Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure–Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(1H-benzo[d]imidazol-2(3H)-ylidene)Benzenesulfonamides

Autor:	Krzysztof Szafrański, Łukasz Tomorowicz, Beata Żołnowska, Jarosław Sławiński, Anna Kawiak
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Models Molecular Quantitative structure–activity relationship Molecular model synthesis Stereochemistry Molecular Conformation Quantitative Structure-Activity Relationship Antineoplastic Agents Chemistry Techniques Synthetic Ligands Catalysis Article Inorganic Chemistry HeLa 03 medical and health sciences 0302 clinical medicine Molecular descriptor Catalytic Domain Cell Line Tumor Humans 1 3 5-triazines Physical and Theoretical Chemistry Cytotoxicity Molecular Biology IC50 Spectroscopy Cell Proliferation Sulfonamides biology Dose-Response Relationship Drug Molecular Structure Chemistry QSAR Organic Chemistry Active site Proto-Oncogene Proteins c-mdm2 General Medicine molecular docking biology.organism_classification Computer Science Applications benzenesulfonamide Molecular Docking Simulation 030104 developmental biology 030220 oncology & carcinogenesis biology.protein cytotoxicity Drug Screening Assays Antitumor Selectivity
Zdroj:	International Journal of Molecular Sciences Volume 21 Issue 8
ISSN:	1422-0067
DOI:	10.3390/ijms21082924
Popis:	A series of novel 2-[(4-amino-6-R2-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(5-R1-1H-benzo[d]imidazol-2(3H)-ylidene)benzenesulfonamides 6&ndash 49 was synthesized by the reaction of 5-substituted ethyl 2-{5-R1-2-[N-(5-chloro-1H-benzo[d]imidazol-2(3H)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, 22 and 46, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC50: 7&ndash 11 µ M 15&ndash 24 µ M and 11&ndash 18 µ M), respectively. Further QSAR (Quantitative Structure&ndash Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds, 22 and 46, within the active site of the MDM2 protein.
Databáze:	OpenAIRE
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