On interactions of cytostatic benzylidine hydrazines with SH-groups.
The cytostatic and mutagenic compound N'-methyl-N'-cyano-(p-chloro)-benzaldehyde hydrazone (CyB4) has been found to be a strong SH-blocking agent since it reacts with the thiol groups of glutathione and of the cell membrane of Ehrlich ascites carcinoma cells (EAC). Furthermore, it decreases the intracellular, non-proteinogenic SH(NPSH)-level of tumor cells. CyB4 is not able to alkylate 4-(p-nitrobenzyl)-pyridine (NBP) by a nucleophilic substitution reaction, but it could be shown that the reactivity of CyB4 with thiol groups is due to a Michael-addition-type reaction of SH-groups with the cyano-group of CyB4. On the other hand, cytostatic beta-chloroethyl hydrazones showed a negligible reactivity against glutathione and led even to an increase of thiol groups, detectable by the 5,5'-dithiobis-2-nitrobenzoic acid (DTNB)-method, at the cell membrane of EAC when incubated in the presence of beta-chloroethyl hydrazones N-benzylidene-N'-methyl-N'-(2-chloroethyl) hydrazine (B1) and N-(4-dimethylaminobenzylidene)-N'-methyl-N'-(2-chloroethyl) hydrazine (B2). Therefore, it is concluded that the cytostatic efficiency of CyB4 is due to its SH-blocking while that of the beta-chloroethyl hydrazones is due to a rearrangement of the tumor cell membrane, as indicated by the increased level of reactive SH-groups.
D000477:Alkylating Agents; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology*; D006835:Hydrazones / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009578:Nitrobenzenes / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D006834:Hydrazines; D006835:Hydrazones; D009578:Nitrobenzenes; D011725:Pyridines; D013438:Sulfhydryl Compounds; C008633:4-(4-nitrobenzyl)pyridine; D005978:Glutathione