Synthesis and antitumor activity of 4- and 5-substituted derivatives of isoquinoline-1-carboxaldehyde thiosemicarbazone.
Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Condensation of 4-bromo-1-methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamine, and N-acetylethylenediamine gave the corresponding 4-amino, 4-methylamino, 4-ethylamino, and 4-N-(acetylethyl)amino derivatives, which were then converted to amides and subsequently oxidized to aldehydes followed by condensation with thiosemicarbazide to yield thiosemicarbazones 8a-c, 9a-c, and 16. Nitration of 4, followed by oxidation with selenium dioxide, produced aldehyde 18, which was then converted to the cyclic ethylene acetal 19. Condensation of 19 with morpholine followed by catalytic reduction of the nitro group and treatment with thiosemicarbazide afforded 5-amino-4-morpholinoisoquinoline-1-carboxaldehyde thiosemicarbazone (22). N-Oxidation of 1,5-dimethylisoquinoline, followed by rearrangement with acetic anhydride, gave, after acid hydrolysis, 1,5-dimethyl-4-hydroxyisoquinoline, which was converted to its acetate and then oxidized to yield 4-acetoxy-5-methylisoquinoline-1-carboxaldehyde (32). Sulfonation of 1,4-dimethylisoquinoline, followed by reaction with potassium hydroxide, acetylation, and oxidation, gave 5-acetoxy-4-methylisoquinoline-1-carboxaldehyde (40). Condensation of compounds 32 and 39 with thiosemicarbazide afforded the respective 4- and 5-acetoxy(5- and 4-methyl)thiosemicarbazones 33 and 40, which were then converted to their respective 4- and 5-hydroxy derivatives 34 and 41 by acid hydrolysis. The most active compounds synthesized were 4-aminoisoquinoline-1-carboxaldehyde thiosemicarbazone (9a) and 4-(methylamino)isoquinoline-1-carboxaldehyde thiosemicarbazone (9b), which both produced optimum % T/C values of 177 against the L1210 leukemia in mice when used at a daily dosage of 40 mg/kg for 6 consecutive days. Furthermore, when 9a was given twice daily at a dosage of 40 mg/kg for 6 consecutive days, a T/C value of 165 was obtained and 60% of the mice were 60-day long-term survivors.
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D005965:Glucuronates / Q000378:metabolism; D006878:Hydroxides; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D017680:Potassium Compounds; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000627:therapeutic use
C096255:4-(methylamino)isoquinoline-1-carboxaldehyde thiosemicarbazone; C096253:4-aminoisoquinoline-1-carboxaldehyde thiosemicarbazone; D000970:Antineoplastic Agents; D005965:Glucuronates; D006878:Hydroxides; D007546:Isoquinolines; D017680:Potassium Compounds; D013882:Thiosemicarbazones; C029943:potassium hydroxide