Abstract
A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs. Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively. The model ester was transformed into the corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-Alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropan-amides and methyl-2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction of corresponding acid or hydrazide with amines and amino acid esters via DCC and azide coupling methods. Methyl-3-aryl-3-(4-chlorophenyl)-2,2-dimethylpropanoates were obtained in good yields and short reaction time from the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf (0.1 eq.%) via C–C bond formation. The antiproliferative and apoptotic activity were further studied with molecular docking. The 48 post-treatments showed that out of 24 compounds, 12 compounds showed inhibitory actions on HCT-116 cells, we have calculated the inhibitory action (IC50) of these compounds on HCT-116 and we have found that the IC50 values were in between 0.12 mg mL−1 to 0.81 mg mL−1. The compounds (7a & 7g) showed highest inhibitory activity (0.12 mg mL−1), whereas compound 7d showed the lowest inhibitory activity (0.81 mg mL−1). We have also examined inhibitory action on normal and non-cancerous cells (HEK-293 cells) and confirmed that action of these compounds was specific to cancerous cells. The cancerous cells were also examined for nuclear disintegration through staining with DAPI, (4′,6-diamidino-2-phenylindole) is a blue-fluorescent DNA stain, and we have found that there was loss of DAPI staining in the compound treated cancerous cells. The compounds were found to potentially act through the HSP90 and TRAP1 mediated signaling pathway. Compounds 7a and 7g showed the highest selectivity to TRAP1 which explained its superior activity.
Highlights
Malignancy is one of the signi cant factors behind loss of life in the developed countries.[1,2,3] Chemotherapy with cytotoxic medications is one of the primary approaches to dealing withRecently, we reported the synthesis of 3-(4-(2chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate and 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs.[8]
We report the synthesis of a series of compounds based on structure modi cation of the model methyl-3-(4chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate (3) as promising HDACIs
DCC and azide coupling methods are well-recognized in peptide synthesis centered on carboxylic acid-carbonyl group activation to be attacked by nucleophiles as amines or even weaker nucleophiles as amino acids to form a peptide bond.[10,11,12,13]
Summary
Malignancy is one of the signi cant factors behind loss of life in the developed countries.[1,2,3] Chemotherapy with cytotoxic medications is one of the primary approaches to dealing withRecently, we reported the synthesis of 3-(4-(2chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate and 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs.[8]. Paper nature that mimic peptide inhibitors and non-peptide inhibitors, together with being more suitable for pharmaceutical manipulations and development and this work provides integration of our research effort in discovering and modifying new anticancer agents.[8,9]
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