Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, United States.
J Med Chem. 2013 Nov 27;56(22):9170-9. doi: 10.1021/jm4012438. Epub 2013 Nov 7.
Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.
氮芥类药物被广泛用作化疗药物，但安全性和疗效有限。线粒体缺乏功能性核苷酸切除修复机制来修复 DNA 加合物，并且对烷化剂敏感。重要的是，癌细胞的线粒体膜电位（Δψmt）比正常细胞高。因此，基于 Δψmt 选择性地将氮芥类药物靶向癌细胞线粒体可以克服这些限制。本文描述了三苯基膦衍生物氮芥类药物氯丁醇（Mito-Chlor）的设计、合成和评估。我们发现 Mito-Chlor 定位于癌细胞线粒体，在那里它作用于 mtDNA 以阻止细胞周期并诱导细胞死亡，导致一系列对亲本药物不敏感的乳腺癌和胰腺癌细胞系的细胞杀伤增强 80 倍。值得注意的是，Mito-Chlor 在人胰腺癌的小鼠异种移植模型中延迟了肿瘤进展。这是氯丁醇（一种未用于乳腺癌和胰腺癌治疗的药物）重新用作这些疾病的新型候选药物的首例。
