Reynolds, V. L., McGovren, J. P., & Hurley, L. H. (1986). The chemistry, mechanism of action and biological properties of CC-1065, a potent antitumor antibiotic. Journal of Antibiotics, 39(3), 319-334.
Hurley, L. H., Gairola, C., & Zmijewski Jr., M. J. (1975). Biosynthesis of the antiviral antibiotic 11-demethyltomaymycin by Streptomyces achromogenes. Journal of the Chemical Society, Chemical Communications, 120-121.
Abstract:
The building blocks for 11-demethyltomay-mycin have been established as trytophan, tyrosine and a one carbon unit via methionine.
Dai, J., Hatzakis, E., Hurley, L. H., & Yang, D. (2010). I-motif structures formed in the human c-MYC promoter are highly dynamic--insights into sequence redundancy and I-motif stability. PloS one, 5(7), e11647.
The GC-rich nuclease hypersensitivity element III1 (NHE III1) of the c-MYC promoter largely controls the transcriptional activity of the c-MYC oncogene. The C-rich strand in this region can form I-motif DNA secondary structures. We determined the folding pattern of the major I-motif formed in the NHE III1, which can be formed at near-neutral pH. While we find that the I-motif formed in the four 3' consecutive runs of cytosines appears to be the most favored, our results demonstrate that the C-rich strand of the c-MYC NHE III1 exhibits a high degree of dynamic equilibration. Using a trisubstituted oligomer of this region, we determined the formation of two equilibrating loop isomers, one of which contains a flipped-out cytosine. Our results indicate that the intercalative cytosine+-cytosine base pairs are not always necessary for an intramolecular I-motif. The dynamic character of the c-MYC I-motif is intrinsic to the NHE III1 sequence and appears to provide stability to the c-MYC I-motif.
Hornemann, U., Hurley, L. H., Speedie, M. K., & Floss, H. G. (1971). The biosynthesis of indolmycin. Journal of the American Chemical Society, 93(12), 3028-3035.
PMID: 5095271;Abstract:
Indolmycin, an antibiotic produced by a strain of Streptomyces griseus, is formed from (S)-tryptophan, which loses from its side chain the amino nitrogen atom, the hydrogen atom from C-2, and one of the hydrogen atoms from C-3, two intact methyl groups of (S)-methionine, and the guanido carbon atom of (S)-arginine. (R)-β-Methylindolepyruvate and (2S,3R)-indolmycenic acid are intermediates in the biosynthesis. The absolute configuration of indolmycin has been determined by chemical correlation with (-)-(R)-indoleisopropionic acid. Studies with cell-free extracts of S. griseus revealed the presence of a transaminase which converts (S)-tryptophan into indolepyruvate and a methyltransferase which C-methylates indolepyruvate.
Shaw, A. Y., Henderson, M. C., Flynn, G., Samulitis, B., Han, H., Stratton, S. P., Chow, H. S., Hurley, L. H., & Dorr, R. T. (2009). Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer. Journal of Pharmacology and Experimental Therapeutics, 331(2), 636-647.
PMID: 19657049;PMCID: PMC2775253;Abstract:
A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 μM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.