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Special Issue "G-Quadruplex Ligands and Cancer"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 September 2018

Special Issue Editor

Guest Editor
Prof. Danzhou Yang

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, Purdue Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907, USA
Website | E-Mail
Interests: DNA structures and functions; G-quadruplexes; anticancer drugs; NMR; ligand interactions

Special Issue Information

Dear Colleagues,

G-quadruplexes are four-stranded nucleic acid secondary structures, which form in guanine-rich DNA and RNA sequences. Once a laboratory curiosity, these non-canonical structures are now known to form readily under physiological conditions in regions of biological significance, such as human telomeres, oncogene promoter regions, replication initiation sites, and 5’ and 3’-untranslated (UTR) regions. Many G-quadruplex forming sequences are found to be associated with cancer, thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In recent years, G-quadruplexes have received elevated research interest, and G-quadruplex interactive ligands have been identified to exhibit antiproliferative and chemosensitizing effects against tumor models both in vitro and in vivo. Notably, quarfloxin, a G-quadruplex-interactive fluoroquinoline derivative, reached phase II clinical trials for the treatment of carcinoid/neuroendocrine tumors. While significant advances have been made towards targeting G-quadruplex structures, many questions and challenges on the subject remain to be addressed. This Special Issue aims to provide opportunity to share new findings and recent advances on G-quadruplex targeted small-molecules toward the development of new anticancer drugs.

Prof. Danzhou Yang
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G-quadruplexes nucleic acid secondary structures
  • molecular targets for cancer therapeutics
  • G-quadruplex-targeted ligands
  • anticancer and chemosensitizing effects

Published Papers (4 papers)

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Research

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Open AccessArticle HnRNPA1 Specifically Recognizes the Base of Nucleotide at the Loop of RNA G-Quadruplex
Molecules 2018, 23(1), 237; doi:10.3390/molecules23010237
Received: 13 December 2017 / Revised: 5 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we
[...] Read more.
Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we report on a detailed analysis of hnRNPA1 binding to telomere RNA G-quadruplexes with a group of loop variants using an electrophoretic mobility shift assay (EMSA) and circular dichroism (CD) spectroscopy. We found that the hnRNPA1 binds to RNA G-quadruplexes with the 2’-O-methyl and DNA loops, but fails to bind with the abasic RNA and DNA loops. These results suggested that hnRNPA1 binds to the loop of the RNA G-quadruplex by recognizing the base of the loop’s nucleotides. The observation provides the first evidence that the base of the loop’s nucleotides is a key factor for hnRNPA1 specifically recognizing the RNA G-quadruplex. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Design, Synthesis and Biological Evaluation of New Substituted Diquinolinyl-Pyridine Ligands as Anticancer Agents by Targeting G-Quadruplex
Molecules 2018, 23(1), 81; doi:10.3390/molecules23010081
Received: 8 December 2017 / Revised: 20 December 2017 / Accepted: 29 December 2017 / Published: 30 December 2017
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Abstract
G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore
[...] Read more.
G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 μM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Investigation of ‘Head-to-Tail’-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes
Molecules 2017, 22(12), 2160; doi:10.3390/molecules22122160
Received: 27 October 2017 / Revised: 22 November 2017 / Accepted: 2 December 2017 / Published: 6 December 2017
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Abstract
Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the
[...] Read more.
Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the formed oxazoles and their subsequent C–C cross-coupling to 2-bromopyridines in order to assemble a library of variable-length, ‘head-to-tail’-connected, pyridyl-oxazole ligands. Through investigation of the interaction of the three longer ligands (5-mer, 6-mer, 7-mer) with cancer-relevant G-quadruplex structures (human telomeric/22AG and c-Myc oncogene promoter/Myc2345-Pu22), the asymmetric pyridyl-oxazole motif has been demonstrated to be a prominent recognition element for G-quadruplexes. Fluorescence titrations reveal excellent binding affinities of the 7-mer and 6-mer for a Na+-induced antiparallel 22AG G-quadruplex (KD = 0.6 × 10−7 M−1 and 0.8 × 10−7 M−1, respectively), and satisfactory (albeit lower) affinities for the 22AG/K+ and Myc2345-Pu22/K+ G-quadruplexes. All ligands tested exhibit substantial selectivity for G-quadruplex versus duplex (ds26) DNA, as evidenced by competitive Förster resonance energy transfer (FRET) melting assays. Additionally, the 7-mer and 6-mer are capable of promoting a sharp morphology transition of 22AG/K+ G-quadruplex. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Review

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Open AccessReview Natural Alkaloids and Heterocycles as G-Quadruplex Ligands and Potential Anticancer Agents
Molecules 2018, 23(2), 493; doi:10.3390/molecules23020493
Received: 30 December 2017 / Revised: 4 February 2018 / Accepted: 20 February 2018 / Published: 23 February 2018
PDF Full-text (1793 KB) | HTML Full-text | XML Full-text
Abstract
G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are
[...] Read more.
G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are found to be associated with cancer, and thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this mini review, we summarize recent advances made by our lab in the study of G-quadruplex-targeted natural alkaloids and their derivatives toward the development of potential anticancer agents. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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