Synthesis of 2,2′-dithiobis- and 2,2′-trithiobis-3-pyridinecarboxylic acid derivatives as new potential radiosensitizers/radioprotectors

This paper reports the synthesis of dithio and trithio derivatives of 1,2-dihydro-2-thioxopyridine, starting with 1,2-dihydro-2-thioxo-3-pyridine carboxylic acid 1 . This compound reacted with thionyl chloride to give the respective dithiobis (acyl chloride) 2 , which hydrolyzed to the corresponding dithio acid 3 . On the other hand, 1 reacted with sulfur dichloride to give trithio acid 4 , which on treatment with thionyl chloride gave the trithiobis (acyl chloride) 5 . Treatment of 2 and 5 with ethanol/pyridine, gave 8 and 12 respectively. Compounds 2–5, 8 and 12 were unstable in alkaline medium and they were degraded to 1 . The bis(acyl chloride) 2 and 5 reacted with ammonia and primary and secondary amines to give the respective bis(amide) 9 and 13 . Most of these amides (R = H, alkyl, aryl, R' = H) were found to be unstable in the presence of bases such as triethylamines, pyridine or excess of the starting amine, which promotes disproportion to give (see Scheme 3) the respective N-substituted (R) 1,2-dihydro-2-thioxo-3-pyridinecarboxamide 10 and the respective 2-substituted (R)-3-oxo-isothiazolo5,4-b]pyridine 11 . On the other hand, compounds 11 were unstable to strong bases and they were transformed into the respective compounds 10 by an unknown mechanism. Boiling 11f with sodium hydroxide in ethanol gave 10f (50%). According to these last results, boiling 9h or 13d with sodium hydroxide in ethanol 10h (68%) and 10d (70%) were obtained.