Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Letters in Drug Design & Discovery
  4. Fast Track Articles
  5. Fast Track Article
image of Design, Synthesis, Biological Evaluation, Molecular Docking, and Molecular Dynamics Simulation Studies of Fmoc-L-Lysine Carboxamides as Promising Cytotoxic Agents

Abstract

Background

Despite advancements in treatment modalities, the search for new cytotoxic agents remains vital in the fight against cancer. This ongoing effort aims to introduce novel molecules that serve as potent cytotoxic agents while minimizing adverse effects.

Objective

The objective of the study is to design, synthesize, and evaluate Fmoc-L-Lysine Carboxamides for cytotoxic activities.

Methods

The title compounds were synthesized by esterification followed by reduction of Fmoc-Lys (Boc)-OH to alcohol, then coupled with various aryl/alkyl/alicyclic carboxylic acids. These compounds were then analysed using 13C NMR, 1H NMR, FT-IR, and Mass spectroscopic techniques and evaluated for cytotoxic activity by MTT assay, apoptosis induction, cell cycle analysis, EGFR-TK inhibition activity, molecular docking, and molecular dynamics simulation studies.

Results

The results obtained by MTT assay indicated that compounds and demonstrated significant cytotoxicity against A549 and SKOV3 cell lines, with IC values of 2.75 and 1.91μM compared to doxorubicin. Further, the analysis of the Cell cycle and apoptosis proposed that arrested the cell cycle in the G0/G1 phase, whereas arrested the cell cycle in the G2/M phase and triggered apoptosis in cancer cells. Notably, compound demonstrated the highest inhibition of EGFR with IC, 0.189μM, and acted as its potential inhibitor. Molecular docking and dynamics simulation studies further confirmed the stability of in the active site of EGFR.

Conclusion

Overall, these results suggested that the synthesized derivatives offer a promising approach for the advancement of new and effective cancer therapies.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808324766240930062735
2024-10-03
2024-11-26

  • From This Site

    /content/journals/lddd/10.2174/0115701808324766240930062735
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Gomari M.M. Abkhiz S. Pour T.G. Lotfi E. Rostami N. Monfared F.N. Ghobari B. Mosavi M. Alipour B. Dokholyan N.V. Peptidomimetics in cancer targeting. Mol. Med. 2022 28 1 146 10.1186/s10020‑022‑00577‑3 36476230
    [Google Scholar]
  2. Marques A.C. Costa P.J. Velho S. Amaral M.H. Functionalizing nanoparticles with cancer-targeting antibodies: A comparison of strategies. J. Control. Release 2020 320 180 200 10.1016/j.jconrel.2020.01.035 31978444
    [Google Scholar]
  3. Mahmoudi Gomari M. Rostami N. Ghodrati A. Hernandez Y. Fadaie M. Sadegh Eslami S. Tarighi P. Implementation of docking, molecular dynamics and free energy to investigate drug potency of novel BCR-ABLT315I inhibitors as an alternative to ponatinib. Comput. Toxicol. 2021 20 100180 10.1016/j.comtox.2021.100180
    [Google Scholar]
  4. Kumar V. Mudgal M.M. Rani N. Jha A. Jaggi M. Singh A.T. Sanna V.K. Singh P. Sharma P.K. Irchhaiya R. Burman A.C. Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents. J. Enzyme Inhib. Med. Chem. 2009 24 3 763 770 10.1080/14756360802362975 18720190
    [Google Scholar]
  5. Irfandi R. Raya I. Ahmad A. Fudholi A. Riswandi Santi S. Azalea W.P. Putri S.E. Alam M.N. Supratman U. Design anticancer potential of Zn(II)isoleucinedithiocarbamate complex on MCF-7 cell lines: Synthesis, characterization, molecular docking, molecular dynamic, ADMET, and in-vitro studies Mol. Divers. 2023 1 16
    [Google Scholar]
  6. Zhou Y. Deng R. Zhen M. Li J. Guan M. Jia W. Li X. Zhang Y. Yu T. Zou T. Lu Z. Guo J. Sun L. Shu C. Wang C. Amino acid functionalized gadofullerene nanoparticles with superior antitumor activity via destruction of tumor vasculature in vivo. Biomaterials 2017 133 107 118 10.1016/j.biomaterials.2017.04.025 28433934
    [Google Scholar]
  7. Sharma R. Yadav L. Nasim A.A. Yadav R.K. Chen R.H. Kumari N. Ruiqi F. Sharon A. Sahu N.K. Ippagunta S.K. Coghi P. Wong V.K.W. Chaudhary S. Chemo-/regio-selective synthesis of novel functionalized spiro[pyrrolidine-2,3′-oxindoles] under microwave irradiation and their anticancer activity. Molecules 2023 28 18 6503 10.3390/molecules28186503 37764279
    [Google Scholar]
  8. Yuan C. Li S. Li C. Chen S. Huang W. Wang G. Pan C. Zhang Y. New strategy for the synthesis of functionalized phosponic acids. Pure Appl. Chem. 1996 68 4 907 912 10.1351/pac199668040907
    [Google Scholar]
  9. Camerman A. Hempel A. Mastropaolo D. Camerman N. 2-Acetamido- N -benzyl-2-(methoxyamino)acetamides: Functionalized amino acid anticonvulsants. Acta Crystallogr. C 2005 61 7 o417 o419 10.1107/S0108270105014745 15997070
    [Google Scholar]
  10. Niu Y. Wang M. Cao Y. Nimmagadda A. Hu J. Wu Y. Cai J. Ye X.S. Rational design of dimeric lysine N-alkylamides as potent and broad-spectrum antibacterial agents. J. Med. Chem. 2018 61 7 2865 2874 10.1021/acs.jmedchem.7b01704 29569910
    [Google Scholar]
  11. Smriga M. Ghosh S. Mouneimne Y. Pellett P.L. Scrimshaw N.S. Lysine fortification reduces anxiety and lessens stress in family members in economically weak communities in Northwest Syria. Proc. Natl. Acad. Sci. USA 2004 101 22 8285 8288 10.1073/pnas.0402550101 15159538
    [Google Scholar]
  12. Bloch D.N. Sandre M. Ben Zichri S. Masato A. Kolusheva S. Bubacco L. Jelinek R. Scavenging neurotoxic aldehydes using lysine carbon dots. Nanoscale Adv. 2023 5 5 1356 1367 10.1039/D2NA00804A 36866263
    [Google Scholar]
  13. Hallinan E.A. Tsymbalov S. Dorn C.R. Pitzele B.S. Hansen D.W. Jr Moore W.M. Jerome G.M. Connor J.R. Branson L.F. Widomski D.L. Zhang Y. Currie M.G. Manning P.T. Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J. Med. Chem. 2002 45 8 1686 1689 10.1021/jm010420e 11931623
    [Google Scholar]
  14. Gonzalez J. Ramirez J. Schwans J.P. Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase. Amino Acids 2016 48 12 2755 2763 10.1007/s00726‑016‑2310‑4 27522651
    [Google Scholar]
  15. Stagi L. de Forni D. Innocenzi P. Blocking viral infections with lysine-based polymeric nanostructures: A critical review. Biomater. Sci. 2022 10 8 1904 1919 10.1039/D2BM00030J 35297436
    [Google Scholar]
  16. Chiangjong W. Chutipongtanate S. Hongeng S. Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review). Int. J. Oncol. 2020 57 3 678 696 10.3892/ijo.2020.5099 32705178
    [Google Scholar]
  17. Dai Y. Cai X. Shi W. Bi X. Su X. Pan M. Li H. Lin H. Huang W. Qian H. Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane. Amino Acids 2017 49 9 1601 1610 10.1007/s00726‑017‑2453‑y 28664269
    [Google Scholar]
  18. Khmara I. Koneracka M. Kubovcikova M. Zavisova V. Antal I. Csach K. Kopcansky P. Vidlickova I. Csaderova L. Pastorekova S. Zatovicova M. Preparation of poly-L-lysine functionalized magnetic nanoparticles and their influence on viability of cancer cells. J. Magn. Magn. Mater. 2017 427 114 121 10.1016/j.jmmm.2016.11.014
    [Google Scholar]
  19. Hu J. Jing H. Lin H. Sirtuin inhibitors as anticancer agents. Future Med. Chem. 2014 6 8 945 966 10.4155/fmc.14.44 24962284
    [Google Scholar]
  20. Su L. Fang H. Yang K. Xu Y. Xu W. Design, synthesis and biological evaluation of novel l-lysine ureido derivatives as aminopeptidase N inhibitors. Bioorg. Med. Chem. 2011 19 2 900 906 10.1016/j.bmc.2010.11.066 21194957
    [Google Scholar]
  21. Ueki N. Wang W. Swenson C. McNaughton C. Sampson N.S. Hayman M.J. Synthesis and preclinical evaluation of a highly improved anticancer prodrug activated by histone deacetylases and cathepsin L. Theranostics 2016 6 6 808 816 10.7150/thno.13826 27162551
    [Google Scholar]
  22. Yang H. Wang M. Huang Y. Qiao Q. Zhao C. Zhao M. In vitro and in vivo evaluation of a novel mitomycin nanomicelle delivery system. RSC Advances 2019 9 26 14708 14717 10.1039/C9RA02660F 35516345
    [Google Scholar]
  23. Kalariya R. Ojha D. Rana S. Rode A. Bhosale R. Yadav J.S. Novel fluorinated amino acid derivatives as potent antitumor agents against MCF-7 and HepG2 cells: Synthesis, characterization, in vitro assays and molecular docking studies. Results Chem. 2023 5 100954 10.1016/j.rechem.2023.100954
    [Google Scholar]
  24. Zhang Z. Fan E. Solid-phase and solution-phase syntheses of oligomeric guanidines bearing peptide side chains. J. Org. Chem. 2005 70 22 8801 8810 10.1021/jo051226t 16238312
    [Google Scholar]
  25. Alsayed S.S.R. Lun S. Bailey A.W. Suri A. Huang C.C. Mocerino M. Payne A. Sredni S.T. Bishai W.R. Gunosewoyo H. Design, synthesis and evaluation of novel indole-2-carboxamides for growth inhibition of Mycobacterium tuberculosis and paediatric brain tumour cells. RSC Advances 2021 11 26 15497 15511 10.1039/D0RA10728J 35481189
    [Google Scholar]
  26. Özdemir A. Sever B. Altıntop M. Temel H. Atlı Ö. Baysal M. Demirci F. Synthesis and evaluation of new oxadiazole, thiadiazole, and triazole derivatives as potential anticancer agents targeting MMP-9. Molecules 2017 22 7 1109 10.3390/molecules22071109 28677624
    [Google Scholar]
  27. Samec T. Boulos J. Gilmore S. Hazelton A. Alexander-Bryant A. Peptide-based delivery of therapeutics in cancer treatment. Mater. Today Bio 2022 14 100248 10.1016/j.mtbio.2022.100248 35434595
    [Google Scholar]
  28. Subba Rao A.V. Swapna K. Shaik S.P. Lakshma Nayak V. Srinivasa Reddy T. Sunkari S. Shaik T.B. Bagul C. Kamal A. Synthesis and biological evaluation of cis -restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers. Bioorg. Med. Chem. 2017 25 3 977 999 10.1016/j.bmc.2016.12.010 28034647
    [Google Scholar]
  29. Lalitha L.J. Sales T.J. Clarance P.P. Agastian P. Kim Y.O. Mahmoud A.H. Mohamed S.E. Tack J.C. Na S.W. Kim H.J. In-vitro phytopharmacological and anticancer activity of Loranthus Longiflorus Desv. Var. Falcatuskurz against the human lung cancer cells. J. King Saud Univ. Sci. 2020 32 1246 1253 10.1016/j.jksus.2019.11.022
    [Google Scholar]
  30. Prasad C.V. Nayak V.L. Ramakrishna S. Mallavadhani U.V. Novel menadione hybrids: Synthesis, anticancer activity, and cell‐based studies. Chem. Biol. Drug Des. 2018 91 1 220 233 10.1111/cbdd.13073 28734085
    [Google Scholar]
  31. Martin S.J. Finucane D.M. Amarante-Mendes G.P. O’Brien G.A. Green D.R. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J. Biol. Chem. 1996 271 46 28753 28756 10.1074/jbc.271.46.28753 8910516
    [Google Scholar]
  32. Baig M.F. Nayak V.L. Budaganaboyina P. Mullagiri K. Sunkari S. Gour J. Kamal A. Synthesis and biological evaluation of imidazo[2,1-b]thiazole-benzimidazole conjugates as microtubule-targeting agents. Bioorg. Chem. 2018 77 515 526 10.1016/j.bioorg.2018.02.005 29459129
    [Google Scholar]
  33. El-Sayed M.A.A. El-Husseiny W.M. Abdel-Aziz N.I. El-Azab A.S. Abuelizz H.A. Abdel-Aziz A.A.M. Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: Molecular docking study. J. Enzyme Inhib. Med. Chem. 2018 33 1 199 209 10.1080/14756366.2017.1407926 29251017
    [Google Scholar]
  34. El-Husseiny W.M. El-Sayed M.A.A. Abdel-Aziz N.I. El-Azab A.S. Ahmed E.R. Abdel-Aziz A.A.M. Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study. J. Enzyme Inhib. Med. Chem. 2018 33 1 507 518 10.1080/14756366.2018.1434519 29455554
    [Google Scholar]
  35. Stamos J. Sliwkowski M.X. Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 2002 277 48 46265 46272 10.1074/jbc.M207135200 12196540
    [Google Scholar]
  36. Maadwar S. Galla R. Cytotoxic oxindole derivatives: In vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics studies. J. Recept. Signal Transduct. Res. 2019 39 5-6 460 469 10.1080/10799893.2019.1683865 31814499
    [Google Scholar]
  37. Verma R. Boshoff H.I.M. Arora K. Bairy I. Tiwari M. Varadaraj B.G. Shenoy G.G. Synthesis, evaluation, molecular docking, and molecular dynamics studies of novel N ‐(4‐[pyridin‐2‐yloxy]benzyl)arylamine derivatives as potential antitubercular agents. Drug Dev. Res. 2020 81 3 315 328 10.1002/ddr.21623 31782209
    [Google Scholar]
  38. Priyankha S. Polk S. Thilagavathi R. Prakash M. Kathiravan M.K. Lakshmana Prabhu S. Brunozi de Oliveira I. Selvam C. The virtual screening of compounds from the ZINC database against PARP‐1 in triple‐negative breast cancer. ChemistrySelect 2024 9 10 e202304729 10.1002/slct.202304729
    [Google Scholar]
/content/journals/lddd/10.2174/0115701808324766240930062735
Loading
Design, Synthesis, Biological Evaluation, Molecular Docking, and Molecular Dynamics Simulation Studies of Fmoc-L-Lysine Carboxamides as Promising Cytotoxic Agents
Bentham Science Publishers ; https://doi.org/10.2174/0115701808324766240930062735
/content/journals/lddd/10.2174/0115701808324766240930062735
/content/journals/lddd/10.2174/0115701808324766240930062735
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: molecular dynamics ; Anticancer ; EGFR ; cytotoxic ; docking ; lysine

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test