title: Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure.
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.
authors.affiliation: College of Pharmacy, The University of Arizona, 1703 East Mabel, Tucson, Arizona 85721, USA.
authors.forename: Jeyaprakashnarayanan
authors.initials: J
authors.lastname: Seenisamy
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Daekyu
authors.initials: D
authors.lastname: Sun
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-Ya
authors.forename: Elizabeth
authors.initials: E
authors.lastname: White
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
mesh_terms: D001667:Binding, Competitive; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D054856:G-Quadruplexes; D016259:Genes, myc; D006147:Guanine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018036:Selenium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D016615:Telomere / Q000737:chemistry / Q000378:metabolism
chemical_list: C499730:5,10,15,20-(tetra(N-methyl-3-pyridyl))-26,28-diselenasapphyrin chloride; D004277:DNA, Single-Stranded; D010080:Oxazoles; D011166:Porphyrins; D018036:Selenium Compounds; C431888:telomestatin; C021096:tetra(4-N-methylpyridyl)porphine; D006147:Guanine; D004247:DNA