Synthesis and activity of N-sulfonylamides of tripeptides as potential urokinase inhibitors.
Twelve peptides of the general X-SO(2)-D-Ser-Ala-Arg-OH formula (where X = methyl, phenyl, α-tolyl, p-tolyl, 4-methylbenzyl, 1-naphtyl, 2-naphtyl, 4-chlorophenyl, 4-bromophenyl, 2-mesityl, 2,4,6-triisopropylphenyl, 4-acetamidophenyl) were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. 2,4,6-triisopropylphenyl-SO(2)-D-Ser-Ala-Arg-OH was the most selective inhibitor of urokinase and α-tolyl-SO(2)-D-Ser-Ala-Arg-OH was the most active inhibitor of uPA with K(i) value 24 µM. The compounds were tested for their in vitro antitumour activity in the following human breast cancer cells: standard MCF-7 and estrogen-independent MDA-MB-231. Four of the synthesized peptides showed cytotoxic effects against MDA-MB-231 cell lines in the range from 2.9 to 8.5 µM. The examined compound did not influence to MCF-7 cancer cells. The synthesized peptides were nontoxic to pig's erythrocytes.
Markowska
Agnieszka
A
Department of Organic Chemistry, Medical University of Bialystok, Bialystok, Poland. agnieszka.markowska@umwb.edu.pl
Bruzgo
Irena
I
Miltyk
Wojciech
W
Midura-Nowaczek
Krystyna
K
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D001798:Blood Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013455:Sulfur; D013552:Swine
D000577:Amides; D001798:Blood Proteins; D010455:Peptides; C031220:urokinase inhibitor; D013455:Sulfur