BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Ignacio Garrido-Laguna; Ian Krop; Howard A Burris; Erika Hamilton; Fadi Braiteh; Amy M Weise; Maysa Abu-Khalaf; Theresa L Werner; Steven Pirie-Shepherd; Christopher J Zopf; Mani Lakshminarayanan; Jaymes S Holland; Raffaele Baffa; David S Hong Journal: Int J Cancer Date: 2019-02-23 Impact factor: 7.396