Chemistry

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Proton relay plays an important role in many biocatalytic pathways. In order to mimic such processes in the context of molecular switches, we developed coordination-coupled deprotonation (CCD) driven signaling and signal enhancement sequences. This was accomplished by using the zinc(ii)-initiated CCD of a hydrazone switch to instigate an acid catalyzed imine bond hydrolysis that separates a quencher from a fluorophore thus leading to emission amplification. Because CCD is a reversible process, we were able to show that the catalysis can be regulated and turned "on" and "off" using a metalation/demetalation cycle. This journal is © The Royal Society of Chemistry.

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(SoNS) School of Natural Sciences

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Chemical Science

Regulating signal enhancement with coordination-coupled deprotonation of a hydrazone switch

One of the principal tools in the theoretical study of biological molecules is the method of molecular dynamic simulation. MD simulations have provided detailed information on the fluctuation and conformation changes of the system. It offers the prospects of detailed description of the dynamical structure with ion and water at molecular level. In this work, we have taken an oligomeric part of human telomeric DNA, d(TAGGGT), to form a tetrameric quadruplex structure and generate four modified complexes. For modification, we have taken locked nucleic acid. Here, we report the relative stability of these modified structures under K+ ion conditions and binding interaction between the strands as determined by MD simulation followed by energy calculation. MM-PBSA method is performed for the determination of most stable complex. In free energy calculation, different strands are taken as the ligand and receptor. The energetic study shows that a modified quadruplex, in which first two modified strands are bind with other two unmodified strands, is more stable than other complexes. The formation and stabilization of these quadruplexes have been shown to inhibit the activity of telomerase, thus establishing telomeric quadruplex as an attractive target for cancer therapeutic intervention. © 2014 Springer Science+Business Media New York.

Medicinal Chemistry Research

MD simulation of LNA-modified human telomeric G-quadruplexes: A free energy calculation

The vibrational modes of the deoxyribose-phosphodiester backbone moiety of DNA and their interactions with the interfacial aqueous environment are addressed with two-dimensional (2D) infrared spectroscopy on a femto- to picosecond time scale. Beyond the current understanding in the harmonic approximation, the anharmonic character and delocalization of the backbone modes in the frequency range from 900 to 1300 cm-1 are determined with both diagonal anharmonicities and intermode couplings on the order of 10 cm-1. Mediated by the intermode couplings, energy transfer between the backbone modes takes place on a picosecond time scale, parallel to vibrational relaxation and energy dissipation into the environment. Probing structural dynamics noninvasively via the time evolution of the 2D lineshapes, limited structural fluctuations are observed on a 300 fs time scale of low-frequency motions of the helix, counterions, and water shell. Structural disorder of the DNA-water interface and DNA-water hydrogen bonds are, however, preserved for times beyond 10 ps. The different interactions of limited strength ensure ultrafast vibrational relaxation and dissipation of excess energy in the backbone structure, processes that are important for the structural integrity of hydrated DNA. © 2015 American Chemical Society.

Journal of Physical Chemistry B

Anharmonic Backbone Vibrations in Ultrafast Processes at the DNA-Water Interface

A novel zwitterionic near-infrared (NIR) dye, ZWCC, has been designed and synthesized. It shows significantly enhanced photostability and chemical stability compared to the existing zwitterionic NIR dye. In addition, the feasibility of labeling ZWCC with biological ligands was investigated and used in live cell imaging applications. This journal is © The Royal Society of Chemistry 2015.

Chemical Communications

The development of a highly photostable and chemically stable zwitterionic near-infrared dye for imaging applications

We investigated the changes in amino acid (AA) metabolism induced in MCF10A, a human mammary epithelial cell line, by the sequential knock-in of K-Ras and PI3K mutant oncogenes. Differentially regulated genes associated to AA pathways were identified on comparing gene expression patterns in the isogenic cell lines. Additionally, we monitored the changes in the levels of AAs and transcripts in the cell lines treated with kinase inhibitors (REGO: a multi-kinase inhibitor, PI3K-i: a PI3K inhibitor, and MEK-i: a MEK inhibitor). In total, 19 AAs and 58 AA-associated transcripts were found to be differentially regulated by oncogene knock-in and by drug treatment. In particular, the multi-kinase and MEK inhibitor affected pathways in K-Ras mutant cells, whereas the PI3K inhibitor showed a major impact in the K-Ras/PI3K double mutant cells. These findings may indicate the dependency of AA metabolism on the oncogene mutation pattern in human cancer. Thus, future therapy might include combinations of kinase inhibitors and drug targeting enzymes of AA pathways. © The Royal Society of Chemistry 2015.

Molecular BioSystems

Effect of oncogene activating mutations and kinase inhibitors on amino acid metabolism of human isogenic breast cancer cells

Development of highly sensitive and selective sensing systems of divalent zinc ion (Zn2+) in organisms has been a growing interest in the past decades owing to its pivotal role in cellular metabolism, apoptosis, and neurotransmission. Herein, we report the rational design and synthesis of a Zn2+ fluorescent-based probe by assembling lanthanide-doped upconversion nanoparticles (UCNPs) with chromophores. Specifically, upconversion luminescence (UCL) can be effectively quenched by the chromophores on the surface of nanoparticles via a fluorescence resonant energy transfer (FRET) process and subsequently recovered upon the addition of Zn2+, thus allowing for quantitative monitoring of Zn2+. Importantly, the sensing system enables detection of Zn2+ in real biological samples. We demonstrate that this chromophore-UCNP nanosystem is capable of implementing an efficient in vitro and in vivo detection of Zn2+ in mouse brain slice with Alzheimers disease and zebrafish, respectively. © 2015 American Chemical Society.

Journal of the American Chemical Society

High-efficiency in vitro and in vivo detection of Zn2+ by dye-assembled upconversion nanoparticles

DNA opoisomerase I is a potential chemotherapeutic target. Here, we designed and synthesized a library comprising of hydantoin and thiohydantoin derivatives and tested them against human and Leishmania Top1. One of the thiohydantoin compounds with substituted thiophenyl as the central moiety (compound 15) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines. Molecular modeling studies with HTop1 rationalized the inhibitory mechanism of compound 15. © 2015 Elsevier Masson SAS.

Life Sciences

European Journal of Medicinal Chemistry

Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity

Several natural product inspired fused and spiro-heterocyclic scaffolds were prepared by ring distortion and ring construction strategies and evaluated for anti-breast cancer activity. A facile domino Pictet-Spengler lactamization (PSL) afforded nine natural product inspired indolo[2,3-a]quinolizidine and indolo[8,7-b]indolizidine scaffolds which are converted to seven other scaffolds by functional group transformation, ring distortion and ring construction strategies. In vitro screenings of this library of sixteen scaffolds with six distinct architectures against MCF7 cell lines afforded two compounds (10 and 21) with modest activity. Principal component analysis of this library against databases of FDA approved drugs, commercial compounds and FDA approved breast cancer compounds indicated an eclectic mix of structures among the molecules. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

New Journal of Chemistry

Diverse synthesis of natural product inspired fused and spiro-heterocyclic scaffolds via ring distortion and ring construction strategies

Malaria a global pandemic has engulfed nearly 0.63 million people globally. It is high time that a cure for malaria is required to stop its ever increasing menace. Our commentary discusses the advent and contribution of genetic algorithm (GA) in the drug discovery efforts towards developing cure for malaria. GAs are computational models of Darwinian evolution, ideally capture and mimic the principles of genetic variation and natural selection to evolve good solutions through multiple iterations on the space of all possible candidate solutions, called the search space, to a given optimization problem. Herein we will discuss the applications, advantages, disadvantages and future directions of GA with respect to malaria. © 2015, Springer Science+Business Media Dordrecht.

Mathematics

Systems and Synthetic Biology

Innovative techniques to discover novel antimalarials

The problem associated with metal nanoparticle (NP) agglomeration when trying to achieve a high loading amount has been solved by a new method of functionalization of MOFs' pores with terminal alkyne moieties. The alkynophilicity of the Au3+ ions has been utilized successfully for an exceptionally high loading (∼50 wt%) of Au-NPs on supported functionalized MOFs.

A smart approach to achieve an exceptionally high loading of metal nanoparticles supported by functionalized extended frameworks for efficient catalysis