Rush G F, Rinzel S, Boder G, Heim R A, Toth J E, Ponsler G D
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285.
Biochem Pharmacol. 1992 Dec 15;44(12):2387-94. doi: 10.1016/0006-2952(92)90684-b.
Diarylsulfonylureas, such as N-(4-chlorophenyl)aminocarbonyl-2,3-dihydro-1-indene-5-sulfonamide (LY186641, Sulofenur) and N-(4-chlorophenyl)aminocarbonyl-4-methylbenzene sulfonamide (LY181984), have been shown to be effective antitumor agents in a variety of in vivo and in vitro animal models. Their mechanism of action is unknown but does not appear to be the result of nonselective destruction of actively dividing cell populations. Mitochondria have been shown to accumulate Sulofenur and therefore may be targets of drug action. The purpose of these investigations was to examine the effects of a variety of diarylsulfonylureas in mitochondria and attempt to determine the relevance of these changes to antitumor activity. Many of the diarylsulfonylureas which were effective antitumor agents in animal models were also uncouplers of mitochondrial oxidative phosphorylation. They increased state 4 respiration and dissipated the mitochondrial membrane potential in a concentration-related fashion. The mechanism of uncoupling appeared to be related to a dissociable hydrogen ion as these molecules had pKa values that ranged from 6.0 to 6.2 and were highly lipophilic. Thus, the uncoupling action appears to be the result of hydrogen ion translocation. The mechanism of antitumor activity does not appear to be the result of uncoupling as no correlation was evident between inhibition of cell growth and uncoupling action of a variety of active and inactive diarylsulfonylureas. In vitro, Sulofenur is cytotoxic at high concentrations and inhibits cell growth at lower concentrations in the absence of any overt cell kill. The inhibition of cell growth also did not appear to be related to the uncoupling action of these drugs. In contrast, uncoupling may have played a partial role in the early, high exposure cell kill that can occur with these compounds.
二芳基磺酰脲类化合物，如N-(4-氯苯基)氨基甲酰基-2,3-二氢-1-茚-5-磺酰胺（LY186641，舒洛芬脲）和N-(4-氯苯基)氨基甲酰基-4-甲基苯磺酰胺（LY181984），在多种体内和体外动物模型中已被证明是有效的抗肿瘤药物。它们的作用机制尚不清楚，但似乎不是对活跃分裂细胞群体进行非选择性破坏的结果。线粒体已被证明会积累舒洛芬脲，因此可能是药物作用的靶点。这些研究的目的是检查多种二芳基磺酰脲类化合物对线粒体的影响，并试图确定这些变化与抗肿瘤活性的相关性。许多在动物模型中有效的抗肿瘤二芳基磺酰脲类化合物也是线粒体氧化磷酸化的解偶联剂。它们增加了状态4呼吸，并以浓度相关的方式消散线粒体膜电位。解偶联机制似乎与可解离的氢离子有关，因为这些分子的pKa值范围为6.0至6.2，且具有高度亲脂性。因此，解偶联作用似乎是氢离子转运的结果。抗肿瘤活性机制似乎不是解偶联的结果，因为在多种活性和非活性二芳基磺酰脲类化合物的细胞生长抑制和解偶联作用之间没有明显的相关性。在体外，舒洛芬脲在高浓度下具有细胞毒性，在较低浓度下可抑制细胞生长，且无明显的细胞杀伤作用。细胞生长抑制似乎也与这些药物的解偶联作用无关。相比之下，解偶联可能在这些化合物早期高暴露时发生的细胞杀伤中起到了部分作用。
