Analysis of Diazofluorene DNA Binding and Damaging Activity: DNA Cleavage by a Synthetic Monomeric Diazofluorene

Abstract

The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.Lomaiviticins A-E (1-5) [1] and kinamycins (6-8) [2] are com-

Diazo Compounds: Versatile Tools for Chemical Biology

“…Smaller analogues that are easier to synthesize provide a partial solution. 40 One such analogue, a monomeric lomaiviticin aglycon, is capable of inducing DNA damage, albeit at higher concentrations than does (−)-lomaiviticin A. Both (−)-lomaiviticin A and this monomeric lomaiviticin aglycon activate homologous recombination and the non-homologous end-joining repair of DNA in cells.…”

Bayer Early Excellence in Science Award: C. M. Woo / Blavatnik Young Scientist Award: E. P. Balskus / Tetrahedron Young Investigator Awards: N. Maulide und E. P. Balskus

“…Woos Gruppe forscht über aktuelle Themen der chemischen Glykobiologie, um regulatorische Hotspots in natürlichen zuckerbasierten Signalwegen zu finden, und der chemischen Proteomik, um Hotspot‐Mimetika in Zellen und mechanistisch neue Therapieansätze zu erschließen. Sie war unter den Autoren einer Angewandte‐Chemie ‐Zuschrift über die Bindung und Schädigung von DNA durch Diazofluoren …”

Bayer Early Excellence in Science Award: C. M. Woo / Blavatnik Young Scientist Award: E. P. Balskus / Tetrahedron Young Investigator Awards: N. Maulide and E. P. Balskus

“…Woo's research group operates at the forefront of chemical glycobiology, to illuminate Nature's use of regulatory hotspots in sugar‐based signaling pathways, and chemical proteomics, to reveal tractable hotspot mimics in cells and new mechanisms for therapeutic intervention. She was among the authors of a Communication in Angewandte Chemie on the DNA binding and damaging activity of diazofluorene …”

“…She was among the authors of aC ommunication in Angewandte Chemie on the DNAbinding and damaging activity of diazofluorene. [1]…”