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Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents
Author(s) -
Aggile Kadirappa,
Alagumuthu Manikandan,
Mundre Reddy Sailaja,
Napoleon Ayyakannu Arumugam
Publication year - 2018
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.3202
Subject(s) - chemistry , docking (animal) , enzyme , stereochemistry , pi3k/akt/mtor pathway , doxorubicin , breast cancer , ether , cancer , pharmacology , biochemistry , chemotherapy , organic chemistry , apoptosis , medicine , nursing
A new strategy for the preparation of 8‐quinolyl ethers 3 ( a – g ), 5 ( a – g ), and 7 ( a – d ) was studied by copper (II)‐catalyzed methodology in the presence of Cs 2 CO 3 and acetone–water mixture (1:1). Screening of quinolinyl‐8‐ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF‐7), skin cancer (G‐361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide‐3‐kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a – c were inactive (IC 50 > 5 μM), while 3e – g , 5a , 5c – e , 5g , 7a , and 7d showed a moderate activity (IC 50 ≥ 0.05 μM). Compounds ( 5b , 5f , 7b , and 7c ) showed significant activity (IC 50 < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF‐7); 5b , 5f , 7b , and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC 50 values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC 50 = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b , 5f , 7b , and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure–activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer‐related diseases.