Heald, R. A., Dexheimer, T. S., Vankayalapati, H., Siddiqui-Jain, A., Szabo, L. Z., Gleason-Guzman, M. C., & Hurley, L. H. (2005). Conformationally restricted analogues of psorospermin: Design, synthesis, and bioactivity of natural-product-related bisfuranoxanthones. Journal of Medicinal Chemistry, 48(8), 2993-3004.
PMID: 15828838;Abstract:
The antileukemic xanthone psorospermin is a topoisomerase II-dependent DNA alkylator in advanced preclinical development. Efforts have been made to further understand the structural requirements of its mechanism of action through the synthesis of ring-constrained analogues, based on the skeleton of the bisfuranoxanthone natural products. Molecules were designed that contain the bisfuran and xanthone portions of naturally occurring psorofebrins, and molecular modeling was used to assess their DNA alkylating potential and to refine the structures. A short, diastereoselective synthetic process to access bisfuranoxanthones was developed, culminating in the first total synthesis of (±)-isohydroxypsorofebrin. Two compounds designed and synthesized were of particular interest, chlorohydrin 7 and epoxide 6, which are reactive analogues of the natural product isohydroxypsorofebrin. The chlorohydrin retains the psorospermin-like DNA alkylation characteristics despite its rigid structure and high innate affinity for DNA. Molecular modeling has been used to rationalize the increased activity of the chlorohydrin. The chlorohydrin and epoxide show increased cytotoxicity compared to isohydroxypsorofebrin against a range of human tumor cell lines. © 2005 American Chemical Society.
Hurley, L. (2016). Specific G-quadruplex ligands regulate the alternative splicing of Bcl-x. Nature Chemical Biology.
Hurley, L. H. (1989). DNA and associated targets for drug design. Journal of Medicinal Chemistry, 32(9), 2027-2033.
Maine, I. P., Sun, D., Hurley, L. H., & Kodadek, T. (1992). Erratum: The antitumor agent CC-1065 inhibits helicase-catalyzed unwinding of duplex DNA (Biochemistry (April 28, 1992) 31:16 (3968-3975)). Biochemistry, 31(43), 10642-.
Chen, Y., Agrawal, P., Brown, R. V., Hatzakis, E., Hurley, L., & Yang, D. (2012). The major G-quadruplex formed in the human platelet-derived growth factor receptor β promoter adopts a novel broken-strand structure in K+ solution. Journal of the American Chemical Society, 134(32), 13220-3.
Overexpression of platelet-derived growth factor receptor β (PDGFR-β) has been associated with cancers and vascular and fibrotic disorders. PDGFR-β has become an attractive target for the treatment of cancers and fibrotic disorders. DNA G-quadruplexes formed in the GC-rich nuclease hypersensitivity element of the human PDGFR-β gene promoter have been found to inhibit PDGFR-β transcriptional activity. Here we determined the major G-quadruplex formed in the PDGFR-β promoter. Instead of using four continuous runs with three or more guanines, this G-quadruplex adopts a novel folding with a broken G-strand to form a primarily parallel-stranded intramolecular structure with three 1 nucleotide (nt) double-chain-reversal loops and one additional lateral loop. The novel folding of the PDGFR-β promoter G-quadruplex emphasizes the robustness of parallel-stranded structural motifs with a 1 nt loop. Considering recent progress on G-quadruplexes formed in gene-promoter sequences, we suggest the 1 nt looped G(i)NG(j) motif may have been evolutionarily selected to serve as a stable foundation upon which the promoter G-quadruplexes can build. The novel folding of the PDGFR-β promoter G-quadruplex may be attractive for small-molecule drugs that specifically target this secondary structure and modulate PDGFR-β gene expression.
