Fast screening and structural elucidation of G-quadruplex ligands from a mixture via G-quadruplex recognition and NMR methods.

Currently, there is a considerable interest in discovering G-quadruplex ligands. Plant-derived agents, because of their diversity in structure and bioactivity and low toxicity, may be a very diverse source of G-quadruplex ligands. However, up to now, the screening of G-quadruplex ligands from natural plant extract has not been reported. Herein, in order to develop a simple method for fast identifying G-quadruplex ligands from plant extract, we intended to substitute the spectral shift in the imino region (delta 10-12) in (1)H NMR spectra of G-quadruplex for in vitro bioassay to judge the existence/nonexistence of G-quadruplex ligand(s) in plant extract, and then couple G-quadruplex recognition with NMR based structure elucidation to identify the structure of the ligand(s) without the need of prior separation. In this paper, we successfully screened a G-quadruplex ligand from a simulated plant extract using this approach. This research work provides a promising tactic to find new leading compounds from nature plant extract.

[1]  Yalin Tang,et al.  Regulation and recognization of the extended G-quadruplex by rutin. , 2007, Biochemical and biophysical research communications.

[2]  Craig M. Crews,et al.  Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials , 2007, Cell.

[3]  S. Balasubramanian,et al.  Targeting nucleic acid secondary structures with polyamides using an optimized dynamic combinatorial approach. , 2005, Angewandte Chemie.

[4]  Jean-Louis Mergny,et al.  G-quadruplex DNA: A target for drug design , 1998, Nature Medicine.

[5]  T. Tsuruo,et al.  FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis. , 1999, Cancer research.

[6]  S. Balasubramanian,et al.  Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: small molecule regulation of c-kit oncogene expression. , 2007, Journal of the American Chemical Society.

[7]  D. Patel,et al.  Solution structure of a parallel-stranded G-quadruplex DNA. , 1993, Journal of molecular biology.

[8]  K. Shin‐ya,et al.  Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia , 2006, Oncogene.

[9]  Jean-Louis Mergny,et al.  Detection of telomerase inhibitors based on g-quadruplex ligands by a modified telomeric repeat amplification protocol assay. , 2002, Cancer research.

[10]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[11]  J. Mergny,et al.  The development of telomerase inhibitors: the G-quartet approach. , 1999, Anti-cancer drug design.

[12]  Mengfen Lin,et al.  Diffusion-Edited NMR−Affinity NMR for Direct Observation of Molecular Interactions , 1997 .

[13]  J. Mergny,et al.  Ethidium derivatives bind to G-quartets, inhibit telomerase and act as fluorescent probes for quadruplexes. , 2001, Nucleic acids research.

[14]  M. Searle,et al.  Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat. , 2003, Journal of Molecular Biology.

[15]  D. Bearss,et al.  Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  P. Pečinka,et al.  DNA tetraplex formation in the control region of c-myc. , 1998, Nucleic acids research.

[17]  M F Balandrin,et al.  Natural plant chemicals: sources of industrial and medicinal materials. , 1985, Science.

[18]  David M. Prescott,et al.  Inhibition of telomerase by G-quartet DMA structures , 1991, Nature.

[19]  M. Searle,et al.  Recognition and stabilization of quadruplex DNA by a potent new telomerase inhibitor: NMR studies of the 2:1 complex of a pentacyclic methylacridinium cation with d(TTAGGGT)4 , 2001 .

[20]  E. De Pauw,et al.  Selective interaction of ethidium derivatives with quadruplexes: an equilibrium dialysis and electrospray ionization mass spectrometry analysis. , 2003, Biochemistry.

[21]  Laurence H. Hurley,et al.  DNA and its associated processes as targets for cancer therapy , 2002, Nature Reviews Cancer.

[22]  G. Morris,et al.  A novel NMR method for screening soluble compound libraries , 2001 .

[23]  Dinshaw J. Patel,et al.  Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics , 2007, Nucleic acids research.

[24]  M. Shapiro,et al.  Screening Mixtures by Affinity NMR , 1997 .

[25]  S. Neidle,et al.  Natural and synthetic G-quadruplex interactive berberine derivatives. , 2006, Bioorganic & medicinal chemistry letters.