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

多药耐药是癌症化疗的主要障碍。为了获得有效的多药耐药调节剂，我们合成了一系列末端含有苯、甲基苯环或氯取代苯环的二胺、二甲酰胺和二磺酰胺化合物，并检测了它们对多药耐药小鼠白血病P388/ADR细胞中vinblastine积累的影响。这些化合物的药效顺序大致为二磺胺类、bb0二胺类、bb1二羧胺类。具有末端甲基苯环或氯取代苯环结构的n -甲基化二胺和二磺酰胺化合物也表现出相当强的功效。根据这些发现，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]二嗪，该化合物在体外有效地逆转了多重耐药。此外，我们还合成了1,3,5-三氮杂环庚烷，并检测了其逆转p -糖蛋白依赖性多药耐药的作用。这些化合物大多增加了多药耐药小鼠白血病P388/ADR细胞内长春碱的摄取，而不影响P388/S细胞内长春碱的积累。1,5-二苄基-1,3,5-三氮杂环庚烷对长春花碱积累的促进作用顺序为2,4-二硫氧基>2-氧基-4-硫氧基=4-（甲基硫基）- 2,4-二氧基>。当苯基转化为氯苯基时，疗效进一步提高。其中，1,5-二（4-氯苯基）-1,5,6,7-四氢-4-甲基硫)- 2h -1,3,5-三氮平-2-one比长春碱单用更能增强长春碱、阿霉素和丝裂霉素C对P388/ADR细胞的体外抑制作用，延长P388/ADR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.