Sun, D., & Hurley, L. H. (1992). Structure-activity relationships of (+)-CC-1065 analogues in the inhibition of helicase-catalyzed unwinding of duplex DNA. Journal of Medicinal Chemistry, 35(10), 1773-1782.
PMID: 1588557;Abstract:
(+)-CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis. Previous studies have shown that the potent cytotoxic and antitumor activities of (+)-CC-1065 are due to the ability of this compound to covalently modify DNA. (+)-CC-1065 reacts with duplex DNA to form a (NS-adenine)-DNA adduct which lies in the minor groove of DNA overlapping with a five base-pair region. As a consequence of covalent modification with (+)-CC-1065, the helix bends into the minor groove and also undergoes winding and stiffening. In the studies described here, we have constructed templates for helicase-catalyzed unwinding of DNA that contain site-directed (+)-CC-1065 and analogue DNA adducts. Using these templates we have shown that (+)-CC-1065 and select synthetic analogues, which have different levels of cytotoxicity, all produce a significant inhibition of unwinding of a 3′-tailed oligomer duplex by helicase II when the displaced strand is covalently modified. However, the extent of helicase II inhibition is much more significant for (+)-CC-1065 and an analogue which also produced DNA winding when the winding effects are transmitted in the opposite direction to the helicase unwinding activity. This observed pattern of inhibition of helicase-catalyzed unwinding of drug-modified templates was the same for a 3′-T-tail, for different duplex region sequences, and with the Escherichia coli rep protein. Unexpectedly, the gel mobility of the displaced drug-modified single strand was dependent on the species of drug attached to the DNA. Last, strand displacement by helicase II coupled to primer extension by E. coli DNA polymerase I showed the same pattern of inhibition when the lagging strand was covalently modified. In addition, the presence of helicase II on single-stranded regions of templates caused the premature termination of primer extension by DNA polymerase. These results are discussed from the perspective that (+)-CC-1065 and its analogues have different effects on DNA structure, and these resulting structural changes in DNA molecules are related to the different in vivo biological consequences caused by these drug molecules. © 1992 American Chemical Society.
Hornemann, U., Speedie, M. K., Kelley, K. M., Hurley, L. H., & Floss, H. G. (1969). Biosynthesis of indoleisopropionic acid by Claviceps. Biological C-methylation involving an intact methyl group. Archives of Biochemistry and Biophysics, 131(2), 430-440.
PMID: 5787216;Abstract:
(R)-Indoleisopropionic acid (I) [(2R)-(3-indolyl)-propionic acid], a metabolite of a Claviceps strain, is formed from l-tryptophan and the intact methyl group of l-methionine. Indoleacetic acid is not incorporated into indoleisopropionic acid. (2R,S), (3S,R)-3-methyltryptophan (β-methyltryptophan, isomer B) was efficiently incorporated, but no evidence for its formation by the organism could be obtained. A hypothetical scheme for the biosynthesis of indoleisopropionic acid is presented. © 1969.
Park, H. -., & Hurley, L. H. (1997). Covalent modification of N3 of guanine by (+)-CC-1065 results in protonation of the cross-strand cytosine. Journal of the American Chemical Society, 119(3), 629-630.
Hurley, L. H., Chandler, C., Garner, T. F., Petrusek, R., & Zimmer, S. G. (1979). DNA binding, induction of unscheduled DNA synthesis, and excision of anthramycin from DNA in normal and repair-deficient human fibroblasts.. Journal of Biological Chemistry, 254(3), 605-608.
PMID: 762084;Abstract:
The reaction of the antitumor antibiotic anthramycin with cellular DNA and the ability of normal human fibroblasts cells and xeroderma pigmentosum (XP) cells to respond to this injury has been evaluated. The binding of [15-3H]anthramycin to cellular DNA in human skin fibroblasts occurred in a linear manner up to 6 h. Treatment with unlabeled antibiotic resulted in unscheduled (repair) DNA synthesis in human skin fibroblasts maintained in hydroxyurea, whereas negligible unscheduled DNA synthesis was observed in cells of an excision-defective strain of XP. Confluent nondividing normal skin fibroblast cells were able to remove 86% of the bound anthramycin within 72 h, however XP cells were only able to remove 49% during the same incubation period. These results are discussed in terms of the types of DNA damage produced by anthramycin in vitro and the likely repair pathways involved in removing lesions produced on DNA by anthramycin.
Hurley, L. H., & Boyd, F. (1988). DNA as a target for drug action. Trends in Pharmacological Sciences, 9(11), 402-407.
PMID: 3078076;Abstract:
DNA is the presumed target for a number of clinically useful anticancer drugs. In this review, Laurence Hurley and Leslie Boyd discuss the appropriateness of the term 'receptor' for DNA and outline the forseeable problems in designing drugs that will produce a defined pharmacological response through interaction with DNA. They describe the structural features which present DNA as an attractive target for drug design, and the possible characteristics of drugs that react with DNA to produce a predetermined biochemical response. Finally, they outline modern approaches to elucidating the structural and biological consequences of drug modification. © 1998.
