Novel pyridine-containing histone deacetylase inhibitors strongly arrest proliferation, induce apoptosis and modulate miRNAs in cancer cells

Uracil‐ and Pyridine‐Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells

“…Afterwards, treatment in sequence of 10 with i) ethyl chloroformate and triethylamine in dry THF, ii) O ‐(2‐methoxy‐2‐propyl)hydroxylamine in dry THF, and iii) Amberlyst 15 ion‐exchange resin in methanol at room temperature furnished the hydroxamate 6 (Scheme 1A). Compound 7 was obtained starting from the 3‐(4‐(((4‐oxo‐6‐phenylpyrimidin‐2‐yl)thio)methyl)phenyl) acrylate 11 , [27b] which was treated with benzyl bromide and anhydrous potassium carbonate in dry DMF to furnish the O ‐benzyl derivative 12 . Subsequent hydrolysis of 12 with lithium hydroxide monohydrate in a THF/water 1 : 1 (v/v) mixture at room temperature provided the corresponding carboxylic acid 13 , which was converted into the hydroxamate 7 through the method already described for 6 (Scheme 1B).…”

“…CSCs are an exceptionally aggressive subset of cancer cells that are extremely resistant to conventional cancer therapies and are responsible for metastases onset, relapse or recurrence [17] . In a program for screening of epi‐drugs in CRC and GBM CSCs, [21–22] we selected seven HDACi ( 1 – 7 ) from our in‐house library, either known ( 1 – 5 ) [20,27b] or newly synthesized ( 6 , 7 ). These HDACi include hydroxamates ( 1 , 2 , 5 – 7 ) and 2′‐aminoanilides ( 3 , 4 ) and belong to the pyridine‐containing and UBHA series.…”

“…Synthesis of ethyl 3‐(4‐(((4‐(benzyloxy)‐6‐phenylpyrimidin‐2‐yl)thio)methyl)phenyl)acrylate (12) : A mixture of ethyl 3‐(4‐(((4‐(benzyloxy)‐6‐phenylpyrimidin‐2‐yl)thio)methyl)phenyl)acrylate 11 [27b] (1.53 mmol, 600 mg, 1 eq), benzyl bromide (1.68 mmol, 0.20 mL, 1.1 eq), and anhydrous potassium carbonate (1.68 mmol, 232 mg, 1.1 eq) in dry DMF (3 mL) was stirred at r.t. for 2 h. After completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (4×30 mL) yielding the crude 12 which was purified by silica gel column chromatography eluting with an ethyl acetate/hexane (1 : 8 v/v ) mixture to afford the desired compound as a white solid; mp: 78–80 °C; yield: 39 %. Recrystallization system: cyclohexane.…”

“…These two compound classes include the most potent inhibitors reported by us in both enzyme and cell‐based assays. Compounds 1 – 4 belong to the pyridine‐based series and bear either an hydroxamate ( 1 , 2 ) or a 2′‐aminoanilide ( 3 , 4 ) function as enzyme inhibiting group (Figure 1), [27b] while the UBHA 5 was described as a highly effective antiproliferative agent in human sarcoma stem cells [20] and later reported as a potent anti‐ Plasmodium [29] and Toxoplasma gondii [30] agent, with moderate or no activity against Tripanosoma cruzi , Leishmania and Schistosoma mansoni [31] (Figure 1). In addition, to explore a wider chemical space, we designed and synthesized two more UBHA analogs, the 6‐((5‐benzyl‐4‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐yl)thio)‐ N ‐hydroxyhexanamide 6 and the 3‐(4‐(((4‐(benzyloxy)‐6‐phenylpyrimidin‐2‐yl)thio)methyl)phenyl)‐ N ‐hydroxyacrylamide 7 .…”

Histone Deacetylase 6 Inhibitor 5-Phenylcarbamoylpentyl Selenocyanide (SelSA) Suppresses Hepatocellular Carcinoma by Downregulating Phosphorylation of the Extracellular Signal-Regulated Kinase 1/2 Pathway

“…Furthermore, the majority of reported HDAC6 inhibitors contain a hydroxamic acid as the zinc-binding group (ZBG), which typically exhibits moderate HDAC6 selectivity, instability, poor pharmacokinetics, and potential genotoxicity. , To address the aforementioned limitations, a range of nonhydroxamate ZBGs including 2-aminoanilide, α-ketoester, thiol, and hydrazide have been developed and evaluated. However, these modifications have typically resulted in reduced potency. − …”