Investigations into the binding of jadomycin DS to human topoisomerase IIβ by WaterLOGSY NMR spectroscopy

Abstract

The jadomycins are a family of secondary metabolites produced by S. venezuelae ISP5230. Specific jadomycins have been shown to possess a variety of anticancer, antifungal, and antibacterial properties, with different molecular mechanisms of action. Herein we demonstrate qualitative and quantitative direct binding between the validated anticancer target human topoisomerase IIβ and jadomycin DS using WaterLOGSY NMR spectroscopy. Additionally, we report for the first time, that jadomycin DS also binds a variety of other proteins, likely in a non-specific manner. Such interactions may rationalize the potential polypharmacology of jadomycin DS.

Reactions of [2‐(2‐Naphthyl)phenyl]acetylenes and 2‐(2‐Naphthyl)benzaldehyde O‐Phenyloximes: Synthesis of the Angucycline Tetrangulol and 1,10,12‐Trimethoxy‐8‐methylbenzo[c]phenanthridine

“…Examples include the aromatic quinone tetrangulol ( 1 ) and the more complex quinone aquayamycin ( 2 ) (Figure ). The biosynthetically related complex natural products jadomycin A ( 3 ) and jadomycin Y ( 4 ) also show interesting biological properties . The simpler benzo[ b ]phenanthridine skeleton is found in the natural product phenanthroviridone ( 5 ), which shows anticancer activity …”

Investigating Protein–Ligand Interactions by Solution Nuclear Magnetic Resonance Spectroscopy

“…In order to maximize the magnetization transfer rate, WaterLOGSY is using all magnetization transfer pathways such as spin diffusion, etc. . Whenever, the residence time is longer than ≈300 ps the NOEs change sign and increase in magnitude.…”

“…After subtracting the on-resonance spectra from the off-resonances pectra, a negative NOE in case of ab inding eventc an be observed. In order to maximize the magnetization transfer rate, WaterLOG-SY is using all magnetizationt ransfer pathways such as spin diffusion, etc.. [47] Whenever,t he residence time is longer than % 300 ps the NOEs change sign and increase in magnitude.I n general,t he bigger the protein the longer the rotational correlation time and consequently,t he magnetization transfer is more efficient. The correlation time of the protein can be increasedb yd ecreasing the temperature or increasing the solution viscosity.…”

Using NMR Spectroscopy in the Fragment‐Based Drug Discovery of Small‐Molecule Anticancer Targeted Therapies

“…In this context, water‐ligand NOEs are measurable phenomena, having negative values in an analogous fashion to the trNOEs measured in an STD NMR experiment [113] . Consequently, the technique allows efficient detection of ligand binding to macromolecules by measuring the magnetization transfer from displaced bulk water at the binding interface [97,114] …”