The human BCL-2 gene contains a 39-bp GC-rich region upstream of the P1 promoter that has been shown to be critically involved in regulation expression. Inhibition expression can decrease cellular proliferation and enhance efficacy chemotherapy. Here we report major G-quadruplex formed Pu39 G-rich strand this region. 1245G4 quadruplex adopts parallel structure with one 13-nt two 1-nt chain-reversal loops. involves four nonsuccessive G-runs, I, II, IV, V, unlike previously reported bcl2 MidG4...

Abstract Human telomeres can form DNA G‐quadruplex (G4), an attractive target for anticancer drugs. telomeric G4s bear inherent structure polymorphism, challenging understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural‐products known to stabilize and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid‐2 G4 predominant in physiologically relevant K + solution converts other forms hybrid‐2, first such example...

Aptamers, that exist naturally in living cells as functional elements and can switch nonfluorescent natural targets to fluorophores, are very useful developing highly sensitive selective biosensors screening agents. This work demonstrates human telomeric G-quadruplex (HTG) serve a potential fluorophore-switching aptamer (FSA) target isoquinoline alkaloid. We found that, among the G-quadruplexes studied here various structurally similar alkaloids including epiberberine (EPI), berberine (BER),...

BMVC is the first fluorescent probe designed to detect G-quadruplexes (G4s) in vivo. The MYC oncogene promoter forms a G4 (MycG4) which acts as transcription silencer. Here, we report high-affinity and specific binding of MycG4 with unusual slow-exchange rates on NMR timescale. We also show that represses cancer cells. determined solution structures 1:1 2:1 BMVC-MycG4 complexes. binds 5'-end form complex well-defined structure. At higher ratio, 3'-end second complex. In both complexes,...

In this study, we screened 17 medicinal plants for binding activity to G-quadruplex d(TTGGGTT)4 by (1)H NMR spectroscopy and found that the crude extract of Peganum harmala L. seeds showed most potential activity. Subsequently, NMR- bioassay-guided isolation P. was performed obtain four pairs partially racemized β-carboline alkaloids, pegaharmines A-D (1-4). Their structures absolute configurations were determined extensive analyses, X-ray crystallography, ECD calculations, CD exciton...

Investigation of the alkaloids from Peganum harmala seeds yielded two pairs unique racemic pyrroloindole alkaloids, (±)-peganines A–B (1–2); rare thiazole derivatives, peganumals (3–4); six new β-carboline pegaharmines F–K (5–10); and 12 known analogues. Their structures, including stereochemistry, were elucidated through spectroscopic analyses, quantum chemistry calculations, single-crystal X-ray diffraction. Notably, incorporation pyrrole indole moieties in peganines A–B, fragments a C-1...

We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand with c-MYC G-quadruplex DNA. The unimolecular parallel DNA formed in nuclease hypersensitivity element III1 of gene promoter regulates transcription is recognized as an emerging drug target cancer therapy. Quindoline derivatives have been shown to stabilize inhibit expression cells. NMR revealed two sites located at 5′ 3′ termini G-quadruplex. Questions about which site more...

XR5944, a deoxyribonucleic acid (DNA) bis-intercalator with potent anticancer activity, can bind the estrogen response element (ERE) sequence to inhibit receptor-α activities. This novel mechanism of action may be useful for overcoming drug resistance currently available antiestrogen treatments, all which target hormone-receptor complex. Here we report nuclear magnetic resonance solution structure 2:1 complex XR5944 naturally occurring TFF1-ERE, exhibits important and unexpected features. In...

The human telomeric G-quadruplex (G4) is an attractive target for developing anticancer drugs. Natural products protoberberine alkaloids are known to bind G4 and inhibit telomerase. Among several structurally similar alkaloids, epiberberine (EPI) shows the greatest specificity in recognizing over duplex DNA other G4s. Recently, NMR study revealed that EPI recognizes specifically hybrid-2 form by inducing large rearrangements 5′-flanking segment loop regions a highly extensive four-layered...

Abstract Human telomeres can form DNA G‐quadruplex (G4), an attractive target for anticancer drugs. telomeric G4s bear inherent structure polymorphism, challenging understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural‐products known to stabilize and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid‐2 G4 predominant in physiologically relevant K + solution converts other forms hybrid‐2, first such example...

Abstract The human BCL-2 gene contains a 39-bp GC-rich region upstream of its P1 promoter which has been shown to be critical for transcriptional regulation. Therapeutic inhibition expression can reduce cell proliferation and the apoptotic threshold tumorigenic cells. Previously, we have reported that major G-quadruplex (G4) formed in Pu39 G-rich sequence adopts stable, parallel-stranded structure with two 1-nt short loops unique 13-nt long central loop. Parallel G-quadruplexes found...

Abstract DNA G-quadruplexes (G4s) are four-stranded non-canonical secondary structures formed in guanine-rich sequences with functional significance and found to be specifically enriched the transcriptional regulatory regions of cancer-related genes. In particular, c-MYC, one most commonly deregulated genes human cancers, has a G4 motif its proximal promoter which functions as transcription inhibitor can targeted by G-quadruplex-interactive compounds, is thus considered an attractive target...

Abstract Human telomeres play critical roles in cancer, aging, and genetic stability. telomeric DNA consists of tandem repeats the sequence d(TTAGGG) can form G-quadruplexes. G-quadruplexes are non-canonical secondary structures formed G-rich sequences, built upon H-bonded G-tetrads stabilized by monovalent cations such as K+ or Na+. Telomerase is a reverse transcriptase activated 80-85% human cancers. Small molecules that stabilize G-quadruplex have been demonstrated to inhibit telomerase...

Human telomeres play critical roles in cancer, aging, and genetic stability. telomeric DNA consists of tandem repeats the sequence d(TTAGGG) can form G-quadruplexes. G-quadruplexes are non-canonical secondary structures formed G-rich sequences, built upon H-bonded G-tetrads stabilized by monovalent cations such as K+ or Na+. Telomerase is a reverse transcriptase activated 80-85% human cancers. Small molecules that stabilize G-quadruplex have been demonstrated to inhibit telomerase disrupt...

Abstract Overexpression of platelet-derived growth factor receptor β (PDGFR-β) is associated with multiple cancers, making PDGFR-β an attractive target for anticancer drugs. Few strategies other than molecular targeting the protein or its cognate ligand have been reported developing inhibitors signaling pathway. DNA G-quadruplexes (G4s) formed in GC-rich nuclease hypersensitivity element human gene promoter found to inhibit transcriptional activity, and stabilization these G4s by...

Abstract The c-MYC proto-oncogene is one of the most deregulated genes in human cancers. Transcriptional repression considered as attractive strategies targeting c-MYC. Previous studies revealed that promoter nuclease hypersensitive element (NHE) III1 region, which regulates 80-95% total transcription, can form DNA G-quadruplex (G4) and stabilization G4 could repress gene expression. We have previously determined molecular structure major formed NHE (MycG4), an intramolecular...

Abstract DNA is a major target for drugs used in cancer therapy. However, interactive chemotherapeutics are limited by adverse effects due to their poor selectivity. The bis-phenazine compound XR5944 bis-intercalator and potent anticancer drug which reached phase I clinical trials. binding mode mechanism of unique, allowing it recognize bind the estrogen response element (ERE) sequence inhibit ERα activity making highly effective against ER-positive breast vitro. Understanding XR5944's novel...