School of Immunity & Infection, The Medical School, Birmingham, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Invest New Drugs. 2012 Aug;30(4):1471-83. doi: 10.1007/s10637-011-9730-5. Epub 2011 Aug 18.
While 3,4-methylenedioxymethamphetamine (MDMA/'ecstasy') is cytostatic towards lymphoma cells in vitro, the concentrations required militate against its translation directly to a therapeutic in vivo. The possibility of 'redesigning the designer drug', separating desired anti-lymphoma activity from unwanted psychoactivity and neurotoxicity, was therefore mooted. From an initial analysis of MDMA analogues synthesized with a modified α-substituent, it was found that incorporating a phenyl group increased potency against sensitive, Bcl-2-deplete, Burkitt's lymphoma (BL) cells 10-fold relative to MDMA. From this lead, related analogs were synthesized with the 'best' compounds (containing 1- and 2-naphthyl and para-biphenyl substituents) some 100-fold more potent than MDMA versus the BL target. When assessed against derived lines from a diversity of B-cell tumors MDMA analogues were seen to impact the broad spectrum of malignancy. Expressing a BCL2 transgene in BL cells afforded only scant protection against the analogues and across the malignancies no significant correlation between constitutive Bcl-2 levels and sensitivity to compounds was observed. Bcl-2-deplete cells displayed hallmarks of apoptotic death in response to the analogues while BCL2 overexpressing equivalents died in a caspase-3-independent manner. Despite lymphoma cells expressing monoamine transporters, their pharmacological blockade failed to reverse the anti-lymphoma actions of the analogues studied. Neither did reactive oxygen species account for ensuing cell death. Enhanced cytotoxic performance did however track with predicted lipophilicity amongst the designed compounds. In conclusion, MDMA analogues have been discovered with enhanced cytotoxic efficacy against lymphoma subtypes amongst which high-level Bcl-2--often a barrier to drug performance for this indication--fails to protect.
虽然 3,4-亚甲二氧基甲基苯丙胺（MDMA/'摇头丸'）在体外对淋巴瘤细胞具有细胞抑制作用，但所需的浓度使其无法直接转化为治疗体内疾病的药物。因此，有人提出了“重新设计设计药物”的可能性，即将所需的抗淋巴瘤活性与不必要的精神活性和神经毒性分离。从对用修饰的α-取代基合成的 MDMA 类似物的初步分析中发现，与 MDMA 相比，将苯环引入增加了对敏感的、Bcl-2 耗竭的 Burkitt 淋巴瘤（BL）细胞的效力 10 倍。从这个先导化合物出发，合成了相关的类似物，其中“最佳”化合物（含有 1-和 2-萘基和对联苯取代基）的活性比 MDMA 对 BL 靶标高 100 倍。当针对来自各种 B 细胞肿瘤的衍生系进行评估时，发现 MDMA 类似物对恶性肿瘤的广谱具有影响。在 BL 细胞中表达 BCL2 转基因仅能为细胞提供少量保护，防止类似物的作用，并且在所有恶性肿瘤中，都没有观察到组成型 Bcl-2 水平与化合物敏感性之间的显著相关性。Bcl-2 耗竭细胞对类似物表现出凋亡死亡的特征，而 BCL2 过表达的对应物则以 caspase-3 非依赖性方式死亡。尽管淋巴瘤细胞表达单胺转运体，但它们的药理学阻断未能逆转所研究的类似物的抗淋巴瘤作用。活性氧也不是导致细胞死亡的原因。增强的细胞毒性作用确实与设计化合物中的预测亲脂性相关。总之，已经发现了对淋巴瘤亚型具有增强的细胞毒性作用的 MDMA 类似物，其中高水平的 Bcl-2-通常是该适应症药物疗效的障碍-无法提供保护。
