Green Synthesis of Uracil Derivatives, DNA Binding Study and Docking-based Evaluation of their Anti-cancer and Anti-viral Potencies
Vadivelan Rengasamy1, Mohd Suhail2* and Arvind Jain1
1Department of Chemistry, School of Basic and Applied Sciences, Galgotias University UP, India
2Department of Chemistry, Jamia Millia Islamia, (A Central University) New Delhi, India
*Corresponding Author: Mohd Suhail, Department of Chemistry, Jamia Millia Islamia, (A Central University) New Delhi, India.
November 22, 2021; Published: December 22, 2021
In the last few decades, the world has faced a lot of major diseases such as cancer, AIDS and COVID-19. With the advent of disease, different medicines were also worked on but not every medicine could work against more than one major disease. Thus, the world needs such medicine that could act alone against different diseases with different mechanisms at the same time. In this condition, uracil derivatives also known as nucleoside derivatives came as a ray of hope, and have played an important role to cure many diseases. Hence, new twelve uracil derivatives were synthesized by a highly efficient one-pot inexpensive method successfully. It is fully confirmed that one-pot synthesis not only produces a maximum yield of products but also gives insights into green chemistry due to the reduction in byproducts, waste, energy and cost. Moreover, as per literature data, uracil derivatives (i) bind with DNA in the cancer-curing step, and (ii) interrupt the replication process of the virus during antiviral activity. Hence, DNA binding study was also done experimentally, whose results suggest that the reported compounds bind to DNA through intercalation modes. Only three out of twelve drugs were found to have a greater affinity towards DNA, which were selected for the docking study so that the binding pockets of DNA for the selected drugs, can be evaluated. The docking results exposed the formation of DNA-compound adduct. Furthermore, by following the same method, a docking study between newly synthesized drugs and their target during the antiviral action, were also done. It revealed that newly synthesized drugs may also exhibit antiviral activity.
Keywords: Uracil Derivatives; DNA Binding Study; Docking Study; Anti-cancer; Anti-HIV
- Shah A., et al. “Photochemistry and Electrochemistry of Anticancer Uracils”. Journal of Photochemistry and Photobiology B: Biology 117 (2012): 269-277.
- Wu C., et al. “Antitumor Activity of Combination Treatment of Lentinus Edodes Mycelium Extracts with 5-Fluorouracil against Human Colon Cancer Cells Xenografted in Nude Mice”. Journal of Cancer Molecules1 (2007): 15-22.
- de Berker D., et al. “Guidelines for the Management of Actinic Keratoses”. British Journal of Dermatology2 (2007): 222-230.
- Ardalan B., et al. “Biomodulation of Fluorouracil in Colorectal Cancer”. Cancer Investigation4 (1998): 237-251.
- Freelove R and Walling A D. “Pancreatic Cancer: Diagnosis and Management”. American Family Physician3 (2006): 485-492.
- Saonere J A. “Awareness Screening Programme Reduces the Risk of Cervical Cancer in Women”. African Journal of Pharmacy and Pharmacology6 (2010): 314-323.
- “5-Fluorouracil Combined with Apigenin Enhances Anticancer Activity through Induction of Apoptosis in Human Breast Cancer MDA-MB-453 Cells”. Oncology Reports 22.06 (2009).
- Longley D B., et al. “5-Fluorouracil: Mechanisms of Action and Clinical Strategies”. Nature Reviews Cancer5 (2003): 330-338.
- Maruyama T., et al. “Antiviral Activity of 3-(3,5-Dimethylbenzyl)Uracil Derivatives Against Hiv-1 and HCMV”. Nucleosides, Nucleotides and Nucleic Acids10-12 (2007): 1553-1558.
- Bertoletti N., et al. “Structural Insights into the Recognition of Nucleoside Reverse Transcriptase Inhibitors by “HIV‐1 Reverse Transcriptase: First Crystal Structures with Reverse Transcriptase and the Active Triphosphate Forms of Lamivudine and Emtricitabine”. Protein Science9 (2019): 1664-1675.
- Hung M., et al. “Elucidating Molecular Interactions of L-Nucleotides with HIV-1 Reverse Transcriptase and Mechanism of M184V-Caused Drug Resistance”. Communications Biology1 (2019): 469.
- Pałasz A and Cież D. “In Search of Uracil Derivatives as Bioactive Agents. Uracils and Fused Uracils: Synthesis, Biological Activity and Applications”. European Journal of Medicinal Chemistry 97 (2015): 582-611.
- Abdel-Mottaleb Y and Abdel-Mottaleb M S A. “Molecular Modeling Studies of Some Uracil and New Deoxyuridine Derivatives”. Journal of Chemistry 2016 (2016): 1-12.
- Awad S M., et al. “Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents”. Molecules10 (2021): 2988.
- Kim Y., et al. “Tipiracil Binds to Uridine Site and Inhibits Nsp15 Endoribonuclease NendoU from SARS-CoV-2”. Communications Biology1 (2021): 193.
- Pillon M C., et al. “Cryo-EM Structures of the SARS-CoV-2 Endoribonuclease Nsp15 Reveal Insight into Nuclease Specificity and Dynamics”. Nature Communications1 (2021): 636.
- Kim Y., et al. “Crystal Structure of Nsp15 Endoribonuclease <scp>NendoU</Scp> from <scp>SARS‐CoV</Scp> ‐2”. Protein Science7 (2020): 1596-1605.
- Yin W., et al. “Structural Basis for Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir”. Science6498 (2020): 1499-1504.
- Imran A., et al. “Anti-Cancer and Anti-Oxidant Potencies of Cuscuta Reflexa Roxb . Plant Extracts”. American Journal of Advanced Drug Deliverycan Journal of Advanced Drug Delivery2 (2019): 92-113.
- Ali I., et al. “Role of Unani Medicines in Cancer Control and Management”. Current Drug Therapy 2 (2019): 92-113.
- Suhail M and Ali I. “An Advanced Computational Evaluation for the Most Biologically Active Enantiomers of Chiral Anti-Cancer Agents”. Anti-Cancer Agents in Medicinal Chemistry 21 (2020).
- Ali I., et al. “Advances in Nanocarriers for Anticancer Drugs Delivery”. Current Medicinal Chemistry20 (2016) 2159-2187.
- Murinov Y I., et al. “Pro- and Antioxidant Properties of Uracil Derivatives”. Russian Chemical Bulletin5 (2019): 946-954.
- Feng J., et al. “Discovery of Alogliptin: A Potent, Selective, Bioavailable, and Efficacious Inhibitor of Dipeptidyl Peptidase IV †”. Journal of Medicinal Chemistry10 (2007): 2297-2300.
- Ma H., et al. “Characterization of the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor β-d-2′-Deoxy-2′-Fluoro-2′-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5′-Triphosphate Species”. Journal of Biological Chemistry41 (2007): 29812-29820.
- Bergstrom D E. “Organometallic Intermediates in the Synthesis of Nucleoside Analogs”. Nucleosides and Nucleotides1 (1982): 1-34.
- Hayashi Y. “Pot Economy and One-Pot Synthesis”. Chemical Science2 (2016) 866-880.
- Christensen S., et al. “5-Fluorouracil Treatment Induces Characteristic T>G Mutations in Human Cancer”. Nature Communications1 (2019): 4571.
- De Almeida C V., et al. “Treatment of Colon Cancer Cells with 5-Fluorouracil Can Improve the Effectiveness of RNA-Transfected Antitumor Dendritic Cell Vaccine”. Oncology Reports1 (2017): 561-568.
- Kennard O. “DNA-Drug Interactions”. Pure and Applied Chemistry6 (1993): 1213-1222.
- Barton J K., et al. “Tris(Phenanthroline)Ruthenium(II): Stereoselectivity in Binding to DNA”. Journal of the American Chemical Society7 (1984): 2172-2176.
- Sun H., et al. “A Stabilizing and Denaturing Dual-Effect for Natural Polyamines Interacting with G-Quadruplexes Depending on Concentration”. Biochimie8 (2011): 1351-1356.
- Jaumot J and Gargallo R. “Experimental Methods for Studying the Interactions between G-Quadruplex Structures and Ligands”. Current Pharmaceutical Design14 (2012): 1900-1916.
- Wei C., et al. “Spectroscopic Study on the Binding of Porphyrins to (G4T4G4)4 Parallel G-Quadruplex”. Biophysical Chemistry1-3 (2010): 51-55.
- Bhadra K and Kumar GS. “Interaction of Berberine, Palmatine, Coralyne, and Sanguinarine to Quadruplex DNA: A Comparative Spectroscopic and Calorimetric Study”. Biochimica et Biophysica Acta (BBA) - General Subjects4 (2011): 485-496.
- Liu X W., et al. “Experimental and DFT Studies on the DNA-Binding Trend and Spectral Properties of Complexes [Ru(Bpy)2L]2+ (L=dmdpq, Dpq, and Dcdpq)”. Inorganica Chimica Acta 12 (2005): 3311-3319.
- Benesi H A and Hildebrand J H. “A Spectrophotometric Investigation of the Interaction of Iodine with Aromatic Hydrocarbons”. Journal of the American Chemical Society8 (1949): 2703-2707.
- Wolfe A., et al. “Polycyclic Aromatic Hydrocarbons Physically Intercalate into Duplex Regions of Denatured DNA”. Biochemistry20 (1987): 6392-6396.
- Morris G M., et al. “AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility”. Journal of Computational Chemistry16 (2009): 2785-2791.
- Trott O and Olson A J. “AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading”. Journal of Computational Chemistry2 (2010): 455-461.
- Laskowski R A and Swindells M B. “LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery”. Journal of Chemical Information and Modeling, 51.10 (2011): 2778-2786.
- Drew H R., et al. “Structure of a B-DNA Dodecamer: Conformation and Dynamics”. Proceedings of the National Academy of Sciences of the United States of America4 (1981): 2179-83.
- Zhao Z., et al. “Novel Indole-3-Sulfonamides as Potent HIV Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)”. Bioorganic and Medicinal Chemistry Letters2 (2008): 554-559.
- Pyle A M., et al. “Mixed-Ligand Complexes of Ruthenium(II): Factors Governing Binding to DNA”. Journal of the American Chemical Society8 (1989): 3051-3058.
- Chen LM., et al. “Synthesis, Characterization, DNA-Binding and Spectral Properties of Complexes [Ru(L)4(Dppz)]2+ (L=Im and MeIm)”. Journal of Inorganic Biochemistry2 (2008): 330-341.
- Zhao P., et al. “Experimental and DFT Studies on DNA Binding and Photocleavage of Two Cationic Porphyrins”. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy4 (2008): 1216-1223.
- Arjmand F., et al. “Molecular Drug Design, Synthesis and Crystal Structure Determination of CuII-SnIV Heterobimetallic Core: DNA Binding and Cleavage Studies”. European Journal of Medicinal Chemistry 49 (2012): 141-150.
- Haq I. “Thermodynamics of Drug-DNA Interactions”. Archives of Biochemistry and Biophysics1 (2002): 1-15.
- Liu X-W., et al. “Synthesis, Characterization, DNA-Binding and Photocleavage of Complexes [Ru(Phen)2(6-OH-Dppz)]2+ and [Ru(Phen)2(6-NO2-Dppz)]2+”. Journal of Inorganic Biochemistry12 (2005): 2372-2380.
- Sirajuddin M., et al. “Drug-DNA Interactions and Their Study by UV-Visible, Fluorescence Spectroscopies and Cyclic Voltametry”. Journal of Photochemistry and Photobiology B: Biology 124 (2013): 1-19.
- Sirajuddin M., et al. “Synthesis, Characterization, Biological Screenings and Interaction with Calf Thymus DNA of a Novel Azomethine 3-((3,5-Dimethylphenylimino)Methyl)Benzene-1,2-Diol”. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 94 (2012): 134-142.
- Shahabadi N., et al. “DNA Interaction Studies of a Platinum(II) Complex, PtCl2(NN) (NN=4,7-Dimethyl-1,10-Phenanthroline), Using Different Instrumental Methods”. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy4 (2009): 757-761.
- Indumathy R., et al. “Cobalt Complexes of Terpyridine Ligands: Crystal Structure and Nuclease Activity”. Polyhedron17 (2008): 3443-3450.
- Arjmand F and Jamsheera, A. “DNA Binding Studies of New Valine Derived Chiral Complexes of Tin(IV) and Zirconium(IV)”. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy1 (2011): 45-51.
- Allardyce C S., et al. “[Ru(Η6-p-Cymene)Cl2(Pta)] (Pta = 1,3,5-Triaza-7-Phosphatricyclo[188.8.131.52]Decane): A Water Soluble Compound That Exhibits PH Dependent DNA Binding Providing Selectivity for Diseased Cells”. Chemical Communications 15 (2001): 1396-1397.
- Psomas G., et al. “Synthesis, Characterization and DNA-Binding of the Mononuclear Dioxouranium(VI) Complex with Ciprofloxacin”. Polyhedron1 (2008): 133-138.
- Butorov E V. “Influence of L-Lysine Amino Acid on the HIV-1 RNA Replication in Vitro”. Antiviral Chemistry and Chemotherapy1 (2015): 39-46.
- Bol S and Bunnik E M. “Lysine Supplementation Is Not Effective for the Prevention or Treatment of Feline Herpesvirus 1 Infection in Cats: A Systematic Review”. BMC Veterinary Research1 (2015): 284.
- Loh P C and Oie H K. “Role of Lysine in the Replication of Reovirus”. Journal of Virology6 (1969): 890-895.
- Corbau, R., et al. “Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1”. Antimicrobial Agents and Chemotherapy10 (2010): 4451-4463.