We demonstrate that the amino acid tyrosine is an excellent reducing agent under alkaline conditions and may be used to reduce Ag+ ions to synthesize stable silver nanoparticles in water. The tyrosine-reduced silver nanoparticles may be separated out as a powder that is readily redispersible in water. The silver ion reduction at high pH occurs due to ionization of the phenolic group in tyrosine that is then capable of reducing Ag+ ions and is in turn converted to a semi-quinone structure. These silver nanoparticles can easily be transferred to chloroform containing the cationic surfactant octadecylamine by an electrostatic complexation process. The now hydrophobic silver nanoparticles may be spread on the surface of water and assembled into highly ordered, linear superstructures that could be transferred as multilayers onto suitable supports by the versatile Langmuir-Blodgett technique. Further, tyrosine molecules bound to the surface of Au nanoparticles through amine groups in the amino acid may be used to selectively reduce silver ions at high pH on the surface of the Au nanoparticles, thus leading to a simple strategy for realizing phase-pure Au core-Ag shell nanostructures.

Particular guanine rich DNA sequences can fold into stable four-stranded G-quadruplex structures, under physiological concentrations of Na + and K + , in vitro.1 Such sequence motifs are found in the telomeres where they can fold into quadruplexes under the control of specific telomere binding proteins.2 G-quadruplex motifs have been identified throughout the genome3 and concentrate immediately upstream of transcription initiation sites.3a A number of these so-called "promoter quadruplex" sequences have been studied for several proto-oncogenes, including c-MYC,4 BCL2,5 VEGF,6 KRAS7 and two G-quadruplexes in the c-kit promoter8 (c-kit1 and c-kit2). One working hypothesis couples quadruplex formation in promoters to transcription, suggesting an opportunity for chemical intervention of gene expression using small molecule G-quadruplex ligands. Some proof-of-concept has been provided for the case of c-MYC where small molecule ligands, TmPyP4,4 and quindoline9 derivatives have been shown to inhibit gene expression, while KRAS gene expression was inhibited by TmPyP4.7The c-kit proto-oncogene encodes a tyrosine kinase receptor for the growth-promoting cytokine SCF (stem cell factor) which plays an important biological role in the control of differentiation.10 A small molecule inhibitor of c-kit, Gleevec (imatinib mesylate), is being effectively used in the treatment of gastrointestinal stromal tumors (GIST).11 A small molecule that inhibits c-kit expression at the transcriptional level would provide further evidence to support the promoter-quadruplex hypothesis and might inspire the exploration of quadruplex-based therapeutic approaches to address GIST. Herein, we report the design, synthesis, biophysical evaluation with primary biological data on 3,8,10-trisubstituted isoalloxazines ( Figure 1).The design of isoalloxazines as potential G-quadruplex ligands was inspired by the observation, arising from SELEX studies, that oxidized riboflavin (7,8-dimethyl-10-ribitylisoalloxazine) binds to an intramolecular G-quartet with moderate binding affinity (K d ) of 1-5 μM.12 Our design principles maintain the planar isoalloxazine scaffold, to enable interactions with G-quartet.13 Amine side chains were introduced to provide potential for interactions with quadruplex loops and grooves and the negatively charged sugar-phosphate backbone. We developed and employed a short and robust synthetic route to 3,8,10-trisubstituted isoalloxazines to prepare ligands of general structure 1 (Figure 1). The key isoalloxazine building blocks were synthesized using modified literature procedures.14 An efficient method was developed for the introduction of amino alkyl side chains to afford 1a-f in good overall yields (see Supporting Information).To evaluate the interaction properties of isoalloxazines 1a-f with a number of DNA targets, we employed surface plasmon resonance (SPR) to evaluate equilibrium binding15 and a fluorescence resonance energy transfer (FRET) melting assay16 to evaluate the stabilizing influence of the ligand. We included thr...

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.

We report bis-phenylethynyl amide derivatives as a potent G-quadruplex binding small molecule scaffold. The amide derivatives were efficiently prepared in 3 steps by employing Sonogashira coupling, ester hydrolysis and a chemoselective amide coupling. Ligand-quadruplex recognition has been evaluated using a fluorescence resonance energy transfer (FRET) melting assay, surface plasmon resonance (SPR), circular dichroism (CD) and 1 H nuclear magnetic resonance (NMR) spectroscopy. While most of the G-quadruplex ligands reported so far comprise a planar, aromatic core designed to stack on the terminal tetrads of a G-quadruplex, these compounds are neither polycyclic, nor macrocyclic and have free rotation around the triple bond enabling conformational flexibility. Such molecules show very good binding affinity, excellent quadruplex:duplex selectivity and also promising discrimination between intramolecular promoter quadruplexes. Our results indicate that the recognition of the c-kit2 quadruplex by these ligands is achieved through groove binding, which favors the formation of a parallel conformation.

A planar trimeric macrocyclic oligoamide of 8-amino-2-quinoline carboxylic acid, bearing ammonium side chains, stabilizes the human telomeric G-quadruplex more strongly than the potent ligand telomestatin. Furthermore, a helical oligoamide tetramer also binds strongly to G-quadruplexes and is a new structural class of quadruplex ligand that appears to interact enantioselectively.