Studes On 4-amino-1, 8-naphthaleneimide Analogues As PARP Inhibitors

Poly(ADP-ribose) polymerase(PARP) in DNA damage and repair pathways plays a key role, which widely participates in the process of DNA damage recognition and signal transduction. PARP provides a new target for cancer treatment, it can promote the development of anti-cancer drugs. Now, many highly selective and sensitive PARP inhibitors have been developed and applied in clinical trials. 4-AN as PARP inhibitor have been reported, it could be used as chemo/radiotherapy sensitizers. However its analogs did not study as PARP inhibitors, we judge that the analogs of 4-AN also can inhibit PARP.ObjectiveBorrowing 4-AN framework, a series of 1H-Benz[de]isoquinoline-1,3(2H)-diones were synthesized and evaluated for inhibition of PARP and biological activity.Elected compounds have PARP-1 inhibitory activity, which can be used as novel PARP inhibitors.Methods(1)Design of 4-Amino-1, 8-naphthalimide derivatives. Borrowing 4-AN framework and PARP-1 pharmacophore, We designed a series of 4- AN derivatives.(2)Synthesis and structure identification of 4-Amino-1,8-naphthalimide derivatives. All the compounds were identified by NMR, HRMS and IR.(3) Test of PARP-1 inhibitory activity. All compounds in this study were evaluated for their ability to inhibit PARP-1 enzymatic activity through the methods of a highly sensitive colorimetric, nonradioactive format enzymatic assay. Compounds with PARP-1 inhibitory ratio>50% at the concentration of 10?M were selected to determine IC50 value.(4)Establish Molecular docking model. Through computer simulation, the molecular docking PARP-1 enzyme was obtained.(5)Evaluation of the biological activity of the compounds. PARP inhibitors were selected to study whether they can potentiate cytotoxicity of cDDP which is DNA-damaging antitumor agent. Data obtained by MTT assay was used to calculatethe combination index(CI) and to evaluate the effects of drug-drug combinations.Results(1)Design and synthesis of a series 1H-Benz[de]isoquinoline-1,3(2H)-dione analogues.(2)Through the screening of PARP activity in vitro, compound 3c, 3e IC50 value were 2.39, 6.08?M, compound 3c showed well cell toxicity and water-soluble.Compound 3d showed an encouraging activity against PARP-1 with IC50 values of0.51?M and good water-soluble.(3)Molecular docking suggests that the hydroxyl group of compound 3d is appropriate of forming a potential electrostatic interaction with the carboxylate group of Glu988 and two H-bonds occurred between the imide and tertiary amine group of compound 3c and Glu988.(4)The cytotoxicity of drug combination studies indicated compound 3d and cDDP have a synergistic effect.ResultsCompound 3d displayed an encouraging activity against PARP-1 with IC50 values of 0.51?M and 2.6-fold solubility compared with 4-AN. The cytotoxicity of drug combination studies indicated compound 3d and cDDP have a synergistic effect. All these data confirmed that compound 3d can be used as PARP-1 inhibitors and a drug candidate for further studies. Meanwhile, compound 3c exhibited good anti-cancer effect.