ABSTRACT
Click chemistry was utilised to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. A novel PROTAC JMC-137 was identified as a HDAC1/2 and HDAC3 degrader in HCT116 cells. However, potency was compromised compared to previously identified class I HDAC PROTACs highlighting the importance in the choice of HDAC ligand, functional group for linker attachment and positioning in PROTAC design.
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BACKGROUND: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. OBJECTIVES: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. METHODS: The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. RESULTS: S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low γ-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a â¼1 log cfu reduction in mycobacterial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. CONCLUSIONS: Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Antitubercular Agents/pharmacology , Immunity , Macrophages/microbiology , Mice , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine. S-MGBs have been found to be active against many different organisms, however, selective antiparasitic activity is required. A panel of seven truncated S-MGBs was prepared and the activities examined against a number of clinically relevant organisms including several bacteria and parasites. The effect of the truncation strategy on S-MGB aggregation in aqueous environment was also investigated using 1H inspection and DOSY experiments. A lead compound, a truncated S-MGB, which possesses significant activity only against trypanosomes and Leishmania has been identified for further study and was also found to be less affected by aggregation compared to its full-length analogue.
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[This corrects the article DOI: 10.1039/D1MD00110H.].
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The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.
Subject(s)
Cell Proliferation/drug effects , Histone Deacetylase Inhibitors/pharmacology , Neoplasms/drug therapy , Ruthenium Compounds/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , HeLa Cells , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 1/genetics , Histone Deacetylase 1/ultrastructure , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/genetics , Histone Deacetylase 6/ultrastructure , Histone Deacetylase Inhibitors/chemistry , Humans , Neoplasms/genetics , Protein Conformation/drug effects , Protein Isoforms/genetics , Ruthenium/chemistry , Ruthenium/pharmacology , Ruthenium Compounds/chemistryABSTRACT
A series of potent histone deacetylase inhibitors is presented that incorporate alkyl or perfluorinated alkyl chains. Several new compounds show greater in vitro antiproliferative activity than the clinically approved inhibitor, SAHA. Furthermore, the new compounds show up to 5-fold greater activity against cancer cells than healthy cells. This selectivity is in contrast to SAHA, which is more active against the healthy cell line than the cancer cell line tested. Finally, we report an increase in activity for SAHA under mild hyperthermia, indicating that it could be an interesting candidate to use in combination with thermal therapy.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Halogenation , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Cell Line, Tumor , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Models, Molecular , Protein Conformation , Repressor Proteins/chemistry , Repressor Proteins/metabolismABSTRACT
For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 µM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.
Subject(s)
Coordination Complexes , Metals, Heavy , Organophosphorus Compounds , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Histidine/chemistry , Histidine/pharmacology , Humans , Metals, Heavy/chemistry , Metals, Heavy/pharmacology , Molecular Structure , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacologyABSTRACT
The first examples of RuII and RhIII piano-stool complex histone deacetylase (HDAC) inhibitors are presented. The novel complexes have antiproliferative activity against H460 non-small-cell lung carcinoma cells that is comparable to the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Strong evidence for HDAC inhibition as a primary mechanism of action is provided. The complexes reported here represent an important step towards the design of highly active and selective HDAC inhibitors.
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We describe two mesocate assemblies that contain either an ethylene glycol or ammonium group which form a heteroleptic one-dimensional infinite chain in the solid state.
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We describe a ligand system that forms either a dinuclear double helicate or a dinuclear double mesocate dependent upon the size of the metal ion or the steric bulk of the ligand strand.
