Swenson, D. H., Li, L. H., Hurley, L. H., Rokem, J. S., Petzold, G. L., Dayton, B. D., Wallace, T. L., Lin, A. H., & Krueger, W. C. (1982). Mechanism of interaction of CC-1065 (NSC 298223) with DNA. Cancer Research, 42(7), 2821-2828.
PMID: 7083173;Abstract:
CC-1065 (NSC 298223), a potent new antitumor antibiotic produced by Streptomyces zelensis, interacts strongly with double-stranded DNA and appears to exert its cytotoxic effects through disruption of DNA synthesis. We undertook this study to elucidate the sites and mechanisms of CC-1065 interaction with DNA. The binding of CC-1065 to synthetic and native DNA was examined by differential circular dichroism or by Sephadex chromatography with photometric detection. The binding of CC-1065 with calf thymus DNA was rapid, being complete within 2 hr, and saturated at 1 drug per 7 to 11 base pairs. The interaction of CC-1065 with synthetic DNA polymers indicated a specificity for adenine- and thymine-rich sites. Agarose gel electrophoresis of CC-1065-treated supercoiled DNA showed that CC-1065 did not intercalate. Site exclusion studies using substitutions in the DNA grooves showed CC-1065 to bind primarily in the minor groove. CC-1065 did not cause DNA breaks; it inhibited susceptibility of DNA to nuclease S1 digestion. It raised the thermal melting temperature of DNA, and it inhibited the thiolium-induced unwinding of DNA. Thus, in contrast to many antitumor agents, CC-1065 stabilized the DNA helix. DNA helix overstabilization may be relevant to the mechanism of action of CC-1065.
Hornemann, U., Hurley, L. H., Speedie, M. K., Guenther, H. F., & Floss, H. G. (1969). Biosynthesis of the antibiotic indolmycin by Streptomyces griseus. C-Methylation at the β-carbon atom of the tryptophan side-chain. Journal of the Chemical Society D: Chemical Communications, 245-246.
Haiyong, H., Cliff, C. L., & Hurley, L. H. (1999). Accelerated assembly of G-quadruplex structures by a small molecule. Biochemistry, 38(22), 6981-6986.
PMID: 10353809;Abstract:
In the presence of alkali cations, notably potassium and sodium, DNA oligomers that possess two G-rich repeats associate into either a tetrameric parallel G-quadruplex or a variety of dimeric antiparallel G-quadruplexes. The formation of such structures is normally a very slow process. Some proteins, such as the β-subunit of the Oxytricha telomere-binding protein, promote the formation of G-quadruplex structures in a chaperone-like manner. In this report, we present data concerning the role of a perylene derivative, PIPER, in the assembly of G-quadruplex structures as the first example of a small ligand behaving as a driver in the assembly of polynucleotide secondary structures. Gel-shift experiments demonstrate that PIPER can dramatically accelerate the association of a DNA oligomer containing two tandem repeats of the human telomeric sequence (TTAGGG) into di- and tetrameric G-quadruplexes. In so doing, PIPER alters the oligomer dimerization kinetics from second to first order. The presence of 10 μM PIPER accelerates the assembly of varied dimeric G-quadruplexes an estimated 100-fold from 2 μM oligomer. These results imply that some biological effects elicited by G-quadruplex- interactive agents, such as the induction of anaphase bridges, may stem from the propensity such compounds have for assembling G-quadruplexes.
Nichol, G. S., Boddupally, P. V., De, B., & Hurley, L. H. (2011). 3-[4-(10H-Indolo[3,2-b]quinolin-11-yl)piperazin-1-yl]propan-1-ol. Acta crystallographica. Section E, Structure reports online, 67(Pt 12), o3465-6.
In the title compound, C(22)H(24)N(4)O, the aromatic moiety is essentially planar (r.m.s. deviation of a least-squares plane fitted through all non-H atoms = 0.0386 Å) and is rotated by 89.98 (4)° from the piperazine ring, which adopts the expected chair conformation. The propanol chain is not fully extended away from the piperazine ring. In the crystal, there are two unique hydrogen-bonding inter-actions. One is an O-H⋯N inter-action which, together with an inversion-related symmetry equivalent, forms a ring motif. The second is an N-H⋯N inter-action which links adjacent mol-ecules by means of a chain motif which propagates in the c-axis direction. Overall, a two-dimensional hydrogen-bonded structure is formed.
Maine, I. P., Sun, D., Hurley, L. H., & Kodadek, T. (1992). The antitumor agent CC-1065 inhibits helicase-catalyzed unwinding of duplex DNA. Biochemistry, 31(16), 3968-3975.
PMID: 1314652;Abstract:
The antitumor drug CC-1065 is thought to exert its effects by covalent bonding to N3 of adenine in DNA and interfering with some aspect of DNA metabolism. Therefore, it is of interest to determine what effect this drug has on enzymes involved in various aspects of DNA metabolism. In this report, we examine the ability of two DNA helicases, the dda protein of phage T4 and helicase II of Escherichia coli, to unwind CC-1065-adducted, tailed, oligonucleotides. It is shown that the presence of the drug on DNA strongly inhibits unwinding catalyzed by the T4 and E. coli proteins. A significant difference between the results obtained with the two helicases is that DNAs containing drug on either the tailed or the completely duplex strands are poor substrates for helicase II but dda protein-mediated unwinding is inhibited only when the drug is on the tailed strand. The drug-modified, helicase-released, strands migrate abnormally through a native gel, suggesting that the drug traps an unusual secondary structure generated in the course of protein-mediated unwinding. A kinetic analysis of the drug-inhibited reactions reveals that the helicases are trapped by the DNA-drug complex. This is evidenced by a decrease in the rate of helicase exchange between drug-bound substrate and drug-free duplex. The implications of these results with respect to the mechanism of action of CC-1065 in vivo are discussed. © 1992 American Chemical Society.