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 Hurley

Research output: Contribution to journalArticle

250 Citations (Scopus)

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

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G-Quadruplexes
Porphyrins
DNA
Propellers
Surface plasmon resonance
Taq Polymerase
Assays
Stabilization
Chemical activation
Chlorides
tetra(4-N-methylpyridyl)porphine
Experiments
Pharmaceutical Preparations
Surface Plasmon Resonance

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. / Seenisamy, Jeyaprakashnarayanan; Bashyam, Sridevi; Gokhale, Vijay; Vankayalapati, Hariprasad; Sun, Daekyu; Siddiqui-Jain, Adam; Streiner, Nicole; Shin-ya, Kazuo; White, Elizabeth; Wilson, W. David; Hurley, Laurence.

In: Journal of the American Chemical Society, Vol. 127, No. 9, 09.03.2005, p. 2944-2959.

Research output: Contribution to journalArticle

Seenisamy, J, Bashyam, S, Gokhale, V, Vankayalapati, H, Sun, D, Siddiqui-Jain, A, Streiner, N, Shin-ya, K, White, E, Wilson, WD & Hurley, L 2005, 'Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure', Journal of the American Chemical Society, vol. 127, no. 9, pp. 2944-2959. https://doi.org/10.1021/ja0444482
Seenisamy, Jeyaprakashnarayanan ; Bashyam, Sridevi ; Gokhale, Vijay ; Vankayalapati, Hariprasad ; Sun, Daekyu ; Siddiqui-Jain, Adam ; Streiner, Nicole ; Shin-ya, Kazuo ; White, Elizabeth ; Wilson, W. David ; Hurley, Laurence. / Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. In: Journal of the American Chemical Society. 2005 ; Vol. 127, No. 9. pp. 2944-2959.
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AU - Vankayalapati, Hariprasad

AU - Sun, Daekyu

AU - Siddiqui-Jain, Adam

AU - Streiner, Nicole

AU - Shin-ya, Kazuo

AU - White, Elizabeth

AU - Wilson, W. David

AU - Hurley, Laurence

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