Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids
| Autor: | Pankaj Sharma, Vunnam Srinivasulu, Kishna Ram Senwar, Karmarajsinh J. Chudasama, Gannoju Srinivasulu, Vegi Ganga Modi Naidu, Ahmed Kamal, Manish Kumar Jeengar, Nagula Shankaraiah, Shalini Nekkanti |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Hydantoin Antineoplastic Agents Biochemistry HeLa chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Humans MTT assay Cytotoxicity Molecular Biology Etoposide Cell Proliferation biology Chemistry Hydantoins Organic Chemistry biology.organism_classification Mechanism of action Cell culture Molecular Medicine medicine.symptom Drug Screening Assays Antitumor medicine.drug Carbolines |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(23) |
| ISSN: | 1464-3405 |
| Popis: | A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08 ± 0.2, IC₅₀ μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction. |
| Databáze: | OpenAIRE |
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