Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma

Cancer is a principal cause of death in the world, and providing a better quality of life and reducing mortality through effective pharmacological treatment remains a challenge. Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 µM, high selectively (SI > 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.

[1]  B. K. Robbs,et al.  Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma , 2022, Molecules.

[2]  M. Battino,et al.  Metabolomic profile and computational analysis for the identification of the potential anti-inflammatory mechanisms of action of the traditional medicinal plants Ocimum basilicum and Ocimum tenuiflorum. , 2022, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[3]  F. Carr,et al.  Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors , 2021, Cancers.

[4]  V. Ochoa-Herrera,et al.  Computational modeling predicts potential effects of the herbal infusion “horchata” against COVID-19 , 2021, Food Chemistry.

[5]  Youfu Luo,et al.  Structure-Guided Design of the First Noncovalent Small-Molecule Inhibitor of CRM1. , 2021, Journal of medicinal chemistry.

[6]  Mina Wang,et al.  PPAR-α Modulators as Current and Potential Cancer Treatments , 2021, Frontiers in Oncology.

[7]  E. Guimarães,et al.  Apoptotic effect of β-pinene on oral squamous cell carcinoma as one of the major compounds from essential oil of medicinal plant Piper rivinoides Kunth , 2021, Natural product research.

[8]  Y. Pérez-Castillo,et al.  Larvicidal Activity of Cinnamic Acid Derivatives: Investigating Alternative Products for Aedes aegypti L. Control , 2020, Molecules.

[9]  Kara Dolinski,et al.  The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions , 2020, Protein science : a publication of the Protein Society.

[10]  B. K. Robbs,et al.  Cytotoxic effect of pure compounds from Piper rivinoides Kunth against oral squamous cell carcinoma , 2020, Natural product research.

[11]  P. Neumann,et al.  Characterization of inhibition reveals distinctive properties for human and Saccharomyces cerevisiae CRM1. , 2020, Journal of medicinal chemistry.

[12]  B. K. Robbs,et al.  Molecular mechanism of action of new 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles with cytotoxic and selective effect against oral squamous cell carcinoma. , 2020, Bioorganic chemistry.

[13]  N. Azizian,et al.  XPO1-dependent nuclear export as a target for cancer therapy , 2020, Journal of Hematology & Oncology.

[14]  H. Magalhães,et al.  Bioactivity and Molecular Docking Studies of Derivatives from Cinnamic and Benzoic Acids , 2020, BioMed research international.

[15]  W. Link,et al.  Small Molecule Inhibitors of CRM1 , 2020, Frontiers in Pharmacology.

[16]  B. Cornils.  white oil , 2020, Catalysis from A to Z.

[17]  Tiziano Tuccinardi,et al.  Application of MM-PBSA Methods in Virtual Screening , 2020, Molecules.

[18]  Wonpil Im,et al.  Improving Protein-Ligand Docking Results with High-Throughput Molecular Dynamics Simulations , 2020, J. Chem. Inf. Model..

[19]  Wei-Chung Cheng,et al.  DriverDBv3: a multi-omics database for cancer driver gene research , 2019, Nucleic Acids Res..

[20]  S. Pantano,et al.  Split the Charge Difference in Two! a Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations. , 2019, Journal of chemical theory and computation.

[21]  R. Pulido,et al.  Protein tyrosine phosphatase PTPN1 modulates cell growth and associates with poor outcome in human neuroblastoma , 2019, Diagnostic Pathology.

[22]  A. Martins,et al.  Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives , 2019, International journal of molecular sciences.

[23]  Huaizhi Wang,et al.  Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway , 2019, Cell Death & Disease.

[24]  J. Ji,et al.  Piplartine suppresses proliferation and invasion of hepatocellular carcinoma by LINC01391-modulated Wnt/β-catenin pathway inactivation through ICAT. , 2019, Cancer letters.

[25]  O. Ozdemir,et al.  NFBTA: A Potent Cytotoxic Agent against Glioblastoma , 2019, Molecules.

[26]  Junmei Wang,et al.  End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design. , 2019, Chemical reviews.

[27]  Olivier Michielin,et al.  SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules , 2019, Nucleic Acids Res..

[28]  D. Bezerra,et al.  Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues , 2019, Journal of Chemistry.

[29]  Jean-Louis Reymond,et al.  Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning , 2018, J. Chem. Inf. Model..

[30]  O. Ozdemir,et al.  Piplartine Analogues and Cytotoxic Evaluation against Glioblastoma , 2018, Molecules.

[31]  B. K. Robbs,et al.  Potential cytotoxic and selective effect of new benzo[b]xanthenes against oral squamous cell carcinoma. , 2018, Future medicinal chemistry.

[32]  M. Hou,et al.  Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage , 2018, Molecules.

[33]  Dongsup Kim,et al.  Utilizing random Forest QSAR models with optimized parameters for target identification and its application to target-fishing server , 2017, BMC Bioinformatics.

[34]  P. Davis,et al.  Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer , 2017, Scientific Reports.

[35]  S. Yarmoluk,et al.  Synthesis and biological evaluation of novel amino-substituted derivatives of pyrido[2,3-d]pyrimidine as inhibitors of protein kinase CK2 , 2017 .

[36]  Howard Y. Chang,et al.  Gene regulation in the immune system by long noncoding RNAs , 2017, Nature Immunology.

[37]  Chris Sander,et al.  CTD2 Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network , 2017, Database J. Biol. Databases Curation.

[38]  Stefan Naulaerts,et al.  Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space , 2017, Scientific Reports.

[39]  Olivier Michielin,et al.  SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules , 2017, Scientific Reports.

[40]  P. Brown,et al.  Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer , 2017, Clinical Cancer Research.

[41]  Isabel Echavarria Díaz-Guardamino.  Identificación de predictores de respuesta a quimioterapia neodayuvante con carboplatino-docetaxel de pacientes con cáncer de mama triple negativo , 2017 .

[42]  K. Westover,et al.  Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine* , 2016, The Journal of Biological Chemistry.

[43]  N. Iranpoor,et al.  Regioselective hydrocarbonylation of phenylacetylene to α,β-unsaturated esters and thioesters with Fe(CO)5 and Mo(CO)6 , 2016 .

[44]  K. Zhao,et al.  Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells , 2016, Oncotarget.

[45]  Sun Mi Gu,et al.  Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway , 2016, Scientific Reports.

[46]  Xiaodong Feng,et al.  Therapeutic Application of Pharmacogenomics in Oncology , 2016, The AAPS Journal.

[47]  Jie Dong,et al.  TargetNet: a web service for predicting potential drug–target interaction profiling via multi-target SAR models , 2016, Journal of Computer-Aided Molecular Design.

[48]  Theodora Katsila,et al.  Computational approaches in target identification and drug discovery , 2016, Computational and structural biotechnology journal.

[49]  A. Pabst,et al.  Diagnosing oral squamous cell carcinoma: How much imaging do we really need? A review of the current literature. , 2016, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[50]  Thomas Monecke,et al.  Structural Basis of Targeting the Exportin CRM1 in Cancer , 2015, Cells.

[51]  Xuejiao Liu,et al.  Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity. , 2015, Chemico-biological interactions.

[52]  D. Pletcher,et al.  N-Heterocyclic Carbene-Mediated Oxidative Electrosynthesis of Esters in a Microflow Cell. , 2015, Organic letters.

[53]  A. Meindl,et al.  Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways , 2015, PloS one.

[54]  Douglas E. V. Pires,et al.  pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures , 2015, Journal of medicinal chemistry.

[55]  Zhaoshen Li,et al.  Role of acetylcholinesterase in lung cancer , 2015, Thoracic cancer.

[56]  R. Cardoso,et al.  Assessment of quality of life in patients with advanced non-small cell lung carcinoma treated with a combination of carboplatin and paclitaxel* , 2015, Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia.

[57]  Mallika Alvala,et al.  Piperlongumine, an alkaloid causes inhibition of PI3 K/Akt/mTOR signaling axis to induce caspase-dependent apoptosis in human triple-negative breast cancer cells , 2014, Apoptosis.

[58]  K. Lee,et al.  Anticancer Principles from Medicinal Piper (胡椒 Hú Jiāo) Plants , 2014, Journal of traditional and complementary medicine.

[59]  L. Costa-Lotufo,et al.  Overview of the therapeutic potential of piplartine (piperlongumine). , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[60]  A. Nogueira-Rodrigues,et al.  First-Line Paclitaxel and Carboplatin in Persistent/Recurrent or Advanced Cervical Cancer: A Retrospective Analysis of Patients Treated at Brazilian National Cancer Institute , 2013, International Journal of Gynecologic Cancer.

[61]  A T Look,et al.  Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells , 2012, Leukemia.

[62]  J. Viola,et al.  NFAT1 C-Terminal Domains Are Necessary but Not Sufficient for Inducing Cell Death , 2012, PloS one.

[63]  L. Feller,et al.  Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment , 2012 .

[64]  Roman A. Laskowski,et al.  LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery , 2011, J. Chem. Inf. Model..

[65]  K. Na-Bangchang,et al.  Cytotoxic activity of Thai medicinal plants against human cholangiocarcinoma, laryngeal and hepatocarcinoma cells in vitro , 2010, BMC complementary and alternative medicine.

[66]  M. O. Moraes,et al.  A Contribuição dos Produtos Naturais como Fonte de Novos Fármacos Anticâncer: Estudos no Laboratório Nacional de Oncologia Experimental da Universidade Federal do Ceará , 2010 .

[67]  Benjamin A. Ellingson,et al.  Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database , 2010, J. Chem. Inf. Model..

[68]  A. S. Sreedhar,et al.  Diferuloylmethane augments the cytotoxic effects of piplartine isolated from Piper chaba. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[69]  V. Bolzani,et al.  Trypanocidal activity of Piper arboreum and Piper tuberculatum (Piperaceae) , 2009 .

[70]  D. Moura,et al.  Evaluation of the genotoxicity of piplartine, an alkamide of Piper tuberculatum, in yeast and mammalian V79 cells. , 2008, Mutation research.

[71]  J. Chang,et al.  Piplartine induces caspase-mediated apoptosis in PC-3 human prostate cancer cells. , 2008, Oncology reports.

[72]  L. Costa-Lotufo,et al.  Piplartine induces inhibition of leukemia cell proliferation triggering both apoptosis and necrosis pathways. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[73]  Artur Ferreira,et al.  Oral squamous cell carcinoma: review of prognostic and predictive factors. , 2006, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[74]  L. Costa-Lotufo,et al.  Antiproliferative Effects of Two Amides, Piperine and Piplartine, from Piper Species , 2005, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[75]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[76]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[77]  P. Kollman,et al.  Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. , 2001, Journal of the American Chemical Society.

[78]  Y. Pang,et al.  Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach. , 2000, Protein science : a publication of the Protein Society.

[79]  José Luis de la Pompa,et al.  Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo , 1998, Cell.

[80]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[81]  C. Broger,et al.  L-Phenylalanine Cyclohexylamide: A Simple and Convenient Auxiliary for the Synthesis of Optically Pure α,α-Disubstituted (R)- and (S)-Amino Acids. , 1995 .

[82]  K. Shadan,et al.  Available online: , 2012 .