Abstract
The activation of transcription factors nuclear factor-kappa B (NF-κ B) and cyclooxygenase-2 (COX-2) is critical in cancer; they act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of NF-κ B and COX-2 present an opportunity for synergistic anticancer efficacy. The ester prodrugs of pentacyclic triterpenoids reduced lantadene A (3), B (4), and its congener 22β-hydroxyoleanonic acid (5) with various non steroidal anti-inflammatory drugs (NSAIDs) present a novel approach. The ester prodrugs of 3 and 4 with diclofenac showed promising dual inhibition of NF-κ B and COX-2. The lead prodrugs 14 and 15 exhibited inhibition of inhibitor of nuclear factor-kappa B kinaseβ (IKKβ ) in the single-digit micromolar range and at the same time, prodrugs 14 and 15 showed marked cytotoxicity against A549 lung cancer cell line with IC50s 0.15 and 0.42 µM, respectively. The prodrugs 14 and 15 exhibited stability in the acidic pH and were hydrolyzed readily in the human blood plasma to release the active parent moieties. Thus, we have synthesized novel hybrid compounds to target both NF-κ B and COX-2 via a prodrug approach, leading to promising anticancer candidates.
Keywords: Cyclooxygenase-2, inhibitor of nuclear factor-kappa B kinaseβ , lantadene-non steroidal anti-inflammatory drug conjugates, nuclear factor-kappa B, prodrugs.
Current Topics in Medicinal Chemistry
Title:Novel Dual Inhibitors of Nuclear Factor-Kappa B (NF-κ B) and Cyclooxygenase- 2 (COX-2): Synthesis, In Vitro Anticancer Activity and Stability Studies of Lantadene–Non Steroidal Anti-inflammatory Drug (NSAID) Conjugates
Volume: 14 Issue: 8
Author(s): Sharad Kumar Suthar, Neetika Sharma, Hong Boon Lee, Khumukcham Nongalleima and Manu Sharma
Affiliation:
Keywords: Cyclooxygenase-2, inhibitor of nuclear factor-kappa B kinaseβ , lantadene-non steroidal anti-inflammatory drug conjugates, nuclear factor-kappa B, prodrugs.
Abstract: The activation of transcription factors nuclear factor-kappa B (NF-κ B) and cyclooxygenase-2 (COX-2) is critical in cancer; they act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of NF-κ B and COX-2 present an opportunity for synergistic anticancer efficacy. The ester prodrugs of pentacyclic triterpenoids reduced lantadene A (3), B (4), and its congener 22β-hydroxyoleanonic acid (5) with various non steroidal anti-inflammatory drugs (NSAIDs) present a novel approach. The ester prodrugs of 3 and 4 with diclofenac showed promising dual inhibition of NF-κ B and COX-2. The lead prodrugs 14 and 15 exhibited inhibition of inhibitor of nuclear factor-kappa B kinaseβ (IKKβ ) in the single-digit micromolar range and at the same time, prodrugs 14 and 15 showed marked cytotoxicity against A549 lung cancer cell line with IC50s 0.15 and 0.42 µM, respectively. The prodrugs 14 and 15 exhibited stability in the acidic pH and were hydrolyzed readily in the human blood plasma to release the active parent moieties. Thus, we have synthesized novel hybrid compounds to target both NF-κ B and COX-2 via a prodrug approach, leading to promising anticancer candidates.
Export Options
About this article
Cite this article as:
Suthar Kumar Sharad, Sharma Neetika, Lee Boon Hong, Nongalleima Khumukcham and Sharma Manu, Novel Dual Inhibitors of Nuclear Factor-Kappa B (NF-κ B) and Cyclooxygenase- 2 (COX-2): Synthesis, In Vitro Anticancer Activity and Stability Studies of Lantadene–Non Steroidal Anti-inflammatory Drug (NSAID) Conjugates, Current Topics in Medicinal Chemistry 2014; 14 (8) . https://dx.doi.org/10.2174/1568026614666140324120503
DOI https://dx.doi.org/10.2174/1568026614666140324120503 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
- Announcements
Related Articles
-
Synthesis and Applications of Hydrogels in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Antiangiogenic Drugs in the Treatment of Advanced Epithelial Ovarian Cancer
Anti-Cancer Agents in Medicinal Chemistry Mechanisms of Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Advanced Non-Small-Cell Lung Cancer: Clinical and Molecular Considerations
Current Medicinal Chemistry Effects of Oxymatrine from Ku Shen on Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Tumor Stroma Manipulation By MSC
Current Drug Targets Zebrafish as a Model System to Screen Radiation Modifiers
Current Genomics Endoscopic Microscopy Using Optical Coherence Tomography
Current Medical Imaging Non-Small Cell Lung Carcinoma: An Overview on Targeted Therapy
Current Drug Targets Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance
Anti-Cancer Agents in Medicinal Chemistry Rhein Derivatives, A Promising Pivot?
Mini-Reviews in Medicinal Chemistry Targeting Trail Towards the Clinic
Current Drug Targets Modulation of TRAIL-Induced Apoptosis by HDAC Inhibitors
Current Cancer Drug Targets Telomere Recombination and the ALT Pathway: A Therapeutic Perspective for Cancer
Current Pharmaceutical Design How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions
Current Topics in Medicinal Chemistry 6,7-Dimethoxyquinazolines as Potential Cytotoxic Agents: Synthesis and in vitro Activity
Letters in Drug Design & Discovery Tumor Markers in Patients with Benign and Malignant Pulmonary Diseases; Competitive Evaluation of ProGRP, NSE and Cyfra 21-1
Recent Patents on Biomarkers Attacking c-Myc: Targeted and Combined Therapies for Cancer
Current Pharmaceutical Design New Opportunities to Treat the T315I-Bcr-Abl Mutant in Chronic Myeloid Leukaemia: Tyrosine Kinase Inhibitors and Molecules that Act by Alternative Mechanisms
Current Medicinal Chemistry Recent Patents Reveal Microtubules as Persistent Promising Target for Novel Drug Development for Cancers
Recent Patents on Anti-Infective Drug Discovery Toxicities of Receptor Tyrosine Kinase Inhibitors in Cancer Pharmacotherapy: Management with Clinical Pharmacology
Current Drug Metabolism