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To obtain potent antitumour agents with low toxicity, sulfonamide derivatives containing 5-flurouracil and nitrogen mustard, respectively are designed and synthesised. 1-(3-(4-Acetylaminobenzenesulfonamido)-3-oxopropyl)-5-fluoropyrimidine-2,4-dione ( 4 ) was obtained by the coupling of p -acetamidobenzenesulfonamide with 3-(5-fluorouracil-1-yl) propionic acid. The hydrolysis of 4 led to 1-(3-(4-aminobenzenesulfonamido)-3-oxopropyl)-5-fluoropyrimidine-2,4-dione ( 5 ). Treatment of p -acetamidobenzenesulfonyl chloride with bis(2-chloroethyl) amine led to 4-acetylamino- N , N -bis(2-chloroethyl)benzenesulfonamide ( 6 ). Subsequent hydrolysis of 6 in hydrochloric acid led to 4-amino- N , N -bis(2-chloroethyl)benzenesulfonamide hydrochloride ( 7 ). Two different synthetic route were investigated in the synthesis of 2-[ N 1 -2-pyrimidyl-aminobenzenesulfonamido] ethyl 4-bis(2-chloroethyl) aminophenyl butyrate ( 12b ). Carbobenzyloxy was proved to be unsuitable for the protection of the aromatic amino group of sulfadiazine since the pyrimidine ring was also hydrogenated at the last step of the first route under the deprotection condition. In another route, acetyl was firstly used as the protective group, then it was replaced by the Schiff's base. The reaction of chlorambucil with 2-[ N 1 -2-pyrimidinyl-( p -acetyl)aminobenzenesulfonamido] ethanol ( 10b ) afforded 2-[ N 1 -2-pyrimidinyl-( p -benzylidene)aminobenzenesulfonamido] ethyl 4-bis(2-chloroethyl) aminophenyl butyrate ( 11b ). Compound 12b was obtained by the hydrolysis of 11b . The acute toxicity and antitumour activity of 5 , 7 and 12b have been investigated in mice. Compound 12b exhibited high antitumour activity and low toxicity with a therapeutic index (TI) of 47.55. |
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