Design and Synthesis of Quinoline Based Golgi Targeting Anion Transporters for Improved Anticancer Activity

Abstract

The Golgi apparatus is a central and indispensable cell-organelle in eukaryotic cell. Its canonical function plays an important role in maintaining cellular homeostasis and complex biological processes. While being essential for normal cell physiology, the Golgi apparatus undergoes significant changes under the influence of oncogenic transformation. A promising therapeutic approach to this involves the induction of organelle-specific stress, which can trigger programmed cell death or apoptosis; similarly, a deliberately induced Golgi stress will result in Golgiphagy. Nowadays, one of the most potent methods for inducing cellular stress is the disruption of ion homeostasis. This disruption of the ion gradient across the cellular and organellar membrane, particularly of Chloride anions, is a well-established trigger for apoptosis.1 A rationale approach for inducing Golgi centric apoptosis is to develop a small molecule capable of selectively disrupting the anion homeostasis in it. So, adopting this concept, we designed a Golgi targeting molecule consisting of Squaramide core, which is a well-established class of synthetic anion transporters,2 coupled with 7 aminoquinoline derivative as the Golgi targeting component.3 Quinoline derivatives have extensively been used for both pharmaceutical agents and bioimaging. In literature, it has been well studied as a Golgi targeting probe. The quinoline moiety containing both amino and trifluoromethyl groups exhibits strong intramolecular charge- transfer fluorescence, which will provide a powerful non-invasive tool for the real-time and in situ visualization of the spatial and temporal fluctuation of bioactive species.4 Anion transport by these small molecules will lead to disruption of the ionic homeostasis within the Golgi apparatus and will trigger the Golgiphagy and apoptosis of cancer cells.