Synthesis and evaluation of anticancer and antiobesity activity of 1-ethoxy carbonyl-3,5-bis (3‿indolyl methylene)-4-pyperidone analogs

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• 作者：Komuraiah Buduma<sup>asup> ; Srinivas Chinde<sup>bsup> ; Anand Kumar Dommati<sup>csup> ; Pooja Sharma<sup>dsup> ; Aparna Shukla<sup>dsup> ; K.V.N. Satya Srinivas<sup>asup> ; Niranjana Kumar Arigari<sup>asup> ; Feroz Khan<sup>dsup> ; Ashok Kumar Tiwari<sup>csup> ; Paramjit Grover<sup>bsup> ; Kotesh Kumar Jonnala<sup>asup><sup> ; sup><sup>koteshkumarj@yahoo.com" class="auth_mail" title="E-mail the corresponding authorsup>
• 关键词：Bisindole ; Pyperidone ; Anticancer activity ; Antiobesity activity ; Docking studies
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：26
• 期：6
• 页码：1633-1638
• 全文大小：1306 K

文摘

A series of eleven novel bisindole derivatives were synthesized and screened for anticancer and antiobesity potentials in in vitro mode. The reaction of 1-ethoxy carbonyl 4-pyperidone <strong class="boldFont">1astrong> with indole-3-carboxaldehyde <strong class="boldFont">1bstrong> in presence of catalytic amount of piperidine gave <strong class="boldFont">2strong> which was N-alkylated with different benzyl halides in the presence of potassium carbonate to afford compounds <strong class="boldFont">3astrong>&ndash;<strong class="boldFont">3kstrong> in quantitative yields. Among the compounds tested for anticancer activity against different human cancer cell lines, <strong class="boldFont">3fstrong> significantly inhibited HepG2 cell line (IC<sub>50sub> 7.33 μM) when compared with standard doxorubicin (IC<sub>50sub> 10.15 μM). Compounds <strong class="boldFont">3estrong> (IC<sub>50sub> 2.75 μM), <strong class="boldFont">3fstrong> (IC<sub>50sub> 4.21 μM) and <strong class="boldFont">3istrong> (IC<sub>50sub> 15.98 μM) showed better activity than the standard curcumin (IC<sub>50sub> 23.54 μM) against A549 cell line. Also, among the synthesized compounds, <strong class="boldFont">3gstrong> (IC<sub>50sub> 14.89 μM), <strong class="boldFont">3cstrong> (IC<sub>50sub> 56.41 μM) and <strong class="boldFont">3istrong> (IC<sub>50sub> 30.88 μM) have potentially inhibited enzyme lipase when compared to standard Orlistat (IC<sub>50sub> 62.25 μM). In in silico docking assays, piperidones <strong class="boldFont">3estrong>, <strong class="boldFont">3fstrong>, <strong class="boldFont">3istrong>, <strong class="boldFont">3cstrong> and <strong class="boldFont">3astrong> showed higher binding affinity towards anti-cancer target of A549 (<strong class="boldFont">3estrong>: &minus;11.1, <strong class="boldFont">3fstrong>: &minus;10.3, <strong class="boldFont">3cstrong>: &minus;11.3, <strong class="boldFont">3istrong>: &minus;11.2 kcal/mol), HepG2 (<strong class="boldFont">3fstrong>: &minus;10.5 kcal/mol), HeLa (<strong class="boldFont">3dstrong>: &minus;10.0 kcal/mol) and SKOV3 (<strong class="boldFont">3fstrong>: &minus;8.4 kcal/mol) cell lines better than standard drug doxorubicin. Docking to lipase protein for compounds <strong class="boldFont">3istrong>, <strong class="boldFont">3gstrong> and <strong class="boldFont">3cstrong> showed scores of &minus;11.1, &minus;10.7 and &minus;10.5 kcal/mol when compared to that of standard drug Orlistat with &minus;6.9 kcal/mol.