The development of the trinuclear platinum(II) complex BBR3464 (also known as triplatin) in the late 1990s was meant to be a revolution in the field of platinum chemotherapy. What made it remarkable was that it defied many of the known structure–activity rules for platinums; it is cationic, has a single labile trans leaving group on each terminal platinum, and it binds DNA in ways different to mononuclear platinum drugs, like cisplatin and oxaliplatin. The flexible, long-range adducts the drug forms with DNA means that it showed activity in cancers not typically sensitive to platinums, and more importantly, BBR3464 demonstrated an ability to overcome acquired resistance to platinum drugs. But while preclinical and phase I testing showed promise, its more severe side effects which greatly limited the deliverable dose when compared with standard platinums, combined with its lack of biostability, led to a lack of activity in phase II trials and its development was halted. But, from its ashes have risen 4^th generation complexes which target the phosphate backbone of DNA. These, and the original BBR3464 drug, could potentially be further developed and gain regulatory approval through formulation with macrocycle-based drug delivery vehicles.

中文翻译：

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BBR3464 怎么了，基于多核铂的抗癌药物从何去何从？


1990 年代后期三核铂 （II） 复合物 BBR3464（也称为三铂）的开发旨在成为铂类化疗领域的一场革命。它的非凡之处在于它违背了许多已知的铂金结构-活性规则;它是阳离子的，在每个末端铂上都有一个不稳定的反式离基，并且它以与顺铂和奥沙利铂等单核铂类药物不同的方式结合 DNA。灵活、长距离的药物形式与 DNA 加合意味着它在通常对铂类不敏感的癌症中显示出活性，更重要的是，BBR3464 显示出克服对铂类药物的获得性耐药的能力。但是，虽然临床前和 I 期测试显示出希望，但与标准铂相比，其更严重的副作用极大地限制了可交付剂量，再加上缺乏生物稳定性，导致 II 期试验缺乏活性，其开发停止。但是，从它的灰烬中出现了针对 DNA 磷酸骨架的^第 4 代复合物。这些药物以及原始BBR3464药物可能会通过使用基于大周期的药物递送载体的配方得到进一步开发并获得监管部门的批准。