Design,Syntheses of Novel Triazenes with Better Druggability and the Investigation on Their Anti-tumor Activities
Eleven novel 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-alkyl(R2)triazenes have been designed and synthesized.Firstly,4-aminobenzoic acid,as starting material,underwent diazo reaction following the reaction with methyl alkylamine to build the triazene scaffold.Condensation of carboxylic group with 2-diethylaminoethylamine re-sulted in all the title compounds.The overall yield of these 3-step reactions was between 46.5％and 68.3％.By using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,l-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-cyclohexyltriazene(6a),l-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-phenyltriazene(6e)～1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)benzyltriazene(6j)were confirmed as good broad-spectrum anti-cancer agents again/st human liver cancer cells(HepG-2),rat glioma cells(C6),human colon cancer cells(SW620),human prostate cancer cells(PC-3),murine melanoma cells(B16),and human non-small-cell lung cancer cells(A549).Among them,1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene(6g)show-ed as the most active agent,where IC50 values of 6g against C6,SW620,PC-3,and B16 cell lines are less than 10 pmol/L,which is far better than the positive dacarbazine.It was found that when R2 is aryl group with propriate electron-withdrawal intensity,the triazene will have good even excellent anti-cancer activity.Through drug safety evaluation,the safety indexes(SI)of 6e,6g,and l-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene(6h)against C6,SW620,and PC-3 cell lines,respectively;6g,6h,and 1-(4-(N-(2-diethylamino)ethyl)aminoformoxyl)phenyl-3-methyl-3-(4-methoxyl)phenyltriazene(6i)against B16 cell line respectively;6e,6h,and 6i against HepG-2 cell line respectively;6i against C6,and SW620 cell lines,respectively;were identified more than 2.0,implied better drug safety than dacarbazine.The parti-tion coefficient(lg P)of 6e,6g～6i lied between 3.0 and 4.0,meaning good membrane permeability.All the data support that the novel triazenes 6e,6g～6i have better druggability.
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