Engineering Small Molecule Inhibitors via Click Chemistry to Combat Breast Cancer Metastasis

One in eight females in the United States will develop breast cancer within their lifetime. With the occurrence of metastasis, survival rates drastically decline as much as 70%. Prior research has confirmed that the overexpression of an inflammatory cytokine (IC) promotes metastasis via the activation of the JAK/STAT signaling pathway, suggesting that the IC is a promising target for repression by a small molecule inhibitor (SMI). Initial computational screenings identified SMI-26 as a promising lead that is undergoing diversification with the goal of improving potency a hundred-fold as well as increasing drug-likeness properties. To accomplish the synthesis of improved analogs, a library of diverse azides were synthesized using one of two pathways; triflyl azide with free amines or sodium azide with anilines. Once the azides were synthesized, a Sonogashira coupling reaction or a nucleophilic aromatic substitution reaction (SNAr) was used to construct the quinoline core with the required alkyne click chemistry coupling partner in place. Once prepared, the azides and alkynes were subjected to the triazole-forming click chemistry cycloaddition reaction using a copper salt catalyst. Subsequent saponification generates an SMI that is ready for testing of inhibitory activity. By utilizing the click chemistry method, we anticipate rapid access to a library of inhibitors that should result in the development of potent and pharmacologically viable small molecule inhibitors. Our findings hold promise in advancing therapeutic options for breast cancer patients with the potential to greatly improve survival outcomes.