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The Different Biological Effects of Telomestatin and TMPyP4 Can Be Attributed to Their Selectivity for Interaction with Intramolecular or Intermolecular G-Quadruplex Structures

College of Pharmacy [M-Y. K., M. G-G., L. H. H.], and Department of Chemistry [L. H. H.], The University of Arizona, Tucson, Arizona 85721; Arizona Cancer Center, Tucson, Arizona 85724 [M-Y. K., M. G-G., L. H. H.]; Institute for Drug Development, San Antonio, Texas 78245 [E. I.]; and Department of Biology, Georgetown University, Washington, DC 20057 [D. N.]

Demonstration of the existence of G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc in human cells has validated these secondary DNA structures as potential targets for drug design. The next important issue is the selectivity of G-quadruplex-interactive agents for the different types of G-quadruplex structures. In this study, we have taken an important step in associating specific biological effects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplex structures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplex interaction. We have demonstrated that telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplex structures over duplex DNA. Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as from single-stranded DNA. Importantly, telomestatin stabilizes these G-quadruplex structures in the absence of monovalent cations, which is a unique characteristic among G-quadruplex-interactive compounds. At noncytotoxic concentrations, telomestatin suppresses the proliferation of telomerase-positive cells within several weeks. In contrast, TMPyP4, a compound that preferentially facilitates the formation of intermolecular G-quadruplex structures, suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well as telomerase-positive cells. We have also demonstrated that TMPyP4 induces anaphase bridges in sea urchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivity of telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplex structures is important in mediating different biological effects: stabilization of intramolecular G-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereas facilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphase bridges.

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