E-pharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylase

[Display omitted] •Non-camptothecin analogues among 11 motifs of pyrazoloquinazolines are reported.•E-pharmacophore drug design guided discovery of Topoisomerase I inhibitors.•Topoisomerase I inhibitors induced apoptosis and were non-DNA intercalators.•4a emerged as a dual inhibitor of Topoisomerase...

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Published in:Bioorganic chemistry 2020-01, Vol.94, p.103409-103409, Article 103409
Main Authors: Joshi, Gaurav, Kalra, Sourav, Yadav, Umesh Prasad, Sharma, Praveen, Singh, Pankaj Kumar, Amrutkar, Suyog, Ansari, Arshad J., Kumar, Santosh, Sharon, Ashoke, Sharma, Sadhana, Sawant, Devesh M., Banerjee, Uttam C., Singh, Sandeep, Kumar, Raj
Format: Article
Language:English
Subjects:
3D Culture
Cell Line, Tumor
DNA Topoisomerases, Type I - drug effects
Dual inhibitors
E-pharmacophore
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - therapeutic use
Histone deacetylases
Histone Deacetylases - drug effects
Humans
Molecular Structure
Pyrazolo[1,5-c]quinazolines
Quinazolines - chemistry
Quinazolines - therapeutic use
Topoisomerase inhibitors
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Summary:[Display omitted] •Non-camptothecin analogues among 11 motifs of pyrazoloquinazolines are reported.•E-pharmacophore drug design guided discovery of Topoisomerase I inhibitors.•Topoisomerase I inhibitors induced apoptosis and were non-DNA intercalators.•4a emerged as a dual inhibitor of Topoisomerase I-HDAC1 with potentiated anticancer effect. In the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) ‘interfacial’ inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2019.103409