The synthesis of macrocyclic molecules related to telomestatin

G-quadruplex DNA represents an attractive target for the development of anti-cancer therapeutic agents as it plays important roles in transcriptional regulation and the maintenance of telomeric length. Oxazole-containing macrocycles such as telomestatin are considered to be a promissing new class of G-quadruplex binding ligands. In this work, poly-oxazole building blocks were synthesized to prepare a tetraoxazole peptide macrocycle in good yield. The macrocycle was obtained by employing standard peptide coupling conditions using a convergent solution phase approach. The synthetic unit of the oxazole amino acid containing compound was prepared by cyclodehydration/oxidation of protected serine and phenylalanine. Two-cycle coupling of the unit gave a linear tetraoxazole amide. The final macrocyclization was accomplished by using O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and the product (45% yield) was characterized by 1H NMR. Finally, the Cu (II) coordination chemistry of the tetraoxazole macrocycle was investigated by spectrophotometric titration.Master of Science (MSc) in Chemical Science

Glutamine metabolism and energy homeostasis during oxidative stress.

When living organisms are exposed to oxidative stress, they are known to devise intricate mechanisms to counter reactive oxygen species (ROS). It is well established that ROS lead to the reduction in the activity of numerous tricarboxylic acid (TCA) cycle enzymes and impede O2- dependent energy production. In this study we demonstrate an alternative metabolic pathway to adenosine triphosphate (ATP) synthesis when the microbe Pseudomonas fluorescens is challenged by H2O2.in a medium with glutamine as the sole source of carbon and nitrogen. Under oxidative stress the microbe utilized glutamine synthease (GS) to release a constant supply of energy locked in the amide bond of glutamine. When grown in presence of H2O2, the level of GS was higher in the stressed cultures compared to the control. The up-regulation of phospho-transfer enzymes such as acetate kinase (ACK), adenylate kinase (AK), and nucleoside diphosphate kinase (NDPK) are involved in maintaining ATP homeostasis in the oxidatively challenged cells. The increased amount of pyruvate phosphate dikinase (PPDK) and phosphoenol pyruvate carboxylase (PEPC) in stressed cells helped fuel the synthesis of ATP. The enhanced activities of isocitrate dehydrogenase-NAD dependent (ICDH-NAD) and glutamate dehydrogenase (GDH) also provided intermediate metabolites for energy generation. These metabolic reconfigurations may reveal crucial therapeutic tools against infectious microbes dependent on host glutamine for proliferation.Master of Science (MSc) in Chemical Scienc