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

被引:279
|
作者
Seenisamy, J
Bashyam, S
Gokhale, V
Vankayalapati, H
Sun, D
Siddiqui-Jain, A
Streiner, N
Shin-ya, K
White, E
Wilson, WD
Hurley, LH
机构
[1] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA
[2] Arizona Canc Ctr, Tucson, AZ 85724 USA
[3] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA
[4] Cylene Pharmaceut, San Diego, CA 92121 USA
[5] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan
[6] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA
关键词
D O I
10.1021/ja0444482
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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-methyl3-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.
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收藏
页码:2944 / 2959
页数:16
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