Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure

Jeyaprakashnarayanan Seenisamy, Sridevi Bashyam, Vijay Gokhale, Hariprasad Vankayalapati, Daekyu Sun, Adam Siddiqui-Jain, Nicole Streiner, Kazuo Shin-ya, Elizabeth White, W. David Wilson, Laurence H. Hurley

Research output: Contribution to journalArticle

261 Scopus citations

Abstract

Cationic porphyrins are known to bind to and stabilize different types of G-quadruplexes. Recent studies have shown the biological relevance of the intramolecular parallel G-quadruplex as a transcriptional silencer in the c-MYC promoter. TMPyP4 also binds to this G-quadruplex and most likely converts it to a mixed parallel/antiparallel G-quadruplex with two external lateral loops and one internal propeller loop, suppressing c-MYC transcriptional activation. To achieve therapeutic selectivity by targeting G-quadruplexes, it is necessary to synthesize drugs that can differentiate among the different types of G-quadruplexes. We have designed and synthesized a core-modified expanded porphyrin analogue, 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28- diselenasapphyrin chloride (Se2SAP). Se2SAP converts the parallel c-MYC G-quadruplex into a mixed parallel/antiparallel G-quadruplex with one external lateral loop and two internal propeller loops, resulting in strong and selective binding to this G-quadruplex. A Taq polymerase stop assay was used to evaluate the binding of TMPyP4 and Se2SAP to G-quadruplex DNA. Compared to TMPyP4, Se2SAP shows a greater selectivity for and a 40-fold increase in stabilization of the single lateral-loop hybrid. Surface plasmon resonance and competition experiments with duplex DNA and other G-quadruplexes further confirmed the selectivity of Se2SAP for the c-MYC G-quadruplex. Significantly, Se2SAP was found to be less photoactive and noncytotoxic in comparison to TMPyP4. From this study, we have identified an expanded porphyrin that selectively binds with the c-MYC G-quadruplex in the presence of duplex DNA and other G-quadruplexes.

Original languageEnglish (US)
Pages (from-to)2944-2959
Number of pages16
JournalJournal of the American Chemical Society
Volume127
Issue number9
DOIs
StatePublished - Mar 9 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Seenisamy, J., Bashyam, S., Gokhale, V., Vankayalapati, H., Sun, D., Siddiqui-Jain, A., Streiner, N., Shin-ya, K., White, E., Wilson, W. D., & Hurley, L. H. (2005). Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. Journal of the American Chemical Society, 127(9), 2944-2959. https://doi.org/10.1021/ja0444482