Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States; Department Pharmaceutical Sciences, College of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States.
Eur J Med Chem. 2019 Jan 1;161:416-432. doi: 10.1016/j.ejmech.2018.10.024. Epub 2018 Oct 15.
Antibody-drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.
抗体药物偶联物（ADCs）代表了癌症化疗的一个新维度，迄今为止的弹头通常涉及抗微管蛋白或 DNA 靶向药物，以达到低至亚纳摩尔的效力。然而，其他具有不同药理机制的有效细胞毒素也在研究中，例如基于α，β-环氧酮的蛋白酶体抑制剂。这些蛋白酶体活性药物是一类新兴的抗癌药物，对一些癌细胞系具有超强的细胞毒性。卡马霉素是我们从海洋蓝细菌中分离和鉴定的属于后一类的代表，这些以及几种合成类似物都具有这种效力。在目前的工作中，我们研究了将这些高活性细胞毒素化合物用作新型 ADC 设计的弹头。我们设计并合成了一系列含有胺基接头的卡马霉素 B 类似物，使其能够与抗体接头连接。这些引入的胺基接头的碱性被证明强烈影响它们的细胞毒性性质。线性胺导致细胞毒性最大降低，而碱性较弱的芳族胺保留了作为 4-磺酰苯胺衍生物证明的有效活性。这些研究确定了卡马霉素中的 P2 残基是接头连接点最适合的位点，因此，我们合成了一种含有 4-磺酰苯胺接头的卡马霉素 B 的高活性类似物，作为接头抗体的连接点。
