Purine Scaffold Hsp inhibitors and theranostics

Abstract

Heat shock proteins (Hsp) and their paralogs have major role in coordinating the various functions including cell proliferation, metabolism and even apoptosis. It is important to that the over expressed Hsp is crucial in cancer growth and propagation. On the other hand, mitochondria is a major organelle in cell and its dysfunction causes a variety of human disorders, including neurodegenerative and neuromuscular diseases, obesity, diabetes, ischemia reperfusion injury, cancer and inherited mitochondrial diseases. Progress in genetics and molecular biology has revealed that mitochondria play a vital role in the homeostasis of vital physiological functions, including electron transfer, apoptosis, and calcium storage. Because of this crucial role in the survival of a cell, targeting mitochondria of cancer cell will be ideal for an efficient therapeutic. The mitochondrial pool of Hsp90 and its mitochondrial paralog, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. At the same time, the field of theranostics has emerged as an interdisciplinary research area involving chemistry, material science, biology, and medicine that combine diagnostics and therapeutics. Among various diagnosing techniques magnetic resonance imaging (MRI) provides a powerful diagnostic imaging modality, because of its non-invasiveness, high definition and precise three-dimensional positioning ability.3 Paramagnetic complexes of iron(II, III) and Gd(III) are commonly used as MRI contrast agents (CAs) to amplify the signals of MRI tomography and improve the contrast between magnetic similar but histological dissimilar tissues. Here in, we utilized purine scaffold TRAP1 inhibitors, where a TPP unit connected through a hydrophobic linker with the inhibitor was used to target mitochondria. The effect of linker length on cytotoxicity was studied with derivatives of various chain lengths and finally purine-Gd(III) complex was synthesized and studied the theranostics applications.