A novel series of G-quadruplex ligands with selectivity for HIF-expressing osteosarcoma and renal cancer cell lines.
A series of naphthalene derivatives with disubstituted triazole side-arms have been assembled by click chemistry. Lead compounds show a high level of selectivity for renal, osteo- and Ewing's sarcomas that express the HIF-1α transcription factor. They also interact selectively with the quadruplex DNAs located in the promoter of the HIF genes and it is suggested that the mechanism of action involves inhibition of transcription by drug-mediated quadruplex stabilization in these regions.
UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Caterina M
CM
Lombardo
Sarah J
SJ
Welsh
Sandra J
SJ
Strauss
Aaron G
AG
Dale
Alan K
AK
Todd
Rupesh
R
Nanjunda
W David
WD
Wilson
Stephen
S
Neidle
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D015394:Molecular Structure; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human