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Enantioselective total syntheses of FR901464 and spliceostatin A and evaluation of splicing activity of key derivatives.

Ghosh AK, Chen ZH, Effenberger KA, Jurica MS - J. Org. Chem. (2014)

Bottom Line: To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps.These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner.Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 4790, United States.

ABSTRACT
FR901464 (1) and spliceostatin A (2) are potent inhibitors of spliceosomes. These compounds have shown remarkable anticancer activity against multiple human cancer cell lines. Herein, we describe efficient, enantioselective syntheses of FR901464, spliceostatin A, six corresponding diastereomers and an evaluation of their splicing activity. Syntheses of spliceostatin A and FR901464 were carried out in the longest linear sequence of 9 and 10 steps, respectively. To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps. The remarkable diastereoselectivity of the Michael addition was specifically demonstrated with different substrates under various reaction conditions. The side chain B was prepared from an optically active alcohol, followed by acetylation and hydrogenation over Lindlar's catalyst. The other densely functionalized tetrahydropyran C-ring was derived from readily available (R)-isopropylidene glyceraldehyde through a route featuring 1,2-addition, cyclic ketalization, and regioselective epoxidation. These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner. Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

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Structures of FR901464, spliceostatin A, and pladienolideB.
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fig1: Structures of FR901464, spliceostatin A, and pladienolideB.

Mentions: FR901464 (1) was isolated from a fermentation brothof the bacterium Pseudomonas sp. No. 2663 by FujisawaPharmaceutical Co. in 1996 (Figure 1).1 It exhibited potent anticancer activity. It showedenhancement of activity of a promoter of the SV40 DNA tumor virusat 10 nM concentration in M-8 cells. It also displayed dominant cytotoxicityagainst multiple human cancer cell lines with IC50 valuesranging from 0.6 to 3.4 nM in vitro and exhibited a prominent effectat 0.056–1 mg/kg dosage against human solid tumors implantedin mice.1b Yoshida and co-workers alsoreported that spliceostatin A (2) displayed remarkableantitumor activity similar to FR901464.2 Spliceostatin A is a methoxy derivative of FR901464 at the C1 positionand shows better chemical stability than FR901464. Most importantly,both FR901464 and spliceostatin A exhibited a novel mechanism of actionby inhibiting in vitro splicing and promoting pre-mRNA accumulationby binding to SF3b, a protein in the spliceosome.2b To date, FR901464 and the structurally distinct pladienolideB (3),3,4 which has entered human clinicaltrials for cancer,5 are the only knownmolecular scaffolds capable of modulating splicing and generatingan antitumor response.


Enantioselective total syntheses of FR901464 and spliceostatin A and evaluation of splicing activity of key derivatives.

Ghosh AK, Chen ZH, Effenberger KA, Jurica MS - J. Org. Chem. (2014)

Structures of FR901464, spliceostatin A, and pladienolideB.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4066912&req=5

fig1: Structures of FR901464, spliceostatin A, and pladienolideB.
Mentions: FR901464 (1) was isolated from a fermentation brothof the bacterium Pseudomonas sp. No. 2663 by FujisawaPharmaceutical Co. in 1996 (Figure 1).1 It exhibited potent anticancer activity. It showedenhancement of activity of a promoter of the SV40 DNA tumor virusat 10 nM concentration in M-8 cells. It also displayed dominant cytotoxicityagainst multiple human cancer cell lines with IC50 valuesranging from 0.6 to 3.4 nM in vitro and exhibited a prominent effectat 0.056–1 mg/kg dosage against human solid tumors implantedin mice.1b Yoshida and co-workers alsoreported that spliceostatin A (2) displayed remarkableantitumor activity similar to FR901464.2 Spliceostatin A is a methoxy derivative of FR901464 at the C1 positionand shows better chemical stability than FR901464. Most importantly,both FR901464 and spliceostatin A exhibited a novel mechanism of actionby inhibiting in vitro splicing and promoting pre-mRNA accumulationby binding to SF3b, a protein in the spliceosome.2b To date, FR901464 and the structurally distinct pladienolideB (3),3,4 which has entered human clinicaltrials for cancer,5 are the only knownmolecular scaffolds capable of modulating splicing and generatingan antitumor response.

Bottom Line: To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps.These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner.Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 4790, United States.

ABSTRACT
FR901464 (1) and spliceostatin A (2) are potent inhibitors of spliceosomes. These compounds have shown remarkable anticancer activity against multiple human cancer cell lines. Herein, we describe efficient, enantioselective syntheses of FR901464, spliceostatin A, six corresponding diastereomers and an evaluation of their splicing activity. Syntheses of spliceostatin A and FR901464 were carried out in the longest linear sequence of 9 and 10 steps, respectively. To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps. The remarkable diastereoselectivity of the Michael addition was specifically demonstrated with different substrates under various reaction conditions. The side chain B was prepared from an optically active alcohol, followed by acetylation and hydrogenation over Lindlar's catalyst. The other densely functionalized tetrahydropyran C-ring was derived from readily available (R)-isopropylidene glyceraldehyde through a route featuring 1,2-addition, cyclic ketalization, and regioselective epoxidation. These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner. Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

Show MeSH
Related in: MedlinePlus