Design and Synthesis of an Expanded Porphyrin That Has Selectivity for the c-MYC G-Quadruplex Structure

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• 作者：Jeyaprakashnarayanan Seenisamy ; Sridevi Bashyam ; Vijay Gokhale ; Hariprasad Vankayalapati ; Daekyu Sun ; Adam Siddiqui-Jain ; Nicole Streiner ; Kazuo Shin-ya ; Elizabeth White ; W. David Wilson ; and Laurence
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：March 9, 2005
• 年：2005
• 卷：127
• 期：9
• 页码：2944 - 2959
• 全文大小：658K
• 年卷期：v.127,no.9(March 9, 2005)
• ISSN：1520-5126

文摘

Cationic porphyrins are known to bind to and stabilize different types of G-quadruplexes. Recentstudies have shown the biological relevance of the intramolecular parallel G-quadruplex as a transcriptionalsilencer in the c-MYC promoter. TMPyP4 also binds to this G-quadruplex and most likely converts it to amixed 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. Wehave 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-quadruplexinto a mixed parallel/antiparallel G-quadruplex with one external lateral loop and two internal propellerloops, resulting in strong and selective binding to this G-quadruplex. A Taq polymerase stop assay wasused to evaluate the binding of TMPyP4 and Se2SAP to G-quadruplex DNA. Compared to TMPyP4, Se2SAPshows a greater selectivity for and a 40-fold increase in stabilization of the single lateral-loop hybrid. Surfaceplasmon resonance and competition experiments with duplex DNA and other G-quadruplexes furtherconfirmed the selectivity of Se2SAP for the c-MYC G-quadruplex. Significantly, Se2SAP was found to beless photoactive and noncytotoxic in comparison to TMPyP4. From this study, we have identified anexpanded porphyrin that selectively binds with the c-MYC G-quadruplex in the presence of duplex DNAand other G-quadruplexes.