Abstract
Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((E)-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((E)-2-bromobenzylidene) cyclic compounds 4a–n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a–n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (4d), benzyl (4e), or acyl (4k–m) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (4f) and 3-phenylpropyl (4g) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (4h–j). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.
Highlights
Polypharmacology is a new emerging approach for chemotherapy, useful when the single-targeted therapy tailored for a specific disease remains without or loses its effect [1]
In U937 cells, 4e, 4k, 4l, In the tested solid tumor cell lines, MCF-7 and SH-SY5Y, the 4 compounds were generally less potent and 4m exhibited a percentage of apoptosis over 30% (Figure 3B), the others being less effective
Mass spectra were recorded on an API-TOF Mariner by Perspective Biosystem (Stratford, Texas, USA), samples were injected by a Harvard pump using a flow rate of 5−10 μL/min, infused in the Electrospray system
Summary
Polypharmacology is a new emerging approach for chemotherapy, useful when the single-targeted therapy tailored for a specific disease remains without or loses its effect [1]. This can happen because multifactorial diseases, such as neurodegenerative disorders or cancer, typically feature multiple dysfunctions of several biological pathways, which can elicit resistance towards a Molecules 2020, 25, 3122; doi:10.3390/molecules25143122 www.mdpi.com/journal/molecules. Alterations in histone acetylation and/or methylation or in DNA methylation modify the transcription regulation leading to aberrant events characterized by either gene silencing or activation [5,6,7,8,9]. Such dysfunctions can activate selected cellular programs for cell cycle arrest and block of differentiation and/or apoptosis allowing cancer initiation and development, and can be managed by using orthosteric and allosteric inhibitors, peptidomimetics, and degraders [10]
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