Nicolaou K C, Pitsinos E N, Theodorakis E A, Saimoto H, Wrasidlo W
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Chem Biol. 1994 Sep;1(1):57-66. doi: 10.1016/1074-5521(94)90041-8.
Calicheamicin gamma 1I is a bacterial product that is a prominent member of the enediyne class of antitumor antibiotics, and has been extensively studied. Calicheamicin gamma 1I binds to DNA, causing double-stranded breaks, and cells exposed to it eventually become apoptotic. It can now be made synthetically, and highly potent biological mimics have been designed. Such molecules have many potential clinical applications, but are complex to make. We therefore investigated whether simplified versions of these molecules are biologically active.
We designed and synthesized a number of simple calicheamicin mimics and evaluated their biological activity. We also constructed mimics that are particularly suitable for conjugation to proteins, oligonucleotides, and other delivery systems. Several active mimics were found, and two in particular, which lack the trisulfide and oligosaccharide moieties of calicheamicin, had potent DNA-cleaving and cytotoxic activities. They caused chiefly single-stranded cuts in DNA, however, unlike the natural molecule, which causes double-stranded DNA cuts. Although they were able to induce apoptosis, they were less potent than the natural compound in this assay.
The simple enediyne mimics were less potent than calicheamicin gamma 1I, presumably because they lack the oligosaccharide DNA-binding domain. Nevertheless, considering their relatively primitive structures, they have remarkable biological properties. They may be useful biological tools and are potential leads for the development of chemotherapeutic agents. We propose that the ability of the enediynes to induce apoptosis is related to their ability to make double-stranded cuts in DNA.
加利车霉素γ1I是一种细菌产物，是抗肿瘤抗生素烯二炔类的重要成员，已得到广泛研究。加利车霉素γ1I与DNA结合，导致双链断裂，暴露于其中的细胞最终会发生凋亡。现在它可以通过合成制备，并且已经设计出了高效的生物模拟物。这类分子有许多潜在的临床应用，但合成过程复杂。因此，我们研究了这些分子的简化版本是否具有生物活性。
我们设计并合成了一些简单的加利车霉素模拟物，并评估了它们的生物活性。我们还构建了特别适合与蛋白质、寡核苷酸和其他递送系统偶联的模拟物。发现了几种活性模拟物，特别是其中两种，它们缺少加利车霉素的三硫化物和寡糖部分，具有强大的DNA切割和细胞毒性活性。然而，它们主要导致DNA单链切割，与天然分子导致双链DNA切割不同。尽管它们能够诱导凋亡，但在该测定中其效力不如天然化合物。
简单的烯二炔模拟物的效力不如加利车霉素γ1I，可能是因为它们缺少寡糖DNA结合结构域。然而，考虑到它们相对简单的结构，它们具有显著的生物学特性。它们可能是有用的生物学工具，并且是开发化疗药物的潜在先导物。我们提出烯二炔诱导凋亡的能力与其在DNA中产生双链切割的能力有关。
