA allow for the assembly of the polyketide chain two carbons at a time.  These chain-extending condensation reactions are performed by groups of enzymes referred to as modules.  These modules also include active sites that reduce the ketone group formed by the previous module.  Ketoreductase (KR), Dehydratase (DH), and Enoyl Reductase (ER) domains reduce the ketone to a hydroxyl, enoyl, or saturated hydrocarbon, respectively.  At the end of the polyketide chain extension, a thioesterase domain catayzes the cyclization of the twelve membered ring, creating an ester linkage.  After synthsis of the polyketide precursor is complete, three more modifications are necessary.  Namely, an epoxidation, an acetylation, and a hydroxylation event must take place before the final compound is synthesized.  The biosynthetic pathway of pladienolides was outlined in a patent (3).  A schematic diagram of the modular Pladienolide synthase is shown below (3).



Recently, two research groups have worked towards the total synthesis of Pladienolide B in order to elucidate the stereochemistry of the various functional groups and to investigate the possiblity of synthesis in the pharmaceutical industry.  In early 2007, Kotake et al. reported the total syntheses of Pladienolides B and D (4).  They were able to confirm the absolute stereochemistry by comparison of their synthetic product with the compound isolated from bacterial cultures.

Stereochemical Configuration of Pladienolides.  In Pladienolide B, R=H and R'=Ac   



The authors of this study utilized a strategy where all of their stereogenic centers are included in the initial precursor reagents.  This strategy is advantageous because it is easier to change the stereocenters in the initial reagents than it is to change stereocenters on larger, more complex structures.  The retrosynthetic strategy used by Kotake and coworkers is outlined below.





1)Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu.  Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107.

   I. Taxonomy, Fermentation, Isolation and Screening.  The Journal of Antibiotics.  Vol. 57, No.3.  (2004).

2)Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu.  Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107.

   II. Physico-chemical Properties and Structure Elucidation.  The Journal of Antibiotics.  Vol. 57, No.3.  (2004).

3)Machida,Kazihiro; Arisawa,Akira; Yoshida,Masahi; Tsuchida,Toshio; Takeda,Susumu.  DNA Coding for Polypeptide Participating in Biosynthsis of Pladienolide.  Canadian Intellectual Property Office CA2574092.

4)Kanada, R.M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui, Y.; Abe, S.; Kotake, Y.  Total Synthesis of the Potent Antitumor Macrolides Pladienolide B and D.  Angewandte Chemie International Edition, 46, (2007).












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