Design And Biological Evaluation Of DNA-targeted Anticancer Agents Of Naphthalene Carboxamide Derivatives

Three series of DNA-targeted anticancer agents based on the restructuring of 1,8-naphthalimide and benzo[c, d]indol-2(1H)-one were designed.20 compounds were successfully synthesized and their DNA binding and anti-tumor abilities in vitro were evaluated.By applying the new suggestion that the "non-fused" aromatic system strategy, 6-[1H-benzo[d]imidazole-2-yl]-1,8-naphalimides were designed and synthesized. UV-Vis spectra, Fluorescence spectra, CD spectra and Viscosity measurement all showed that the derivatives could intercalate with DNA by classic intercalating mode. Both intercalating and electrostatic binding modes existed when R (Ccom/CDNA)> 0.6. Except compound M3, all compounds exhibited excellent inhibition of growth of tumor cells, in particular M1, the value of IC50 for MCF-7 could amount to 10-/M, indicating that its potent was higher than amonfide.Benzo[c,d]indol-2(1H)-one, an naphthalene lactam derivatives, is a kind of novel potential DNA-intercaltors and by linking the flexible side chains instead of previously rigidness to the nitrogen of benzo[c,d]indol-2(1H)-one,9 novel anti-tumor agents were successfully synthesized. The results of UV-Vis spectra, Fluorescence spectra, CD spectra and viscosity measurement showed that all the compounds with the binding constants about 104 can intercalate into the base pairs of DNA and stabilize the B-DNA. It's also could be found by fluorescence that derivatives were better excellent "light up" probe for DNA than EB. The serial of compounds A1-5 which length of side chains were 3 had a distinct higher potent than that of serials of B1-4 which had a shorter length of side chains. When bearing N,N-dimethylamino, piperazinyl and N-methylpiperazinyl at the side chains, the activity of inhibition of cell proliferation was excellent, such as compound A1 that the potent was 4.8 fold higher than amonafide.Based on the bioactivity of triazole, we designed and synthesized 5 novel benzo[c,d]indol-2(1H)-one derivatives by employing "click" method with Cu(Ⅱ) catalysis. The effect of triazole made hyperchromicity and hypochromatic shift of the UV spectra, no clearly change of CD spectra and increasing of viscosity of DNA, suggesting both groove binding and intercalating mode occurred. Compound T2 own a sharp signal of ICD in 510 nm indicating that molecular intercalated into the base pairs by perpendicular to the axis of DNA. In view of fluorescence, we deduced that T1, T2 and T3 could be an excellent "light up" probe for DNA. The study of CDC25B inhibition showed that derivatives had stronger potent for CDC25B, such as T2 with inhibition ratio amount to 99.99% at 50μM. The value of IC50 for MCF-7 of compound T2 were 0.626μM, indicating that it's potent was higher than amonfide.