Relationship of spontaneous chemical transformation of arylsulfonylhydrazones of 2-pyridinecarboxaldehyde 1-oxide to anticancer activity.
The arylsulfonyl-hydrazones of 2-pyridinecarboxaldehyde 1-oxide represent a relatively new class of antineoplastic agents with the potential for clinical usefulness. The requirement for spontaneous chemical transformation of these agents to exert anticancer activity was evaluated using as the prototype the most potent member of this class synthesized to date, the 3,4-dimethoxybenzene sulfonylhydrazone of 2-pyridinecarboxaldehyde 1-oxide (3,4-DSP. 3,4-DSP was chemically unstable, decomposing with a half-life of 19 min in 0.01 M potassium phosphate buffer (pH 7.4) at 37 degrees. The major chemical decomposition product was identified as 2-pyridylcarbinol 1-oxide by comparison with the authentic compound. This carbinol is hypothesized to be formed via the intramolecular abstraction of hydrogen from the arylsulfonyl-hydrazone, a process that leads to the release of 3,4-dimethoxybenzenesulfinic acid and the formation of 1-oxidopyridin-2-yldiazomethane, which subsequently reacts with water. The diazomethane intermediate is a potent alkylating agent which, if generated in cells, would have the potential to alkylate nucleophilic groups of biologically important macromolecules. The proposed reactive species was trapped using both 4-(4-nitrobenzyl)pyridine (NBP) and morpholine, and the latter product was characterized by mass spectroscopy. The importance of the chemical formation of an alkylating species to cytotoxicity was demonstrated by studies in which solutions of 3,4-DSP were "aged" prior to addition to L1210 leukemia cells in culture and prior to incubation with NBP. The "aging" of 3,4-DSP for 20 min resulted in a 4-fold decrease in cytotoxicity, and aging for 1 to 3 hr led to complete loss of cytotoxicity. Correspondingly, a 20-min aging period decreased alkylation of NBP by 51%, and 3-hr aging resulted in essentially no alkylation of the nucleophile. Further support for the above proposed chemical activation pathway was provided by correlations between in vitro cytotoxicity, in vivo antineoplastic activity, chemical stability, and the degree of alkylation of NBP by a wide variety of arylsulfonyl-hydrazones. The lack of the 1-oxide, envisioned to be required for intramolecular hydrogen abstraction, the steric prevention of the abstraction, or the replacement of the proton of the nitrogrn of the side-chain by a methyl group resulted in a marked increase in chemical stability and a corresponding loss of the ability to alkylate NBP and to inhibit the replication of L1210 leukemia cells in culture.
D000477:Alkylating Agents; D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D006207:Half-Life; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D009540:Nicotinyl Alcohol; D011725:Pyridines; D012513:Sarcoma, Experimental / Q000473:pathology; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D006835:Hydrazones; D011725:Pyridines; C008633:4-(4-nitrobenzyl)pyridine; C037562:2-pyridinecarboxaldehyde-1-oxide-3,4-dimethoxybenzene sulfonylhydrazone; D009540:Nicotinyl Alcohol