A LAT1‐Compatible, Leadlike Tyrosine‐Naphthoquinone Conjugate With Anticancer Activity

ABSTRACT A L‐type amino acid transporter 1 (LAT1)‐compatible, anticancer‐active tyrosine‐naphthoquinone (NQ) conjugate was successfully developed. The conjugate was designed to exploit LAT1 overexpression in cancers with the goal of achieving selective cytotoxicity for cancerous over noncancerous cells. The tyrosine‐NQ molecule was subjected to cell viability, imaging, docking and in silico pharmacological studies along with structure‐activity relationship (SAR) assessment. Cell viability investigations included IC 50 and substrate‐competition studies. Cells of cancerous (PC3) and noncancerous (HEK293) origin with high and minimal expressions of LAT1, respectively, were employed for biochemical investigations. The tyrosine‐NQ assembly showed significant cytotoxic selectivity toward PC3 over HEK293, with activity comparable to that of the parent molecule NQ and doxorubicin (DOX), an approved drug. Docking studies demonstrated that the conjugate is LAT1‐compatible as it interacts with key residues along the protein's transport pathway. Cell viability competition studies verify a LAT1‐facilitated uptake. SAR studies revealed that the conjugate's anticancer activity is due to its aryloxy‐naphthoquinone motif. In silico pharmacological investigations determined that the conjugate is leadlike and therefore, well‐suited for structural modifications for further drug development. Finally, imaging investigations showed that, with PC3, the conjugate caused drug‐induced stress‐responses in nuclear morphology. Overall, findings demonstrate that the tyrosine‐NQ conjugate is a promising lead for the design of LAT1‐targeting, NQ‐based chemotherapeutics.