Stabilized Cyclopropane Analogs of the Splicing Inhibitor FD-895

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Aug 8

PMID 23919277

Citations 10

Authors

Reymundo Villa

Manoj Kumar Kashyap

Deepak Kumar

Thomas J Kipps

Januario E Castro

James J La Clair

Michael D Burkart

Affiliations

Soon will be listed here.

Abstract

Targeting the spliceosome with small molecule inhibitors provides a new avenue to target cancer by intercepting alternate splicing pathways. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. These findings have encouraged recent academic and industrial efforts to develop natural product spliceosome inhibitors, including FD-895 (1a), pladienolide B (1b), and pladienolide D (1c), into next-generation anticancer drugs. The present study describes the application of semisynthesis and total synthesis to reveal key structure-activity relationships for the spliceosome inhibition by 1a. This information is applied to deliver new analogs with improved stability and potent activity at inhibiting splicing in patient derived cell lines.

Citing Articles

Modulation of RNA splicing associated with Wnt signaling pathway using FD-895 and pladienolide B.

Kumar D, Kashyap M, Yu Z, Spaanderman I, Villa R, Kipps T Aging (Albany NY). 2022; 14(5):2081-2100.

PMID: 35230971 PMC: 8954975. DOI: 10.18632/aging.203924.

Role of RNA Splicing in Regulation of Cancer Stem Cell.

Tripathi G, Tripathi A, Johnson J, Kashyap M Curr Stem Cell Res Ther. 2021; 18(1):3-6.

PMID: 34875992 DOI: 10.2174/1574888X16666211207103628.

A Challenging Pie to Splice: Drugging the Spliceosome.

Leon B, Kashyap M, Chan W, Krug K, Castro J, La Clair J Angew Chem Int Ed Engl. 2017; 56(40):12052-12063.

PMID: 28371109 PMC: 6311392. DOI: 10.1002/anie.201701065.

Splicing factor gene mutations in hematologic malignancies.

Saez B, Walter M, Graubert T Blood. 2016; 129(10):1260-1269.

PMID: 27940478 PMC: 5345729. DOI: 10.1182/blood-2016-10-692400.

Modulating splicing with small molecular inhibitors of the spliceosome.

Effenberger K, Urabe V, Jurica M Wiley Interdiscip Rev RNA. 2016; 8(2).

PMID: 27440103 PMC: 5253128. DOI: 10.1002/wrna.1381.

References

Mizui Y, Sakai T, Iwata M, Uenaka T, Okamoto K, Shimizu H . Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. III. In vitro and in vivo antitumor activities. J Antibiot (Tokyo). 2004; 57(3):188-96. DOI: 10.7164/antibiotics.57.188. View

Lagisetti C, Pourpak A, Jiang Q, Cui X, Goronga T, Morris S . Antitumor compounds based on a natural product consensus pharmacophore. J Med Chem. 2008; 51(19):6220-4. PMC: 2701350. DOI: 10.1021/jm8006195. View

Machida K, Arisawa A, Takeda S, Tsuchida T, Aritoku Y, Yoshida M . Organization of the biosynthetic gene cluster for the polyketide antitumor macrolide, pladienolide, in Streptomyces platensis Mer-11107. Biosci Biotechnol Biochem. 2008; 72(11):2946-52. DOI: 10.1271/bbb.80425. View

Kanada R, Itoh D, Nagai M, Niijima J, Asai N, Mizui Y . Total synthesis of the potent antitumor macrolides pladienolide B and D. Angew Chem Int Ed Engl. 2007; 46(23):4350-5. DOI: 10.1002/anie.200604997. View

Asai N, Kotake Y, Niijima J, Fukuda Y, Uehara T, Sakai T . Stereochemistry of pladienolide B. J Antibiot (Tokyo). 2007; 60(6):364-9. DOI: 10.1038/ja.2007.49. View

Gundluru M, Pourpak A, Cui X, Morris S, Webb T . Design, synthesis and initial biological evaluation of a novel pladienolide analog scaffold. Medchemcomm. 2011; 2(9):904-908. PMC: 3171832. DOI: 10.1039/C1MD00040C. View

Machida K, Aritoku Y, Tsuchida T . One-pot fermentation of pladienolide D by Streptomyces platensis expressing a heterologous cytochrome P450 gene. J Biosci Bioeng. 2009; 107(6):596-8. DOI: 10.1016/j.jbiosc.2009.01.023. View

Gonzalez-Perez M, Gomez-Bombarelli R, Arenas-Valganon J, Perez-Prior M, Garcia-Santos M, Calle E . Connecting the chemical and biological reactivity of epoxides. Chem Res Toxicol. 2012; 25(12):2755-62. DOI: 10.1021/tx300389z. View

Villa R, Mandel A, Jones B, La Clair J, Burkart M . Structure of FD-895 revealed through total synthesis. Org Lett. 2012; 14(21):5396-9. PMC: 3518397. DOI: 10.1021/ol3023006. View

10.

Yokoi A, Kotake Y, Takahashi K, Kadowaki T, Matsumoto Y, Minoshima Y . Biological validation that SF3b is a target of the antitumor macrolide pladienolide. FEBS J. 2011; 278(24):4870-80. DOI: 10.1111/j.1742-4658.2011.08387.x. View

11.

Gao Y, Vogt A, Forsyth C, Koide K . Comparison of splicing factor 3b inhibitors in human cells. Chembiochem. 2012; 14(1):49-52. DOI: 10.1002/cbic.201200558. View

12.

Muller S, Mayer T, Sasse F, Maier M . Synthesis of a pladienolide B analogue with the fully functionalized core structure. Org Lett. 2011; 13(15):3940-3. DOI: 10.1021/ol201464m. View

13.

Chu P, Deforce D, Pedersen I, Kim Y, Kitada S, Reed J . Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002; 99(6):3854-9. PMC: 122613. DOI: 10.1073/pnas.022604399. View

14.

Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65(1-2):55-63. DOI: 10.1016/0022-1759(83)90303-4. View

15.

Skaanderup P, Jensen T . Synthesis of the macrocyclic core of (-)-pladienolide B. Org Lett. 2008; 10(13):2821-4. DOI: 10.1021/ol800946x. View

16.

Folco E, Coil K, Reed R . The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region. Genes Dev. 2011; 25(5):440-4. PMC: 3049285. DOI: 10.1101/gad.2009411. View

17.

Okazaki T, Yamagishi M, Sakai N, Takayama Y, Hanada K, Morimoto S . Isolation and characterization of a new 12-membered macrolide FD-895. J Antibiot (Tokyo). 1994; 47(12):1395-401. DOI: 10.7164/antibiotics.47.1395. View

18.

Zimmer L, Charette A . Enantioselective synthesis of 1,2,3-trisubstituted cyclopropanes using gem-dizinc reagents. J Am Chem Soc. 2009; 131(43):15624-6. DOI: 10.1021/ja906033g. View

19.

Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M . Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol. 2007; 3(9):570-5. DOI: 10.1038/nchembio.2007.16. View

20.

Ghosh A, Anderson D . Enantioselective total synthesis of pladienolide B: a potent spliceosome inhibitor. Org Lett. 2012; 14(18):4730-3. PMC: 3482479. DOI: 10.1021/ol301886g. View