Design, Synthesis and Initial Biological Evaluation of a Novel Pladienolide Analog Scaffold

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2011 Sep 20

PMID 21927710

Citations 11

Authors

Mahesh Kumar Gundluru

Alan Pourpak

Xiaoli Cui

Stephan W Morris

Thomas R Webb

Affiliations

Soon will be listed here.

Abstract

A novel and simplified synthetic scaffold based on pladienolide was designed using a consensus pharmacophore hypothesis. An initial target was synthesized and evaluated to examine the role of the 3-hydroxy group and the methyl groups present at positions 10, 16, 20, 22 in 1, on biological activity. We report the first totally synthetic analog of this macrolide that shows biological activity. Our novel synthetic strategy enables the rapid synthesis of other new analogs of pladienolide in order to develop selective anticancer lead compounds.

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References

Nakajima H, Sato B, Fujita T, Takase S, Terano H, OKUHARA M . New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo). 1996; 49(12):1196-203. DOI: 10.7164/antibiotics.49.1196. View

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

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

Hoye T, Jeffrey C, Shao F . Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat Protoc. 2007; 2(10):2451-8. DOI: 10.1038/nprot.2007.354. 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

Kabat M, Garofalo L, Daniewski A, Hutchings S, Liu W, Okabe M . Efficient synthesis of 1alpha-fluoro A-ring phosphine oxide, a useful building block for vitamin D analogues, from (S)-carvone via a highly selective palladium-catalyzed isomerization of dieneoxide to dieneol. J Org Chem. 2001; 66(18):6141-50. DOI: 10.1021/jo015788y. View

Kumar P, Naidu S, Gupta P . Efficient total synthesis of sapinofuranone B. J Org Chem. 2005; 70(7):2843-6. DOI: 10.1021/jo048087k. View

Corrionero A, Minana B, Valcarcel J . Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev. 2011; 25(5):445-59. PMC: 3049286. DOI: 10.1101/gad.2014311. View

10.

Lagisetti C, Pourpak A, Goronga T, Jiang Q, Cui X, Hyle J . Synthetic mRNA splicing modulator compounds with in vivo antitumor activity. J Med Chem. 2009; 52(22):6979-90. PMC: 2801547. DOI: 10.1021/jm901215m. View

11.

Choudary B, Chowdari N, Jyothi K, Kantam M . Catalytic asymmetric dihydroxylation of olefins with reusable OsO(4)(2-) on ion-exchangers: the scope and reactivity using various cooxidants. J Am Chem Soc. 2002; 124(19):5341-9. DOI: 10.1021/ja017889j. View

12.

Landers J, Cassel S, GEORGE D . Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein. Cancer Res. 1997; 57(16):3562-8. View

13.

Nakajima H, Hori Y, Terano H, OKUHARA M, Manda T, Matsumoto S . New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J Antibiot (Tokyo). 1996; 49(12):1204-11. DOI: 10.7164/antibiotics.49.1204. View

14.

Sakai T, Sameshima T, Matsufuji M, Kawamura N, Dobashi K, Mizui Y . Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. J Antibiot (Tokyo). 2004; 57(3):173-9. DOI: 10.7164/antibiotics.57.173. View

15.

Lafontaine J, Provencal D, Gardelli C, Leahy J . Enantioselective total synthesis of the antitumor macrolide rhizoxin D. J Org Chem. 2003; 68(11):4215-34. DOI: 10.1021/jo034011x. View

16.

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

17.

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

18.

Nakajima H, Takase S, Terano H, Tanaka H . New antitumor substances, FR901463, FR901464 and FR901465. III. Structures of FR901463, FR901464 and FR901465. J Antibiot (Tokyo). 1997; 50(1):96-9. DOI: 10.7164/antibiotics.50.96. View

19.

Haapajarvi T, Pitkanen K, Laiho M . Human melanoma cell line UV responses show independency of p53 function. Cell Growth Differ. 1999; 10(3):163-71. View

20.

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