Cinnamic acid derived oxazolinium ions as novel cytotoxic agents.
Substituted cinnamoyl chlorides, 11, were converted into (2-hydroxyethyl)-oxazolinium chlorides 14, N,N-bis-(2-chloroethyl)amides 16 and (2-chloroethyl)-oxazolinium chlorides 17. Although derivatives 14 which possess electron-donating substituents (Me or MeO) were more potent than those substituted by electron-withdrawing groups (NO(2), Cl or CF(3)), the difference in cytotoxic actin was not significant. Modification of the lipophilic character in a series of alkoxy-substituted derivatives 14 led to more active compounds, where 14t that possesses a 4-octyloxy-phenyl-substituent was the most potent and displayed cytotoxic activity in the microM range. It is assumed that the oxazolinium salts act as alkylating agents, and undergo nucleophilic attack on the methylene adjacent to the ring oxygen where the oxazolinium ring parallels the aziridinium ring intermediate found in classical alkylating agents.
Chemistry Department, Bar Ilan University, 52900, Ramat Gan, Israel.
Lilach
L
Hedvati
Abraham
A
Nudelman
Eliezer
E
Falb
Boris
B
Kraiz
Regina
R
Zhuk
Milon
M
Sprecher
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002934:Cinnamates; D010080:Oxazoles; C029010:cinnamic acid