Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines

Hosadurga K Keerthy; Manoj Garg; Chakrabhavi D Mohan; Vikas Madan; Deepika Kanojia; Rangappa Shobith; Shivananju Nanjundaswamy; Daniel J Mason; Andreas Bender; Basappa; Kanchugarakoppal S Rangappa; H Phillip Koeffler

doi:10.1371/journal.pone.0107118

Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines

PLoS One. 2014 Sep 30;9(9):e107118. doi: 10.1371/journal.pone.0107118. eCollection 2014.

Affiliations

¹ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India.
² Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
³ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India.
⁴ Interdisciplinary Research Group of Infectious Diseases, Singapore-MIT Alliance for Research & Technology Centre (SMART), Singapore, Singapore.
⁵ Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
⁶ Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Division of Hematology and Oncology, Cedar-Sinai Medical Centre, Los Angeles, California, United States of America.

Abstract

The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4 g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4 g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4 g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4 g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4 g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4 g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4 g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Benzopyrans / chemical synthesis
Benzopyrans / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Leukemia, Myeloid, Acute / drug therapy
Molecular Docking Simulation
Molecular Targeted Therapy
Nitriles / chemical synthesis
Nitriles / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / chemistry

Substances

Antineoplastic Agents
BCL2 protein, human
Benzopyrans
Nitriles
Proto-Oncogene Proteins c-bcl-2

Grants and funding

This work was supported by grants from USA National Institutes of Health (R01CA02603830); the Singapore Ministry of Health's National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award; and the Singapore Ministry of Education (to HPK.). This research was also supported by University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, Department of Science and Technology (NO. SR/FT/LS-142/2012) to B. KSR thanks Department of Science and Technology (F.NO.SR/SO/HS-006/2010 [G]) and University Grant Commission (F.No.39-106/2010 [SR Dated 24-12-2010]) for funding. HKK, CDM, and B are thankful to UGC, DST-INSPIRE, and PAVATE foundation for providing fellowships respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.