Synthesis And Study On The Antitumor Activity Of Nitro-containging Foused Heterocyclic Compounds

Based on the action mechanism of antitumor agents that target DNA,three series of compounds were designed,synthesized and charactered by structural modify to natural product furocoumarin and acenaphtho-pyrrole heteroaromatic system and the derivative of lead amonafide.The following studies are made.1.Based on parent compound,furoquinolinone,which is a phototherapeutical agent, N-substituted angular furoquinolinone derivatives were designed by introducing of the side chain to the N-position of furoquinolinone.Twelve target compounds(eleven compounds are not reported) were prepared from m-phenylenediamine and ethyl acetoacetate by six steps including Pechmann condensation,diazotization,hydrolysis,substitution,cyclization and coupling reaction.The evaluation for antitumor activities in vitro indicated that the introduction of amino side chain is an effective way to improve the antitumor activity of the parent.Compound 1h N-(2-dimethylamino-ethyl)-2-(4,8,9- trimethyl-2-oxo-2H- furo[2,3-h]-quinolin-1-yl)-acetamide exhibited the highest activities against P388 and A549 cell lines and its IC₅₀ values are 14.45μM and 20.54μM,respectively.However,the IC₅₀ of the parent compound are＞100μM and 99.29μM at the same experiment,respectively.2.To retain the biological activity of the amonafide and reduce the side effects,5-position aliphatic amine substituted naphthalimide and 5-position aromatic substituted naphthalimide were designed.The target compounds were synthesized from naphthalic anhydride by three steps including bromization,amination and coupling reaction.The nucleophilic substitution reaction at the 5-position of the naphtahlimide is difficult to occur by traditional chemical method due to electron-charge accumulation induced by strong electron-withdrawing ability of carbonyl.Therefore,the third step reaction is the most difficult.In this paper,we first reported the synthesis of 5-aliphatic amine substituted and 5-aromatic substituted naphthalimide derivatives via CuI/proline catalyzed coupling reaction and Suzuki coupling reaction,respectively.Eight 6-aliphatic amine substituted naphthalimide derivatives were synthesized via nucleophilic substitution reactions.The eight new compounds exhibited better activity than amonafide(the IC₅₀ vaIues are 6.02μM and 0.68μM,respectively)against HeLa and P388D1 cell under the same experimental conditions.Among the compounds,3a (5-(Dimethylamino-ethylamino)-2-[2-(dimethylamino)ethyl]-1H- benzo[de]- isoquinoline-1,3 (2H)-dione,IC₅₀ = 0.69μM),3b(5-(Dimethylaminopropylamino)- 2-[2-(dimethylamino) ethyl]- 1H-benzo[de]isoquinoline- 1,3(2H)-dione,IC₅₀ = 0.71μM),4b(6-(dimethylaminoproplamino) -2-[2-(dimethylamino)ethyl]-1H-benzo[de]isoquinoline-1,3(2H)-dione,IC₅₀ = 0.64μM);against P388D1,3b(IC₅₀ = 0.23μM),4b(IC₅₀= 0.23μM).The compounds can avoid the side effect of amonafide due to lack of a primary amine in their structure.The antitumor activities in vitro of the 6-amino substituted naphthalimide derivatives are better than those of 5-amino substituted.Therefore,this work not only can obtain new compounds with antitumor activities for clinical screen,but also expand the structure activity relationships studies of the naphthilimides.3.New 8-oxo-SH-acenaphtho[1,2-b]pyrrole-9-carboxylic acid derivatives were designed and synthesized.Nine target compounds were synthesized from acenaphthene quinone by four steps including Knoevenagel condensation,cyclization,hydrolysis and S_NAr^H reaction. Among the compounds,5d(3-(3-Dimethylamino-propylamino)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid) and 5g(3-Piperidin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid) show better antitumor activities in vitro,the IC₅₀ value of 5d against HL-60 cell is 13.11μM and the IC₅₀ of 5g against HeLa,HL-60,HCT-8,A-3375 and MCF-7 cell are 20.61,20.52,24.42,18.43 and 14.51μM,respectively.Cell cycle analysis indicated that 5d could induce S-phase arrest followed by apoptosis and 5g only induced apoptosis,although the both compounds could bind to DNA in same way.4.DNA-binding of the above mentioned compounds are investigated by fluorescent, UV-vis,CD spectroscopic techniques and viscosity measurement.The results indicate that the compounds bind to DNA mainly via intercalation.The Scatchard-binding constants in 10⁵ order of magnitude are actually moderate DNA-intercalators.