Brown, R. V., Danford, F. L., Gokhale, V., Hurley, L. H., & Brooks, T. A. (2011). Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex. The Journal of biological chemistry, 286(47), 41018-27.
Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III(1) region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III(1) region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.
Mountzouris, J. A., Wang, J., Thurston, D., & Hurley, L. H. (1994). Comparison of a DSB-120 DNA interstrand cross-linked adduct with the corresponding bis-tomaymycin adduct: An example of a successful template-directed approach to drug design based upon the monoalkylating compound tomaymycin. Journal of Medicinal Chemistry, 37(19), 3132-3140.
PMID: 7932537;Abstract:
The interstrand cross-linked DSB-120-d(CICG*ATCICG)2 DNA adduct (* indicates covalently modified guanine) was examined by two-dimensional NMR and compared to the bis-tomaymycin adduct on the same oligomer. Tomaymycin and DSB-120 form self-complementary adducts with the d(CICGATCICG)2 duplex sequence in which the covalent linkage sites occur between C11 of either drug and the exocyclic 2-amino group of the single reactive guanine on each strand of d(CICGATCICG)2. In the case of DSB-120, this is evidence for the formation of a guanine-guanine DNA interstrand cross-link. Both drugs show formation of an S stereochemistry at the covalent linkage site with an associated 3′ orientation. While the majority of DNA in these adducts appears to be B-form, DSB-120 interstrand cross-linking induces atypical properties in the 81 nucleotide, indicated by broadening of the 8IH2 proton resonance, non-C2′ endo sugar geometry, and unusually weak internucleotide NOE connectivity to the 7C nucleotide. Tomaymycin does not produce this regional dislocation. For tomaymycin, while there are strong NOE connectivities from protons on the five-membered ring to the 8IH2 proton on the floor of the minor groove, the equivalent internucleotide connectivities in DSB-120 are weaker. This indicates that the tomaymycin tail is close to the floor of the minor groove, while the five-membered ring of DSB-120 is more shallowly immersed, perhaps due to strain from cross-linking with a very short linker unit. Last, the conformational stresses induced on the duplex by DSB-120 appear to make the region of covalent attachment more accessible to solvent than is the case for tomaymycin. The 4GN2Hb resonance appears in 100% D2O on the tomaymycin adduct but is only observed in 90% H2O/10% D2O for the DSB-120 adduct. On the basis of these results, the strategies for template-directed DNA cross-linker design are assessed. © 1994 American Chemical Society.
Sun, D., Thompson, B., Cathers, B. E., Salazar, M., Kerwin, S. M., Trent, J. O., Jenkins, T. C., Neidle, S., & Hurley, L. H. (1997). Inhibition of human telomerase by a G-Quadruplex-Interactive compound. Journal of Medicinal Chemistry, 40(14), 2113-2116.
Fedoroff, O., Rangan, A., Chemeris, V. V., & Hurley, L. H. (2000). Cationic porphyrins promote the formation of i-motif DNA and bind peripherally by a nonintercalative mechanism. Biochemistry, 39(49), 15083-15090.
PMID: 11106486;Abstract:
Telomeric C-rich strands can form a noncanonical intercalated DNA structure known as an i-motif. We have studied the interactions of the cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl)porphine (TMPyP4) with the i-motif forms of several oligonucleotides containing telomeric sequences. TMPyP4 was found to promote the formation of the i-motif DNA structure. On the basis of 1H NMR studies, we have created a model of the i-motif-TMPyP4 complex that is consistent with all the available experimental data. Two-dimensional NOESY data prompted us to conclude that TMPyP4 binds specifically to the edge of the intercalated DNA core by a nonintercalative mechanism. Since we have shown that TMPyP4 binds to and stabilizes the G-quadruplex form of the complementary G-rich telomeric strand, this study raises the intriguing possibility that TMPyP4 can trigger the formation of unusual DNA structures in both strands of the telomeres, which may in turn explain the recently documented biological effects of TMPyP4 in cancer cells.
Hurley, L. H., & Boyd, F. L. (1987). Chapter 26 Approaches Toward the Design of Sequence-Specific Drugs for DNA. Annual Reports in Medicinal Chemistry, 22(C), 259-268.
