Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Acridonespresent numerous pharmacological activities, includinginhibition of microtubule affinity-regulating kinase 4 (MARK4) kinaseactivity. To investigate structure-activity relationships anddevelop potent MARK4 inhibitors, derivatives of 2-methylacridone weresynthesized and tested for their activity against MARK4 kinase. Selectivesubstitutions at the nitrogen atom were accomplished by treating 2-methylacridonewith alkyl halides in the presence of K2CO3.In addition, amidation of acridone acetic acid 11 withpiperazine or tryptophan methyl ester followed by derivatization withvarious amines gave a series of new acridone derivatives. Among thetested compounds, six were identified as possessing high inhibitoryactivity against MARK4. The molecular modeling studies showed thatthe derivatives bearing piperazine or tryptophan bind well to theATP-binding site of MARK4. The antiproliferative activity of six activecompounds was evaluated against HeLa and U87MG cancer cells. Tryptophanderivatives 23a, 23b, and 23c showed significant cytotoxicity against both cell lines with EC50 values ranging from 2.13 to 4.22 & mu;M, while derivativesbearing piperazine were found to be not cytotoxic. Additionally, compound 23a decreased the proliferation of human MDA-MB-435 and U251cancer cells in the low micromolar range; however, it also affectsthe non-cancerous HGF cells. Due to their high binding affinity againstMARK4, the synthesized compounds could be potential agents to targetMARK4 against cancer and tauopathies.

Automated summary

In this study, derivatives of 2-methylacridone were synthesized and tested for their MARK4 kinase inhibitory activity. The derivatives with piperazine and tryptophan moieties showed high antiproliferative activity against cancer cells.