Synthesis and Biological Evaluation of (-)-dictyostatin and Stereoisomers

Overview

Journal Tetrahedron

Specialty Chemistry

Date 2008 Aug 30

PMID 18728696

Citations 8

Authors

Youseung Shin

Jean-Hugues Fournier

Arndt Bruckner

Charitha Madiraju

Raghavan Balachandran

Brianne S Raccor

Michael C Edler

Ernest Hamel

Rachel P Sikorski

Andreas Vogt

Billy W Day

Dennis P Curran

Affiliations

Soon will be listed here.

Abstract

Total syntheses of (-)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin and a number of other isomers and analogs are reported. Three main fragments-top, middle and bottom-were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (-)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20- to >1000-fold decreases in activity.

Citing Articles

A "methyl extension" strategy for polyketide natural product linker site validation and its application to dictyostatin.

Ho S, Sackett D, Leighton J J Am Chem Soc. 2015; 137(44):14047-50.

PMID: 26522184 PMC: 4811196. DOI: 10.1021/jacs.5b09869.

Conformation-activity relationships of polyketide natural products.

Larsen E, Wilson M, Taylor R Nat Prod Rep. 2015; 32(8):1183-206.

PMID: 25974024 PMC: 4443481. DOI: 10.1039/c5np00014a.

A highly step-economical synthesis of dictyostatin.

Ho S, Bucher C, Leighton J Angew Chem Int Ed Engl. 2013; 52(26):6757-61.

PMID: 23666786 PMC: 3812691. DOI: 10.1002/anie.201302565.

Natural products from the Lithistida: a review of the literature since 2000.

Winder P, Pomponi S, Wright A Mar Drugs. 2012; 9(12):2643-2682.

PMID: 22363244 PMC: 3280575. DOI: 10.3390/md9122643.

(+)-Sorangicin A: evolution of a viable synthetic strategy.

Smith 3rd A, Dong S, Fox R, Brenneman J, Vanecko J, Maegawa T Tetrahedron. 2012; 67(51):9809-9828.

PMID: 22247573 PMC: 3254116. DOI: 10.1016/j.tet.2011.09.035.

References

Kar S, Fan J, Smith M, Goedert M, Amos L . Repeat motifs of tau bind to the insides of microtubules in the absence of taxol. EMBO J. 2002; 22(1):70-7. PMC: 140040. DOI: 10.1093/emboj/cdg001. View

Verdier-Pinard P, Wang Z, MohanaKrishnan A, Cushman M, Hamel E . A steroid derivative with paclitaxel-like effects on tubulin polymerization. Mol Pharmacol. 2000; 57(3):568-75. DOI: 10.1124/mol.57.3.568. View

Prusov E, Rohm H, Maier M . Chemoenzymatic synthesis of the C10-C23 segment of dictyostatin. Org Lett. 2006; 8(6):1025-8. DOI: 10.1021/ol052917e. View

Isbrucker R, Cummins J, Pomponi S, Longley R, Wright A . Tubulin polymerizing activity of dictyostatin-1, a polyketide of marine sponge origin. Biochem Pharmacol. 2003; 66(1):75-82. DOI: 10.1016/s0006-2952(03)00192-8. View

Choy N, Shin Y, Nguyen P, Curran D, Balachandran R, Madiraju C . Simplified discodermolide analogues: synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem. 2003; 46(14):2846-64. DOI: 10.1021/jm0204136. View

Madiraju C, Edler M, Hamel E, Raccor B, Balachandran R, Zhu G . Tubulin assembly, taxoid site binding, and cellular effects of the microtubule-stabilizing agent dictyostatin. Biochemistry. 2005; 44(45):15053-63. DOI: 10.1021/bi050685l. View

Ramachandran P, Srivastava A, Hazra D . Total synthesis of potential antitumor agent, (-)-dictyostatin. Org Lett. 2006; 9(1):157-60. DOI: 10.1021/ol062737k. View

Evans D, Tedrow J, Shaw J, Downey C . Diastereoselective magnesium halide-catalyzed anti-aldol reactions of chiral N-acyloxazolidinones. J Am Chem Soc. 2002; 124(3):392-3. DOI: 10.1021/ja0119548. View

Hamel E, Sackett D, Vourloumis D, Nicolaou K . The coral-derived natural products eleutherobin and sarcodictyins A and B: effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry. 1999; 38(17):5490-8. DOI: 10.1021/bi983023n. View

10.

Kowalski R, Giannakakou P, Gunasekera S, Longley R, Day B, Hamel E . The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells. Mol Pharmacol. 1997; 52(4):613-22. View

11.

Buey R, Barasoain I, Jackson E, Meyer A, Giannakakou P, Paterson I . Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity. Chem Biol. 2005; 12(12):1269-79. DOI: 10.1016/j.chembiol.2005.09.010. View

12.

Vong B, Abraham S, Xiang A, Theodorakis E . Synthetic studies on borrelidin: enantioselective synthesis of the C1-C12 fragment. Org Lett. 2003; 5(10):1617-20. DOI: 10.1021/ol034243i. View

13.

Nettles J, Li H, Cornett B, Krahn J, Snyder J, Downing K . The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography. Science. 2004; 305(5685):866-9. DOI: 10.1126/science.1099190. View

14.

Shin Y, Fournier J, Fukui Y, Bruckner A, Curran D . Total synthesis of (-)-dictyostatin: confirmation of relative and absolute configurations. Angew Chem Int Ed Engl. 2004; 43(35):4634-7. DOI: 10.1002/anie.200460593. View

15.

Lee K, Kim Y, Oh C, Ham W . Facile and efficient total synthesis of (+)-preussin. Org Lett. 2000; 2(25):4041-2. DOI: 10.1021/ol000289p. View

16.

Fukui Y, Bruckner A, Shin Y, Balachandran R, Day B, Curran D . Fluorous mixture synthesis of (-)-dictyostatin and three stereoisomers. Org Lett. 2006; 8(2):301-4. DOI: 10.1021/ol0526827. View

17.

Paterson I, Anderson E . Chemistry. The renaissance of natural products as drug candidates. Science. 2005; 310(5747):451-3. DOI: 10.1126/science.1116364. View

18.

Vanderwal C, Vosburg D, Sorensen E . Intramolecular allenolate acylations in studies toward a synthesis of FR182877. Org Lett. 2002; 3(26):4307-10. DOI: 10.1021/ol016994v. View

19.

Lowe J, Li H, Downing K, Nogales E . Refined structure of alpha beta-tubulin at 3.5 A resolution. J Mol Biol. 2001; 313(5):1045-57. DOI: 10.1006/jmbi.2001.5077. View

20.

ONeil G, Phillips A . Total synthesis of (-)-dictyostatin. J Am Chem Soc. 2006; 128(16):5340-1. DOI: 10.1021/ja0609708. View