Golgi-modifying Properties of Macfarlandin E and the Synthesis and Evaluation of Its 2,7-dioxabicyclo[3.2.1]octan-3-one Core

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Mar 25

PMID 20332207

Citations 12

Authors

Martin J Schnermann

Christopher M Beaudry

Anastasia V Egorova

Roman S Polishchuk

Christine Sutterlin

Larry E Overman

Affiliations

Soon will be listed here.

Abstract

Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1]octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.

Citing Articles

Bioactive Compounds from Marine Heterobranchs.

Avila C, Angulo-Preckler C Mar Drugs. 2020; 18(12).

PMID: 33371188 PMC: 7767343. DOI: 10.3390/md18120657.

Bridging the gap between natural product synthesis and drug discovery.

Truax N, Romo D Nat Prod Rep. 2020; 37(11):1436-1453.

PMID: 33104139 PMC: 7718793. DOI: 10.1039/d0np00048e.

Transition Metal-Mediated C-C Single Bond Cleavage: Making the Cut in Total Synthesis.

Wang B, Perea M, Sarpong R Angew Chem Int Ed Engl. 2020; 59(43):18898-18919.

PMID: 31984640 PMC: 7772057. DOI: 10.1002/anie.201915657.

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave-Substituted cis-Dioxabicyclo[3.3.0]octanone Fragment.

Allred T, Dieskau A, Zhao P, Lackner G, Overman L Angew Chem Int Ed Engl. 2020; 59(15):6268-6272.

PMID: 31965671 PMC: 8697475. DOI: 10.1002/anie.201916753.

Total synthesis of complex terpenoids employing radical cascade processes.

Hung K, Hu X, Maimone T Nat Prod Rep. 2018; 35(2):174-202.

PMID: 29417970 PMC: 5858714. DOI: 10.1039/c7np00065k.

References

Roberts S, Rainier J . Synthesis of an A-E gambieric acid subunit with use of a C-glycoside centered strategy. Org Lett. 2007; 9(11):2227-30. DOI: 10.1021/ol0707970. View

Takizawa P, Yucel J, Veit B, Faulkner D, Deerinck T, Soto G . Complete vesiculation of Golgi membranes and inhibition of protein transport by a novel sea sponge metabolite, ilimaquinone. Cell. 1993; 73(6):1079-90. DOI: 10.1016/0092-8674(93)90638-7. View

Jamora C, Yamanouye N, Van Lint J, Laudenslager J, Vandenheede J, Faulkner D . Gbetagamma-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell. 1999; 98(1):59-68. DOI: 10.1016/S0092-8674(00)80606-6. View

Keyzers R, Northcote P, Davies-Coleman M . Spongian diterpenoids from marine sponges. Nat Prod Rep. 2006; 23(2):321-34. DOI: 10.1039/b503531g. View

Brady T, Wallace E, Kim S, Guizzunti G, Malhotra V, Theodorakis E . Fragmentation of Golgi membranes by norrisolide and designed analogues. Bioorg Med Chem Lett. 2004; 14(20):5035-9. DOI: 10.1016/j.bmcl.2004.08.003. View

Yadav S, Puri S, Linstedt A . A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing. Mol Biol Cell. 2009; 20(6):1728-36. PMC: 2655245. DOI: 10.1091/mbc.e08-10-1077. View

de Figueiredo P, Polizotto R, Drecktrah D, Brown W . Membrane tubule-mediated reassembly and maintenance of the Golgi complex is disrupted by phospholipase A2 antagonists. Mol Biol Cell. 1999; 10(6):1763-82. PMC: 25369. DOI: 10.1091/mbc.10.6.1763. View

DeCaprio A, Jackowski S, Regan K . Mechanism of formation and quantitation of imines, pyrroles, and stable nonpyrrole adducts in 2,5-hexanedione-treated protein. Mol Pharmacol. 1987; 32(4):542-8. View

Lebsack A, Overman L, Valentekovich R . Enantioselective total synthesis of shahamin K. J Am Chem Soc. 2001; 123(20):4851-2. DOI: 10.1021/ja015802o. View

10.

Pelish H, Westwood N, Feng Y, Kirchhausen T, Shair M . Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product. J Am Chem Soc. 2001; 123(27):6740-1. DOI: 10.1021/ja016093h. View

11.

Cole N, Sciaky N, Marotta A, Song J, Lippincott-Schwartz J . Golgi dispersal during microtubule disruption: regeneration of Golgi stacks at peripheral endoplasmic reticulum exit sites. Mol Biol Cell. 1996; 7(4):631-50. PMC: 275914. DOI: 10.1091/mbc.7.4.631. View

12.

Donaldson J, Finazzi D, Klausner R . Brefeldin A inhibits Golgi membrane-catalysed exchange of guanine nucleotide onto ARF protein. Nature. 1992; 360(6402):350-2. DOI: 10.1038/360350a0. View

13.

Renault L, Guibert B, Cherfils J . Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature. 2003; 426(6966):525-30. DOI: 10.1038/nature02197. View

14.

Pelish H, Peterson J, Salvarezza S, Rodriguez-Boulan E, Chen J, Stamnes M . Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro. Nat Chem Biol. 2006; 2(1):39-46. DOI: 10.1038/nchembio751. View

15.

Brady T, Kim S, Wen K, Theodorakis E . Stereoselective total synthesis of (+)-norrisolide. Angew Chem Int Ed Engl. 2004; 43(6):739-42. DOI: 10.1002/anie.200352868. View

16.

Jamora C, Takizawa P, Zaarour R, Denesvre C, Faulkner D, Malhotra V . Regulation of Golgi structure through heterotrimeric G proteins. Cell. 1997; 91(5):617-26. DOI: 10.1016/s0092-8674(00)80449-3. View

17.

Klausner R, Donaldson J, Lippincott-Schwartz J . Brefeldin A: insights into the control of membrane traffic and organelle structure. J Cell Biol. 1992; 116(5):1071-80. PMC: 2289364. DOI: 10.1083/jcb.116.5.1071. View

18.

Hirschberg K, Miller C, Ellenberg J, Presley J, Siggia E, Phair R . Kinetic analysis of secretory protein traffic and characterization of golgi to plasma membrane transport intermediates in living cells. J Cell Biol. 1998; 143(6):1485-503. PMC: 2132993. DOI: 10.1083/jcb.143.6.1485. View

19.

Radeke H, Digits C, Casaubon R, Snapper M . Interactions of (-)-ilimaquinone with methylation enzymes: implications for vesicular-mediated secretion. Chem Biol. 1999; 6(9):639-47. DOI: 10.1016/s1074-5521(99)80115-x. View

20.

Hughes C, Miller A, Trauner D . An electrochemical approach to the guanacastepenes. Org Lett. 2005; 7(16):3425-8. DOI: 10.1021/ol047387l. View