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首页> 外文期刊>RSC Advances >Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells
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Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells

机译：新合成的3-（4-氯 - 苯基）-3-羟基-2,2-二甲基 - 丙酸甲酯衍生物选择性地抑制结肠癌细胞的增殖

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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 (IC _(50) ) of these compounds on HCT-116 and we have found that the IC _(50) 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.
机译：基于模型甲基-3-（4-氯苯基）-3-羟基-2,2-二甲基丙酸酯作为有效的HDACIS的结构改性，合成了一系列24种化合物。模型酯的皂化和肼溶解，分别得到相应的酸和酰肼。通过与三氯乙腈和乙酸酐的反应分别将型号转化为相应的三氯乙酰亚胺酯或乙酸盐。 N-烷基-3-（4-氯苯基）-3-羟基-2,2-二甲基丙烷 - 酰胺和甲基-2 - [（3-（4-氯苯基）-3-羟基-2,2-二甲基丙醇）氨基]通过DCC和叠氮化物偶联方法将相应的酸或酰肼与胺和氨基酸酯的反应得到链烷酸盐。在TMSOTF存在下通过与C-活性亲核试核开剂的反应得到良好的产率和从相应的三氯乙酰辛酯或乙酸酯的良好产率和短反应时间得到甲基-3-芳基-3-（4-氯苯基）-2,2-二甲基丙二醇酯（0.1当量％）通过C-C键形成。进一步用分子对接进行抗增殖和凋亡活性。 48后处理表明，在24种化合物中，12种化合物在HCT-116细胞上显示出抑制作用，我们已经计算了这些化合物对HCT-116的抑制作用（IC _（50）），我们发现IC _（50）值在0.12mg ml〜（α1）至0.81mg ml〜（α1）之间。化合物（7a＆7g）显示出最高的抑制活性（0.12mg ml〜（α1）），而化合物7d显示出最低的抑制活性（0.81mg ml〜（α1））。我们还研究了正常和非癌细胞（HEK-293细胞）上的抑制作用，并证实了这些化合物的作用对癌细胞特异。还通过用DAPI染色来检查癌细胞，通过用DAPI染色，（4'，6-二脒基-2-苯基吲哚）是蓝荧光DNA染色，并且我们发现在化合物处理的癌症中失去了DAPI染色细胞。发现化合物可能通过HSP90和TRAP1介导的信号通路作用。化合物7a和7g显示对Trap1的最高选择性，其解释了其优异的活性。

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