Antagonists of vitamin B6. Simultaneous and stepwise modification of the 2 and 4 positions.
Methods for the simultaneous and stepwise modification of the 2 and 4 positions of vitamin B6 have been devloped and have been applied to the synthesis of several analogues of this vitamin. 3,alpha5-O-Dibenzylpyridoxol was converted to its N-oxide and was rearranged to an alpha2-hydroxy derivative with (CF3CO)2O. The 2,4-bis(hydroxymethyl) intermediate was oxidized (MnO2) to the 2,4-dialdehyde, which was converted by a Wittig reaction with triphenylmethylphosphorane to the 2,4-divinyl derivative. Removal of the benzyl groups with acid gave the 2,4-divinylpyridioxol analogue, which was phosphorylated in the 5' position to give the cofactor analogue. The 2-CH3 in the known vitamin B6 antagonists, 4-deoxypyridoxol and 4-vinylpyridoxal, was similarly modified to CH2OH, CHO, and CH = CH2. Modifications of the 2 position in the vitamin B6 antagonists are expected to be associated with changes in selectivity for enzymes in various tissues without a concomitant loss of biological activity, because of the well-established bulk tolerance in this position. Active analogues are expected to undergo, in vivo 5-phosphorylation, which is probably a prerequisite for their antagonist activity. Some of the compounds (e.g., the 2,4-divinyl analogue) have substantial growth-inhibitory activity for cultured mouse mammary adenocarcinoma. In contrast to that of the parent compounds, this activity was only partially reversed by pyridoxal.
D000230:Adenocarcinoma / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003497:Cyclic N-Oxides / Q000138:chemical synthesis; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D011736:Pyridoxine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000138:chemical synthesis
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D014753:Vinyl Compounds; D011736:Pyridoxine