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1.
Bioorg Med Chem Lett ; 28(8): 1274-1277, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29576510

ABSTRACT

Structural features from the anticancer prodrug nemorubicin (MMDX) and the DNA-binding molecule DRAQ5™ were used to prepare anthraquinone-based compounds, which were assessed for their potential to interrogate cytochrome P450 (CYP) functional activity and localisation. 1,4-disubstituted anthraquinone 8 was shown to be 5-fold more potent in EJ138 bladder cancer cells after CYP1A2 bioactivation. In contrast, 1,5-bis((2-morpholinoethyl)amino) substituted anthraquinone 10 was not CYP-bioactivated but was shown to be fluorescent and subsequently photo-activated by a light pulse (at a bandwidth 532-587 nm), resulting in punctuated foci accumulation in the cytoplasm. It also showed low toxicity in human osteosarcoma cells. These combined properties provide an interesting prospective approach for opto-tagging single or a sub-population of cells and seeking their location without the need for continuous monitoring.


Subject(s)
Anthraquinones/metabolism , Cytochrome P-450 Enzyme System/metabolism , Fluorescent Dyes/metabolism , Morpholines/metabolism , Anthraquinones/chemical synthesis , Anthraquinones/chemistry , Anthraquinones/toxicity , Cell Line, Tumor , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/toxicity , Humans , Hydroxylation , Morpholines/chemical synthesis , Morpholines/chemistry , Morpholines/toxicity
2.
Curr Comput Aided Drug Des ; 11(2): 124-36, 2015.
Article in English | MEDLINE | ID: mdl-26135342

ABSTRACT

B-Raf mutations are identified in 40-50% of patients with melanoma and among them, the substitution of valine for glutamic acid at position 600 ((V600E)B-Raf) is the most frequent. Treatment of these patients with B-Raf inhibitors has been associated with a clear clinical benefit. Unfortunately, multiple resistance mechanisms have been identified and new potent and selective inhibitors are currently needed. In this work, five different type II inhibitors, which bind (V600E)B-Raf in its DFG-out conformation, have been studied using molecular dynamics, free energy calculations and energy decomposition analysis. The ranking of calculated MM-PB/GBSA binding affinities is in good agreement with the experimentally measured ones. The per-residue decomposition of ΔGbinding, within the MM-GBSA approach, has been used to identify the key residues governing the allosteric binding of the studied compounds to the (V600E)B-Raf protein kinase. Results indicate that although van der Waals interactions are key determinants for binding, hydrogen bonds also play an important role. This work also provides a better structural understanding of the binding of DFG-out inhibitors to (V600E)B-Raf, which can be used in a further step for rational design of a new class of B-Raf potent inhibitors.


Subject(s)
Allosteric Regulation/drug effects , Drug Design , Melanoma/drug therapy , Melanoma/enzymology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Animals , Computer-Aided Design , Databases, Protein , Humans , Hydrogen Bonding , Melanoma/genetics , Molecular Dynamics Simulation , Point Mutation , Protein Binding , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Thermodynamics
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