Structure-based design, synthesis and biological testing of piperazine-linked bis-epipodophyllotoxin etoposide analogs. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Yadav, Arun A.; Chee, Gaik-Lean; Wu, Xing; Patel, Daywin; Yalowich, Jack C.; Hasinoff, Brian B.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3542
• Page End: 3551
• Publication Date: 2015-07-01
• Subjects: VZHGLHMHIIZMQE-XCCZJJLVSA-N -- RKUKDXPXERQSDB-IJIAAYELSA-N -- LUVGOMDSWULCGD-ABLRHOQDSA-N -- IZTBKTHEDFZDJY-WAZWUXIFSA-N -- WEIVKVIMBFRZNP-LYIFVQRYSA-N -- NRMDQWTWRPTGQW-GKMJJFNSSA-N -- AWAXXNITJSMXPD-OYQJTXMHSA-N -- GRLCXUMXOFMFDC-FTHPFZORSA-N; ACN acetonitrile -- Boc di-tert-butyl dicarbonate -- CHO Chinese hamster ovary -- DCM dichloromethane -- DMF dimelthylformamide -- ESI electrospray ionization -- Et3N triethylamine -- kDNA catenated DNA -- K562 cells human erythroleukemic cells -- HRMS high resolution mass spectrometry -- MTS 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium -- r.m.s. root-mean-square -- PAGE polyacrylamide gel electrophoresis -- SDS sodium dodecyl sulfate -- TFA trifluoroacetic acid -- αMEM minimal essential medium alpha; Epipodophyllotoxin -- Topoisomerase II -- Etoposide -- Structure-based design -- Anticancer -- DNA -- COMPARE -- K562 cells -- Molecular modeling -- Docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Drugs that target DNA topoisomerase II, such as the epipodophyllotoxin etoposide, are a clinically important class of anticancer agents. A recently published X-ray structure of a ternary complex of etoposide, cleaved DNA and topoisomerase IIβ showed that the two intercalated etoposide molecules in the complex were separated by four DNA base pairs. Thus, using a structure-based design approach, a series of bis-epipodophyllotoxin etoposide analogs with piperazine-containing linkers was designed to simultaneously bind to these two sites. It was hypothesized that two-site binding would produce a more stable cleavage complex, and a more potent anticancer drug. The most potent bis-epipodophyllotoxin, which was 10-fold more growth inhibitory toward human erythroleukemic K562 cells than etoposide, contained a linker with eight methylene groups. All of the mono- and bis-epipodophyllotoxins, in a variety of assays, showed strong evidence that they targeted topoisomerase II. COMPARE analysis of NCI 60-cell GI50 endpoint data was also consistent with these compounds targeting topoisomerase II.