Abstract
Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancers including colon, breast, and lung cancers. Thus, designing potent and selective Src kinase inhibitors as anticancer agents is a subject of major interest. A series of 4-aryl substituted derivatives of 2-amino-7-dimethylamino-4H-chromene- 3-carbonitrile were synthesized using one-pot reaction of appropriate substituted aromatic aldehydes, malononitrile, and 3-(dimethylamino)phenol in the presence of piperidine. All 23 compounds were evaluated for inhibition of Src kinase and cell proliferation in human colon adenocarcinoma (HT-29) and leukemia (CCRF-CEM) cell lines. Among the tested compounds, 2-chlorophenyl- (4c), 3-nitrophenyl- (4h), 4-trifluoromethyphenyl- (4i), and 2,3-dichlorophenyl- (4k) substituted chromenes showed Src kinase inhibitory effect with IC50 values of 11.1-18.3 μM. Compound 4c was relatively selective against Src (IC50 = 11.1 μM), when compared with selected kinases, epidermal growth factor receptor (EGFR, IC50 > 300 μM), C-terminal Src kinase (Csk, IC50 = 101.7 μM), and lymphocyte-specific protein tyrosine kinase (Lck, IC50 = 46.8 μM). 3-Chlorophenyl substituted thiazole (4v) and 2-chlorophenylsubstituted thiazole (4u) chromene derivatives inhibited the cell proliferation of HT-29 and CCRF-CEM by 80% and 50%, respectively, at a concentration of 50 μM. The data indicate that 4H-chromene-3-carbonitrile scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.
Keywords: Anticancer activity, benzopyranones, carbonitrile, chromenes, inhibitor, protein kinase, Src kinase, cancers, Src kinase inhibitors, leukemia, lead compounds
Medicinal Chemistry
Title: 4-Aryl-4H-Chromene-3-Carbonitrile Derivatives: Evaluation of Src Kinase Inhibitory and Anticancer Activities
Volume: 7 Issue: 5
Author(s): Asal Fallah-Tafti, Rakesh Tiwari, Amir Nasrolahi Shirazi, Tahmineh Akbarzadeh, Deendayal Mandal, Abbas Shafiee, Keykavous Parang and Alireza Foroumadi
Affiliation:
Keywords: Anticancer activity, benzopyranones, carbonitrile, chromenes, inhibitor, protein kinase, Src kinase, cancers, Src kinase inhibitors, leukemia, lead compounds
Abstract: Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancers including colon, breast, and lung cancers. Thus, designing potent and selective Src kinase inhibitors as anticancer agents is a subject of major interest. A series of 4-aryl substituted derivatives of 2-amino-7-dimethylamino-4H-chromene- 3-carbonitrile were synthesized using one-pot reaction of appropriate substituted aromatic aldehydes, malononitrile, and 3-(dimethylamino)phenol in the presence of piperidine. All 23 compounds were evaluated for inhibition of Src kinase and cell proliferation in human colon adenocarcinoma (HT-29) and leukemia (CCRF-CEM) cell lines. Among the tested compounds, 2-chlorophenyl- (4c), 3-nitrophenyl- (4h), 4-trifluoromethyphenyl- (4i), and 2,3-dichlorophenyl- (4k) substituted chromenes showed Src kinase inhibitory effect with IC50 values of 11.1-18.3 μM. Compound 4c was relatively selective against Src (IC50 = 11.1 μM), when compared with selected kinases, epidermal growth factor receptor (EGFR, IC50 > 300 μM), C-terminal Src kinase (Csk, IC50 = 101.7 μM), and lymphocyte-specific protein tyrosine kinase (Lck, IC50 = 46.8 μM). 3-Chlorophenyl substituted thiazole (4v) and 2-chlorophenylsubstituted thiazole (4u) chromene derivatives inhibited the cell proliferation of HT-29 and CCRF-CEM by 80% and 50%, respectively, at a concentration of 50 μM. The data indicate that 4H-chromene-3-carbonitrile scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.
Export Options
About this article
Cite this article as:
Fallah-Tafti Asal, Tiwari Rakesh, Nasrolahi Shirazi Amir, Akbarzadeh Tahmineh, Mandal Deendayal, Shafiee Abbas, Parang Keykavous and Foroumadi Alireza, 4-Aryl-4H-Chromene-3-Carbonitrile Derivatives: Evaluation of Src Kinase Inhibitory and Anticancer Activities, Medicinal Chemistry 2011; 7 (5) . https://dx.doi.org/10.2174/157340611796799258
DOI https://dx.doi.org/10.2174/157340611796799258 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Suramin: Clinical Uses and Structure-Activity Relationships
Mini-Reviews in Medicinal Chemistry Mechanism-Based Inactivators as Probes of Cytochrome P450 Structure and Function
Current Drug Metabolism Novel Therapeutic Approaches Targeting Vascular Endothelial Growth Factor and its Receptors in Haematological Malignancies
Current Cancer Drug Targets New Perspective on the Dual Functions of Indirubins in Cancer Therapy and Neuroprotection
Anti-Cancer Agents in Medicinal Chemistry Update on Hsp90 Inhibitors in Clinical Trial
Current Topics in Medicinal Chemistry Editorial [ Cardiovascular Risk Factor Modification: A sine qua non in the Management of Vascular Surgery Patients ]
Current Vascular Pharmacology Nanoparticle Delivery Systems for DNA/RNA and their Potential Applications in Nanomedicine
Current Topics in Medicinal Chemistry Functional Genome-wide Analysis: a Technical Review, Its Developments and Its Relevance to Cancer Research
Recent Patents on DNA & Gene Sequences Radiolabeled Compounds in the Development of Cytotoxic Agents
Current Pharmaceutical Design Comparative Study and Classification of Human Chemokine Receptors
Current Proteomics Challenges and Successes Using Nanomedicines for Aerosol Delivery to the Airways
Current Gene Therapy Human Embryonic and Induced Pluripotent Stem Cell Based Toxicity Testing Models: Future Applications in New Drug Discovery
Current Medicinal Chemistry Recent Trends in Nanotechnology-Based Drugs and Formulations for Targeted Therapeutic Delivery
Recent Patents on Inflammation & Allergy Drug Discovery Advances in Cancer Stem Cell Therapy: Targets and Treatments
Recent Patents on Regenerative Medicine Fusogenic Oncolytic Herpes Simplex Viruses as a Potent and Personalized Cancer Vaccine
Current Pharmaceutical Biotechnology The Involvement of Lysosomes in Myocardial Aging and Disease
Current Cardiology Reviews From Biology to Therapy: Improvements of Therapeutic Options in Lung Cancer
Anti-Cancer Agents in Medicinal Chemistry Nampt/Visfatin/PBEF: A Functionally Multi-faceted Protein with a Pivotal Role in Malignant Tumors
Current Pharmaceutical Design Thermostable Subunit Vaccines for Pulmonary Delivery: How Close Are We?
Current Pharmaceutical Design Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment
Current Cancer Drug Targets