STRUCTURE-ACTIVITY RELATIONSHIPS OF ALKANEDIAMINES HAVING ANTI-MULTIDRUG RESISTANT ACTIVITY

多药耐药是肿瘤化疗的主要障碍。为了获得有效的多药耐药调节剂，我们合成了一系列的二胺，二甲酰胺，和二磺酰胺化合物与终端苯，甲基或氯取代的苯环在两个末端，并检查长春碱的积累在多药耐药小鼠白血病P388/ADR细胞的效果。这些化合物的药效一般为二磺酰胺类>二胺类>二甲酰胺类。在其结构中具有末端甲基或氯取代的苯环的N-甲基化的二胺和二磺酰胺化合物也显示出相当有效的功效。基于这些发现，我们合成了一种新的二磺酰胺化合物，1，2，3，4，5，6-六氢-2，5-二（对甲苯磺酰基）苯并[2，5]二氮杂环辛，并且该化合物在体外有效地逆转多药耐药性。此外，1，3，5-三氮杂环庚烷的合成和检查逆转P-糖蛋白依赖的多药耐药。大多数化合物能增加耐药小鼠白血病P388/ADR细胞对长春碱的摄取，但不影响长春碱在P388/S细胞中的蓄积。1，5-二苄基-1，3，5-三氮杂环庚烷类化合物增加长春碱蓄积的效果顺序为2，4-二硫代>2-氧代-4-硫代=4-（甲硫基）-2-氧代> 2，4-二氧代。当苄基转化为氯苄基时，效力进一步增加。在这些化合物中，1，5-二（4-氯苄基）-1，5，6，7-四氢-4-甲硫基）-2H-1，3，5-三氮杂卓-2-酮增强长春碱、阿霉素和丝裂霉素C对P388/ADR细胞的体外细胞生长抑制作用，并且与长春碱联合治疗比单独长春碱更延长P388/ADR荷瘤小鼠的寿命。

Multidrug resistance is a major obstacle in cancer chemotherapy. To obtain potent multidrug resistance modulators we synthesized a series of diamine, dicarboxamide, and disulfonamide compounds with terminal benzene, methyl- or chloro-substituted benzene rings at both termini and examined the effect on vinblastine accumulation in multidrug-resistant mouse leukemia P388/ADR cells. The efficacy of these compounds was generally in the order of disulfonamides>diamines>dicarboxamides. N-Methylated diamine and disulfonamide compounds having terminal methyl- or chloro-substituted benzene ring in their structure also showed rather potent efficacy. From these findings, we synthesized a novel disulfonamide compound, 1,2,3,4,5,6-hexahydro-2,5-bis (p-toluenesulfonyl) benzo [2,5] diazicine, and this compound potently reversed multidrug-resistance in vitro. Furthermore, 1,3,5-triazacycloheptanes were synthesized and examined for reversal of P-glycoprotein-dependent multidrug resistance. Most of these compounds increased the intracellular uptake of vinblastine in multidrug-resistant mouse leukemia P388/ADR cells without influence upon the vinblastine accumulation in P388/S cells. The efficacy of 1,5-dibenzyl-1,3,5-triazacycloheptanes in increasing the vinblastine accumulation was in the order of 2,4-dithioxo>2-oxo-4-thioxo=4- (methylthio) -2oxo>2,4-dioxo. The efficacy was further increased when the benzyl group was converted to a chlorobenzyl group. Among these compounds, 1,5-bis (4-chlorobenzyl) -1,5,6,7-tetrahydro-4-methylthio ) -2H-1,3,5-triazepin-2-one increased the in vitro cell growth-inhibitory effect of vinblastine, adriamycin, and mitomycin C on P388/ADR cells and prolonged the life span of P388/ADR-bearing mice in combined therapy with vinblastine more than vinblastine alone.