Liu M C, Lin T S, Penketh P, Sartorelli A C
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
J Med Chem. 1995 Oct 13;38(21):4234-43. doi: 10.1021/jm00021a012.
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.
已合成了多种取代异喹啉 -1- 甲酰基硫代卡巴腙（12种化合物），并在携带L1210白血病的小鼠中评估了其抗肿瘤活性。4-溴 -1- 甲基异喹啉（4）与氢氧化铵、甲胺、乙胺和N - 乙酰乙二胺缩合，得到相应的4-氨基、4-甲基氨基、4-乙基氨基和4-N -（乙酰乙基）氨基衍生物，然后将其转化为酰胺，随后氧化为醛，再与硫代卡巴肼缩合，得到硫代卡巴腙8a - c、9a - c和16。4经硝化，然后用二氧化硒氧化，生成醛18，再将其转化为环状亚乙基缩醛19。19与吗啉缩合，然后催化还原硝基并用硫代卡巴肼处理，得到5-氨基 -4- 吗啉基异喹啉 -1- 甲酰基硫代卡巴腙（22）。1,5 - 二甲基异喹啉经N - 氧化，然后用乙酸酐重排，经酸水解后得到1,5 - 二甲基 -4- 羟基异喹啉，将其转化为乙酸酯，然后氧化得到4 - 乙酰氧基 -5- 甲基异喹啉 -1- 甲酰基（32）。1,4 - 二甲基异喹啉经磺化，然后与氢氧化钾反应、乙酰化和氧化，得到5 - 乙酰氧基 -4- 甲基异喹啉 -1- 甲酰基（40）。化合物32和39与硫代卡巴肼缩合，分别得到相应的4-和5-乙酰氧基（5-和4-甲基）硫代卡巴腙33和40，然后通过酸水解将它们分别转化为相应的4-和5-羟基衍生物34和41。合成的最具活性的化合物是4-氨基异喹啉 -1- 甲酰基硫代卡巴腙（9a）和4-（甲基氨基）异喹啉 -1- 甲酰基硫代卡巴腙（9b），当以40 mg/kg的每日剂量连续给药6天时，它们对小鼠L1210白血病的最佳%T/C值均为177。此外，当9a以40 mg/kg的剂量每日给药两次，连续给药6天时，获得了165的T/C值，并且60%的小鼠成为60天的长期存活者。
