Synthesis and biological evaluation of novel indole-pyrimidine hybrids bearing morpholine and thiomorpholine moieties
| Autor: | Yu-Feng Ma, Pei Liang Zhao, Meng Jin Hu, Peng Cheng Diao, Kwon Ho Hong, Wen Wei You, Qiu Li |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Indoles Pyrimidine Stereochemistry Morpholines Antineoplastic Agents 01 natural sciences HeLa Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Tubulin Cell Line Tumor Neoplasms Morpholine Drug Discovery Humans Moiety Cell Proliferation Pharmacology Indole test biology 010405 organic chemistry Organic Chemistry Cell Cycle Checkpoints General Medicine biology.organism_classification Tubulin Modulators 0104 chemical sciences Molecular Docking Simulation Pyrimidines 030104 developmental biology Thiomorpholine chemistry Cell culture Drug Design Drug Screening Assays Antitumor Lead compound |
| Zdroj: | European Journal of Medicinal Chemistry. 134:110-118 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.04.011 |
| Popis: | Based on our previous screening hit compound 1, a series of novel indole-pyrimidine hybrids possessing morpholine or thiomorpholine moiety were synthesized via an efficient one-pot multistep synthetic method. The antiproliferative activities of the synthesized compounds were evaluated in vitro against four cancer cell lines including HeLa, MDA-MB-231, MCF-7, and HCT116. The results revealed that most compounds possessed moderate to excellent potency. The IC50 values of the most promising compound 15 are 0.29, 4.04, and 9.48 μM against MCF-7, HeLa, and HCT116 cell lines, respectively, which are 48.0, 4.9, and 1.8 folds more active than the lead compound 1. Moreover, fluorescence-activated cell sorting analysis revealed that compound 14 showing the highest activity against HeLa (IC50 = 2.51 μM) displayed a significant effect on G2/M cell-cycle arrest in a concentration-dependent manner in HeLa cell line. In addition, representative nine active hybrids were evaluated for tubulin polymerization inhibitory activities, and compound 15 exhibited the most potent anti-tubulin activity showing 42% inhibition at 10 μM. These preliminary results encourage a further investigation on indole-pyrimidine hybrids for the development of potent anticancer agents that inhibit tubulin polymerization. |
| Databáze: | OpenAIRE |
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