Synthesis And Biological Evaluation Of Nucleic Acid-targeted Anticancer Agents Of Naphthalene Carboxamide Derivatives

According to the principle of molecular hybridization, pharmacophores were introduced into the typical DNA intercalators. Designed and synthesized three series of DNA-targeted anticancer drugs by modifying classical matrix 1,8-naphthalimide and benzo[c, d]indol-2(1H)-one. The structures of the compounds were validated by 1HNMR,13CNMR and MS, inhibitory activity of tumor cells in vitro of which were tested by the MTT method. By spectral qualities and viscosity assay to evaluate their DNA binding abilities.4-Br-1,8-naphthalene anhydride was choosed as starting material to synthesize 6 novel naphthalimide derivatives containing hydrazino methyl formate, hydrazino dithioester and thiosemicarbazide. Their structures were validated by 1HNMR,13CNMR and MS. DNA binding abilities of which were evaluate by UV-vis spectra, Fluroresence spectra, CD spectra and viscosity assay. Inhibitory activity of tumor cells in vitro showed that most of compounds had improved inhibition activity against Hela and MCF-7 cells and low toxicity to HL7702 cells, which exhibited good biological selectivity and IC50 value in microns level. Especially compound D5 was found to be the most effective against MCF-7 (IC50,2.83 μM), also whose IC50 value against HL7702 was 7.6 fold higher than Hela,25 fold higher than MCF-7.Benzo[c, d]indol-2(1H)-one was used as starting material, malononitrile was linked to naphthalene by Knoevenagel condensation.4 novel naphthalene lactam derivatives containing benzothiazole were successfully synthesized. The intensity changes of UV-Vis and fluorescence spectra indicated the compounds had strong interact with DNA, the CD spectra and viscosity test of DNA manifested that which could intercalate into the DNA effectively and turn the conformation of DNA from B to A-like. MTT assay showed compounds L1 and L2 had strong inhibition activity against Hela and MCF-7 cells, whose IC50 value in 5～20 μM. In particular compound L2, the IC50 values against Hela was 6.70 μM, exhibited good selectivity, whose IC50 value against HL7702 was 12.7 fold higher than Hela.Based on bioactivity of aminopyrimidine, we synthesized 4 novel naphthalimide In particular compound T3, the IC50 values against MCF-7 was 0.72 μM, exhibited excellent biological selectivity, whose IC50 value against HL7702 was 16.8 fold higher than Hela,97 fold higher than MCF-7.