Elliott G T, Nagle W A, Kelly K F, McCollough D, Bona R L, Burns E R
Ribi ImmunoChem Research, Inc., Hamilton, Montana 59840.
J Med Chem. 1989 May;32(5):1039-43. doi: 10.1021/jm00125a018.
Two previously synthesized and two structurally novel thiazoline iron chelators are described. N4-Benzyl-N1,N8-bis[[2-(2-hydroxyphenyl)thiazolin-4-yl]carbonyl] homospermidine (5) proved to be the most potent antiproliferative and cytocidal compound in the series with in vitro IC50 values of 3 and 1 microM on L1210 and P388 murine cell lines. The N4-acetyl analogue 7 was considerably less active than 5 with IC50 and cell viability values that were similar to those of the structurally simple thiazolines 2 and 3. The antiproliferative activity of 3 and 7 could be substantially reduced or ablated by delivery to cell suspensions as a 1:1 molar mixture with FeCl3, while the activity of 5 was unaffected by Fe(III) chelation. As expected, 3 induced a G1/S cell cycle block at the 100 microM block consistent with interference with DNA synthesis while 10 microM 5 did not affect L1210 cell cycle distribution. Tritiated thymidine incorporation studies confirmed that 5 was incapable of interfering with DNA synthesis at concentrations below 40 microM. Alkaline elution studies indicate that 5 does not cause DNA strand breaks in vitro at concentrations of 10 microM. The N4-benzyl group of 5 appears to impart in vitro potency as the N4-acetyl analogue 7 lacks comparable in vitro antiproliferative and cytocidal activity.
本文描述了两种先前合成的和两种结构新颖的噻唑啉铁螯合剂。N4-苄基-N1,N8-双[[2-(2-羟基苯基)噻唑啉-4-基]羰基]高亚精胺(5)被证明是该系列中最有效的抗增殖和杀细胞化合物，对L1210和P388小鼠细胞系的体外IC50值分别为3和1 microM。N4-乙酰基类似物7的活性明显低于5，其IC50和细胞活力值与结构简单的噻唑啉2和3相似。当以与FeCl3的1:1摩尔混合物形式递送至细胞悬液时，3和7的抗增殖活性可大幅降低或消除，而5的活性不受Fe(III)螯合的影响。正如预期的那样，3在100 microM时诱导G1/S细胞周期阻滞，这与干扰DNA合成一致，而10 microM的5不影响L1210细胞周期分布。氚标记胸腺嘧啶掺入研究证实，5在浓度低于40 microM时不能干扰DNA合成。碱性洗脱研究表明，5在10 microM浓度下体外不会导致DNA链断裂。5的N4-苄基似乎赋予了体外活性，因为N4-乙酰基类似物7缺乏可比的体外抗增殖和杀细胞活性。
