Design, synthesis and biological evaluation of coumarin coupled nitroimidazoles as potential imaging agents

Abstract

Solid tumors contain regions of hypoxia in comparison to normal tissues. The nitroimidazoles have shown great promise for targeting different types of cancers. The present work involves the design, syntheses, and in vitro and in vivo investigations of hypoxia targeted nitroimidazole radioconjugates (2NIHC and 4NIHC). Flow cytometry analysis showed that the normoxic–hypoxic mean fluorescence of 2NIHC is 10 fold greater than that of 4NIHC and much higher than that of the well-known pimonidazole hypoxia marker. Furthermore, molecular modeling studies of these ligands with CK2α revealed that 2NIHC is a more potential CK2α inhibitor due to π–π interactions and H-bonding with Val116, Glu114, Asp175, Asn161 and His160 in the active pockets of the target. Radio labeling yields for both the complexes with ^99mTc were >98%. Biodistribution in EAT tumor bearing mice demonstrated rapid clearance of ^99mTc-2NIHC and high T/M ratio (3.57% ID/g) as compared to ^99mTc-4NIHC (2.05% ID/g) at 4 h. IC₅₀ values of both ligands were estimated by MTS in different cell lines in addition to tumor regression studies.