title: Synthesis and characterization of novel 2-amino-chromene-nitriles that target Bcl-2 in acute myeloid leukemia cell lines.
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.
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India.
authors.forename: Hosadurga K
authors.initials: HK
authors.lastname: Keerthy
authors.affiliation: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Manoj
authors.initials: M
authors.lastname: Garg
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India.
authors.forename: Chakrabhavi D
authors.initials: CD
authors.lastname: Mohan
authors.affiliation: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Vikas
authors.initials: V
authors.lastname: Madan
authors.affiliation: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Deepika
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Interdisciplinary Research Group of Infectious Diseases, Singapore-MIT Alliance for Research & Technology Centre (SMART), Singapore, Singapore.
authors.forename: Rangappa
authors.initials: R
authors.lastname: Shobith
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India.
authors.forename: Shivananju
authors.initials: S
authors.lastname: Nanjundaswamy
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mason
authors.affiliation: Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
authors.affiliation: 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.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D001578:Benzopyrans; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2