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image of Novel Heterocyclic Compounds Exhibit Potent Antileukemic Activity through 
Selective Induction of Apoptosis and HDAC8 Interaction in AML Cells

Abstract

Introduction

Heterocyclic compounds serve as the structural framework for many commercially available drugs and are well known for their antitumor properties.

Aim

This study aimed to evaluate the cytotoxic effects, apoptosis induction, changes in cell cycle progression, and gene expression alterations of new heterocyclic compounds and their precursors against the acute monocytic leukemia cell line THP-1 through experimentation and computational approaches.

Methods

The study employed cytotoxicity assays, flow cytometry analyses, gene expression evaluations, oral bioavailability studies, and molecular modeling. Among the compounds tested, , , and demonstrated the greatest potency and selectivity, exhibiting substantially increased cytotoxicity (1.18 μM < < 7.66 μM) against the THP-1 cell line. Investigations into apoptosis induction and cell cycle changes revealed that these compounds primarily caused an increase in the number of THP-1 cells undergoing apoptosis after 48 hours of treatment. Additionally, compounds and induced an accumulation of cells in the G0/G1 phase in the same cell line.

Results

Regarding gene expression, a shift in the expression profile of genes associated with apoptotic mechanisms was observed. Furthermore, analysis revealed that these three active compounds potentially interact with histone deacetylase 8 (HDAC8), a protein known to be associated with cancer.

Conclusion

These findings underscore the potential of these compounds as candidates for the development of novel therapeutic approaches in oncology.

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2025-12-08

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References

  1. Pelcovits A. Niroula R. Acute myeloid leukemia: A review. R. I. Med. J. 2020 103 3 38 40
    [Google Scholar]
  2. Daver N. Wei A.H. Pollyea D.A. Fathi A.T. Vyas P. DiNardo C.D. New directions for emerging therapies in acute myeloid leukemia: The next chapter. Blood Cancer J. 2020 10 10 107 10.1038/s41408‑020‑00376‑1 33127875
    [Google Scholar]
  3. Short N.J. Konopleva M. Kadia T.M. Borthakur G. Ravandi F. DiNardo C.D. Daver N. Advances in the treatment of acute myeloid leukemia: New drugs and new challenges. Cancer Discov. 2020 10 4 506 525 10.1158/2159‑8290.CD‑19‑1011 32014868
    [Google Scholar]
  4. Döhner H. Weisdorf D.J. Bloomfield C.D. Acute myeloid leukemia. N. Engl. J. Med. 2015 373 12 1136 1152 10.1056/NEJMra1406184 26376137
    [Google Scholar]
  5. Bukowski K. Kciuk M. Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 2020 21 9 3233 10.3390/ijms21093233 32370233
    [Google Scholar]
  6. Martins P. Jesus J. Santos S. Raposo L. Roma-Rodrigues C. Baptista P. Fernandes A. Heterocyclic anticancer compounds: Recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules 2015 20 9 16852 16891 10.3390/molecules200916852 26389876
    [Google Scholar]
  7. Gomtsyan A. Heterocycles in Drugs and Drug Discovery. Chem. Heterocycl. Compd. 2012 48 7 10
    [Google Scholar]
  8. Nic M. Hovorka L. Jirat J. Kosata B. Znamenacek J. IUPAC. Compendium of Chemical Terminology (the “Gold Book”) International Union of Pure and Applied Chemistry 2015
    [Google Scholar]
  9. Amewu R.K. Sakyi P.O. Osei-Safo D. Addae-Mensah I. Synthetic and naturally occurring heterocyclic anticancer compounds with multiple biological targets. Molecules 2021 26 23 7134 10.3390/molecules26237134 34885716
    [Google Scholar]
  10. Heravi M.M. Zadsirjan V. Prescribed drugs containing nitrogen heterocycles: An overview. RSC Advances 2020 10 72 44247 44311 10.1039/D0RA09198G 35557843
    [Google Scholar]
  11. Lu D.Y. Xu B. Lu T.R. Anticancer drug development: Evaluative architecture. Lett. Drug Des. Discov. 2024 21 5 836 846 10.2174/1570180819666220610102444
    [Google Scholar]
  12. Ma X. Wang Z. Anticancer drug discovery in the future: An evolutionary perspective. Drug Discov. Today 2009 14 23-24 1136 1142 10.1016/j.drudis.2009.09.006 19800414
    [Google Scholar]
  13. Demmer C.S. Bunch L. Benzoxazoles and oxazolopyridines in medicinal chemistry studies. Eur. J. Med. Chem. 2015 97 1 778 785 10.1016/j.ejmech.2014.11.064 25487760
    [Google Scholar]
  14. Arulmurugan S. Kavitha H.P. Vennila J.P. Review on the synthetic methods of biologically potent benzoxazole derivatives. Mini Rev. Org. Chem. 2021 18 6 769 785 10.2174/1570193X17999201020231359
    [Google Scholar]
  15. Xu C. Wang M. Liu Q. Recent advances in metal‐catalyzed bond‐forming reactions of ketene S,S ‐acetals. Adv. Synth. Catal. 2019 361 6 1208 1229 10.1002/adsc.201801070
    [Google Scholar]
  16. Huang L. Wu J. Hu J. Bi Y. Huang D. Ketene dithioacetals in organic synthesis. Tetrahe. Lett. 2020 61 151363 10.1016/j.tetlet.2019.151363
    [Google Scholar]
  17. Thomae D. Perspicace E. Henryon D. Xu Z. Schneider S. Hesse S. Kirsch G. Seck P. One-pot synthesis of new tetrasubstituted thiophenes and selenophenes. Tetrahedron 2009 65 50 10453 10458 10.1016/j.tet.2009.10.021
    [Google Scholar]
  18. Baliza L.R.S.P. Freitas T.R. Gonçalves E.K.S. Antunes G.R. Souza A.J.F. Yoneda J. Duarte C.L. Andrade S.N. Sabino P.d.A. Varotti F.P. Sangi D.P. Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals. Chem. Biol. Drug Des. 2024 104 1 e14581 10.1111/cbdd.14581 38997237
    [Google Scholar]
  19. Sangi D.P. Meira Y.G. Moreira N.M. Lopes T.A. Leite M.P. Pereira-Flores M.E. Alvarenga E.S. Benzoxazoles as novel herbicidal agents. Pest Manag. Sci. 2019 75 1 262 269 10.1002/ps.5111 29885098
    [Google Scholar]
  20. Sangi D.P. Monteiro J.L. Vanzolini K.L. Cass Q.B. Paixão M.W. Corrêa A.G. Microwave-assisted synthesis of N -heterocycles and their evaluation using an acetylcholinesterase immobilized capillary reactor. J. Braz. Chem. Soc. 2014 25 5 887 889 10.5935/0103‑5053.20140056
    [Google Scholar]
  21. Tsuchiya S. Yamabe M. Yamaguchi Y. Kobayashi Y. Konno T. Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP‐1). Int. J. Cancer 1980 26 2 171 176 10.1002/ijc.2910260208 6970727
    [Google Scholar]
  22. Kleiveland C.R. Peripheral Blood Mononuclear Cells. The Impact of Food Bioactives on Health. Cham Springer International Publishing 2015 161 167 10.1007/978‑3‑319‑16104‑4_15
    [Google Scholar]
  23. Evangelista F.C.G. Lopes F.d.A. Andrade S.N. Barbosa S.d.C. Silva d.J.D. Neves A.M.M. Loures M.G.d.C. Brito L.F. Sousa d.L.P. Borges K.B.G. Viana G.H.R. Varotti P.d.F. Sabino P.d.A. Synthetic 3-alkylpyridine alkaloid analogues as a new scaffold against leukemic cell lines: Cytotoxic evaluation and mode of action. Med. Chem. Res. 2019 28 9 1567 1578 10.1007/s00044‑019‑02395‑5
    [Google Scholar]
  24. Koopman B. G. Reutelingsperger C. P. M. Kuijten G. A. M. Keehnen R. M. J. Pals S. T. Oers v.M. H. J. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 1994 84 5 1415 1420
    [Google Scholar]
  25. Chen C. Ma Q. Liu C. Deng P. Zhu G. Zhang L. He M. Lu Y. Duan W. Pei L. Li M. Yu Z. Zhou Z. Exposure to 1800 MHz radiofrequency radiation impairs neurite outgrowth of embryonic neural stem cells. Sci. Rep. 2014 4 1 5103 10.1038/srep05103 24869783
    [Google Scholar]
  26. Jayat C. Ratinaud M-H. Cell cycle analysis by flow cytometry: Principles and applications Biol. Cell. 1993 78 1-2 15 25
    [Google Scholar]
  27. Andrade S.N. Evangelista F.C.G. Seckler D. Marques D.R. Freitas T.R. Nunes R.R. Oliveira J.T. Ribeiro R.I.M.A. Santos H.B. Thomé R.G. Taranto A.G. Santos F.V. Viana G.H.R. Freitas R.P. Humberto J.L. Sabino A.P. Hilário F.F. Varotti F.P. Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs. Med. Chem. Res. 2018 27 11-12 2397 2413 10.1007/s00044‑018‑2244‑3
    [Google Scholar]
  28. Desjardins P. Conklin D. NanoDrop microvolume quantitation of nucleic acids. J. Vis. Exp. 2010 -1 2565 10.3791/2565 21189466
    [Google Scholar]
  29. Livak K.J. Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) Method. Methods 2001 25 4 402 408 10.1006/meth.2001.1262 11846609
    [Google Scholar]
  30. Bender B. J. Gahbauer S. Luttens A. Lyu J. Webb C. M. Stein R. M. Fink E. A. Balius T. E. Carlsson J. Irwin J. J. Shoichet B. K. A practical guide to large-scale docking. Nat Protoc. 2021 16 4799 4832 10.1038/s41596‑021‑00597‑z
    [Google Scholar]
  31. Elokely K.M. Doerksen R.J. Docking challenge: Protein sampling and molecular docking performance. J. Chem. Inf. Model. 2013 53 8 1934 1945 10.1021/ci400040d 23530568
    [Google Scholar]
  32. Stewart J.J.P. Optimization of parameters for semiempirical methods VI: More modifications to the NDDO approximations and re-optimization of parameters. J. Mol. Model. 2013 19 1 1 32 10.1007/s00894‑012‑1667‑x 23187683
    [Google Scholar]
  33. Doye J.P.K. Wales D.J. Surveying a potential energy surface by eigenvector-following applications to global optimisation and the structural transformations of clusters.;Zeitschrift für Physik D Atoms, Molecules and Clusters 1997 40 194 197
    [Google Scholar]
  34. Dutra J.D.L. Filho M.A.M. Rocha G.B. Freire R.O. Simas A.M. Stewart J.J.P. Sparkle/PM7 lanthanide parameters for the modeling of complexes and materials. J. Chem. Theory Comput. 2013 9 8 3333 3341 10.1021/ct301012h 24163641
    [Google Scholar]
  35. Morris G.M. Huey R. Lindstrom W. Sanner M.F. Belew R.K. Goodsell D.S. Olson A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009 30 16 2785 2791 10.1002/jcc.21256 19399780
    [Google Scholar]
  36. Gasteiger J. Marsili M. Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36 2 3219 3228
    [Google Scholar]
  37. Trott O. Olson A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010 31 2 455 461 10.1002/jcc.21334 19499576
    [Google Scholar]
  38. Maia E.H.B. Campos V.A. dos Reis Santos B. Costa M.S. Lima I.G. Greco S.J. Ribeiro R.I.M.A. Munayer F.M. Silva d.A.M. Taranto A.G. Octopus: A platform for the virtual high-throughput screening of a pool of compounds against a set of molecular targets. J. Mol. Model. 2017 23 1 26 10.1007/s00894‑016‑3184‑9 28064377
    [Google Scholar]
  39. Al-Oudat B.A. Alqudah M.A. Audat S.A. Al-Balas Q.A. El-Elimat T. Hassan M.A. Frhat I.N. Azaizeh M.M. Design, synthesis, and biologic evaluation of novel chrysin derivatives as cytotoxic agents and caspase-3/7 activators. Drug Des. Devel. Ther. 2019 13 January 423 433 10.2147/DDDT.S189476 30774307
    [Google Scholar]
  40. Guido R.V.C. Andricopulo A.D. Oliva G. Drug design, biotechnology and medicinal chemistry: Applications to infectious diseases. Estud. Av. 2010 24 70 81 98 10.1590/S0103‑40142010000300006
    [Google Scholar]
  41. Glamočlija U. Padhye S. Špirtović-Halilović S. Osmanović A. Veljović E. Roca S. Novaković I. Mandić B. Turel I. Kljun J. Trifunović S. Kahrović E. Pavelić K.S. Harej A. Klobučar M. Završnik D. Synthesis, biological evaluation and docking studies of benzoxazoles derived from thymoquinone. Molecules 2018 23 12 3297 10.3390/molecules23123297 30545123
    [Google Scholar]
  42. Zilifdar F. Foto E. Ertan-Bolelli T. Aki-Yalcin E. Yalcin I. Diril N. Biological evaluation and pharmacophore modeling of some benzoxazoles and their possible metabolites. Arch. Pharm. 2018 351 2 1700265 10.1002/ardp.201700265 29359805
    [Google Scholar]
  43. Wong X.K. Yeong K.Y. A patent review on the current developments of benzoxazoles in drug discovery. ChemMedChem 2021 16 21 3237 3262 10.1002/cmdc.202100370 34289258
    [Google Scholar]
  44. Rida S. Ashour F. Elhawash S. Elsemary M. Badr M. Shalaby M. Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents. Eur. J. Med. Chem. 2005 40 9 949 959 10.1016/j.ejmech.2005.03.023 16040162
    [Google Scholar]
  45. El-Helby A.G.A. Sakr H. Eissa I.H. Abulkhair H. Al-Karmalawy A.A. El-Adl K. Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors. Arch. Pharm. (Weinheim) 2019 352 10 1900113 10.1002/ardp.201900113 31448458
    [Google Scholar]
  46. Philoppes J.N. Lamie P.F. Design and synthesis of new benzoxazole/benzothiazole-phthalimide hybrids as antitumor-apoptotic agents. Bioorg. Chem. 2019 89 102978 10.1016/j.bioorg.2019.102978 31136900
    [Google Scholar]
  47. Giordano A. Forte G. Terracciano S. Russo A. Sala M. Scala M.C. Johansson C. Oppermann U. Riccio R. Bruno I. Micco D.S. Identification of the 2-Benzoxazol-2-yl-phenol scaffold as new hit for JMJD3 inhibition. ACS Med. Chem. Lett. 2019 10 4 601 605 10.1021/acsmedchemlett.8b00589 30996803
    [Google Scholar]
  48. Pietkiewicz S. Schmidt J.H. Lavrik I.N. Quantification of apoptosis and necroptosis at the single cell level by a combination of imaging flow cytometry with classical annexin v/propidium iodide staining. J. Immunol. Methods 2015 423 99 103 10.1016/j.jim.2015.04.025 25975759
    [Google Scholar]
  49. Poon I.K.H. Hulett M.D. Parish C.R. Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ. 2010 17 3 381 397 10.1038/cdd.2009.195 20019744
    [Google Scholar]
  50. Sapieha P. Mallette F.A. Cellular senescence in postmitotic cells: Beyond growth arrest. Trends Cell Biol. 2018 28 8 595 607 10.1016/j.tcb.2018.03.003 29704982
    [Google Scholar]
  51. Surova O. Zhivotovsky B. Various modes of cell death induced by DNA damage. Oncogene 2013 32 33 3789 3797 10.1038/onc.2012.556 23208502
    [Google Scholar]
  52. Galluzzi L. Vitale I. Aaronson S.A. Abrams J.M. Adam D. Agostinis P. Alnemri E.S. Altucci L. Amelio I. Andrews D.W. Annicchiarico-Petruzzelli M. Antonov A.V. Arama E. Baehrecke E.H. Barlev N.A. Bazan N.G. Bernassola F. Bertrand M.J.M. Bianchi K. Blagosklonny M.V. Blomgren K. Borner C. Boya P. Brenner C. Campanella M. Candi E. Carmona-Gutierrez D. Cecconi F. Chan F.K.M. Chandel N.S. Cheng E.H. Chipuk J.E. Cidlowski J.A. Ciechanover A. Cohen G.M. Conrad M. Cubillos-Ruiz J.R. Czabotar P.E. D’Angiolella V. Dawson T.M. Dawson V.L. Laurenzi d.V. Maria d.R. Debatin K.M. DeBerardinis R.J. Deshmukh M. Daniele D.N. Virgilio D.F. Dixit V.M. Dixon S.J. Duckett C.S. Dynlacht B.D. El-Deiry W.S. Elrod J.W. Fimia G.M. Fulda S. García-Sáez A.J. Garg A.D. Garrido C. Gavathiotis E. Golstein P. Gottlieb E. Green D.R. Greene L.A. Gronemeyer H. Gross A. Hajnoczky G. Hardwick J.M. Harris I.S. Hengartner M.O. Hetz C. Ichijo H. Jäättelä M. Joseph B. Jost P.J. Juin P.P. Kaiser W.J. Karin M. Kaufmann T. Kepp O. Kimchi A. Kitsis R.N. Klionsky D.J. Knight R.A. Kumar S. Lee S.W. Lemasters J.J. Levine B. Linkermann A. Lipton S.A. Lockshin R.A. López-Otín C. Lowe S.W. Luedde T. Lugli E. MacFarlane M. Madeo F. Malewicz M. Malorni W. Manic G. Marine J.C. Martin S.J. Martinou J.C. Medema J.P. Mehlen P. Meier P. Melino S. Miao E.A. Molkentin J.D. Moll U.M. Muñoz-Pinedo C. Nagata S. Nuñez G. Oberst A. Oren M. Overholtzer M. Pagano M. Panaretakis T. Pasparakis M. Penninger J.M. Pereira D.M. Pervaiz S. Peter M.E. Piacentini M. Pinton P. Prehn J.H.M. Puthalakath H. Rabinovich G.A. Rehm M. Rizzuto R. Rodrigues C.M.P. Rubinsztein D.C. Rudel T. Ryan K.M. Sayan E. Scorrano L. Shao F. Shi Y. Silke J. Simon H.U. Sistigu A. Stockwell B.R. Strasser A. Szabadkai G. Tait S.W.G. Tang D. Tavernarakis N. Thorburn A. Tsujimoto Y. Turk B. Berghe V.T. Vandenabeele P. Heiden V.M.G. Villunger A. Virgin H.W. Vousden K.H. Vucic D. Wagner E.F. Walczak H. Wallach D. Wang Y. Wells J.A. Wood W. Yuan J. Zakeri Z. Zhivotovsky B. Zitvogel L. Melino G. Kroemer G. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018 25 3 486 541 10.1038/s41418‑017‑0012‑4 29362479
    [Google Scholar]
  53. Kumari R. Jat P. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Front. Cell Dev. Biol. 2021 9 645593 10.3389/fcell.2021.645593 33855023
    [Google Scholar]
  54. Kuzu B. Hepokur C. Turkmenoglu B. Burmaoglu S. Algul O. Design, synthesis and in vitro antiproliferation activity of some 2-aryl and -heteroaryl benzoxazole derivatives. Future Med. Chem. 2022 14 14 1027 1048 10.4155/fmc‑2022‑0076 35703122
    [Google Scholar]
  55. Zhong W. Tang X. Liu Y. Zhou C. Liu P. Li E. Zhong P. Lv H. Zou Q. Wang M. Benzoxazole derivative K313 induces cell cycle arrest, apoptosis and autophagy blockage and suppresses mTOR/p70S6K pathway in nalm-6 and daudi cells. Molecules 2020 25 4 971 10.3390/molecules25040971 32098126
    [Google Scholar]
  56. AboulWafa O.M. Daabees H.M.G. El-Said A.H. Benzoxazole-appended piperidine derivatives as novel anticancer candidates against breast cancer. Bioorg. Chem. 2023 134 106437 10.1016/j.bioorg.2023.106437
    [Google Scholar]
  57. Aubrey B.J. Kelly G.L. Janic A. Herold M.J. Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018 25 1 104 113 10.1038/cdd.2017.169 29149101
    [Google Scholar]
  58. Fridman J.S. Lowe S.W. Control of apoptosis by p53. Oncogene 2003 22 56 9030 9040 10.1038/sj.onc.1207116 14663481
    [Google Scholar]
  59. Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell. Death Differ. 2018 25 114 132 10.1038/cdd.2017.172
    [Google Scholar]
  60. Nocella C. D’Amico A. Cammisotto V. Bartimoccia S. Castellani V. Loffredo L. Marini L. Ferrara G. Testa M. Motta G. Benazzi B. Zara F. Frati G. Sciarretta S. Pignatelli P. Violi F. Carnevale R. Group S. Structure, activation, and regulation of NOX2: At the crossroad between the innate immunity and oxidative stress-mediated pathologies. Antioxidants 2023 12 2 429 10.3390/antiox12020429 36829988
    [Google Scholar]
  61. Abbas T. Dutta A. p21 in cancer: Intricate networks and multiple activities. Nat. Rev. Cancer 2009 9 6 400 414 10.1038/nrc2657 19440234
    [Google Scholar]
  62. Lee Y.J. Tsai C.H. Hwang J.J. Chiu S.J. Sheu T.J. Keng P.C. Involvement of a p53-independent and post-transcriptional up-regulation for p21WAF/CIP1 following destabilization of the actin cytoskeleton. Int. J. Oncol. 1992 34 2 581 589 10.3892/ijo_00000184 19148495
    [Google Scholar]
  63. Cimmino P.T. Ammendola R. Cattaneo F. Esposito G. NOX dependent ROS generation and cell metabolism. Int. J. Mol. Sci. 2023 24 3 2086 10.3390/ijms24032086 36768405
    [Google Scholar]
  64. Landry W.D. Cotter T.G. ROS Signalling, NADPH Oxidases and Cancer. Biochemical Society Transactions. London Portland Press Ltd 2014 42 934 938 10.1042/BST20140060
    [Google Scholar]
  65. Roy K. Wu Y. Meitzler J.L. Juhasz A. Liu H. Jiang G. Lu J. Antony S. Doroshow J.H. NADPH Oxidases and Cancer. Clinical Science. London Portland Press Ltd 2015 863 875 10.1042/CS20140542
    [Google Scholar]
  66. Skonieczna M. Hejmo T. Poterala-Hejmo A. Cieslar-Pobuda A. Buldak R.J. NADPH Oxidases (NOX): Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. Oxidative Medicine and Cellular Longevity. London Hindawi Limited 2017 2017 1 9420539 10.1155/2017/9420539
    [Google Scholar]
  67. Perillo B. Donato D.M. Pezone A. Zazzo D.E. Giovannelli P. Galasso G. Castoria G. Migliaccio A. ROS in cancer therapy: The bright side of the moon. Exp. Mol. Med. 2020 52 2 192 203 10.1038/s12276‑020‑0384‑2
    [Google Scholar]
  68. Robinson A.J. Davies S. Darley R.L. Tonks A. Reactive oxygen species rewires metabolic activity in acute myeloid leukemia. Front. Oncol. 2021 11 632623 10.3389/fonc.2021.632623 33777786
    [Google Scholar]
  69. Hole P.S. Zabkiewicz J. Munje C. Newton Z. Pearn L. White P. Marquez N. Hills R.K. Burnett A.K. Tonks A. Darley R.L. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood 2013 122 19 3322 3330 10.1182/blood‑2013‑04‑491944 24089327
    [Google Scholar]
  70. Aurelius J. Thorén F.B. Akhiani A.A. Brune M. Palmqvist L. Hansson M. Hellstrand K. Martner A. Monocytic AML cells inactivate antileukemic lymphocytes: Role of NADPH oxidase/gp91phox expression and the PARP-1/PAR pathway of apoptosis. Blood 2012 119 24 5832 5837 10.1182/blood‑2011‑11‑391722 22550344
    [Google Scholar]
  71. Bhatnagar I. Kim S.K. Marine antitumor drugs: Status, shortfalls and strategies. Mar. Drugs 2010 8 10 2702 2720 10.3390/md8102702 21116415
    [Google Scholar]
  72. Evans B.E. Rittle K.E. Bock M.G. DiPardo R.M. Freidinger R.M. Whitter W.L. Lundell G.F. Veber D.F. Anderson P.S. Chang R.S.L. Lotti V.J. Cerino D.J. Chen T.B. Kling P.J. Kunkel K.A. Springer J.P. Hirshfield J. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988 31 12 2235 2246 10.1021/jm00120a002 2848124
    [Google Scholar]
  73. Kiefer J.R. Pawlitz J.L. Moreland K.T. Stegeman R.A. Hood W.F. Gierse J.K. Stevens A.M. Goodwin D.C. Rowlinson S.W. Marnett L.J. Stallings W.C. Kurumbail R.G. Structural insights into the stereochemistry of the cyclooxygenase reaction. Nature 2000 405 6782 97 101 10.1038/35011103 10811226
    [Google Scholar]
  74. Rowsell S. Hawtin P. Minshull C.A. Jepson H. Brockbank S.M.V. Barratt D.G. Slater A.M. McPheat W.L. Waterson D. Henney A.M. Pauptit R.A. Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. J. Mol. Biol. 2002 319 1 173 181 10.1016/S0022‑2836(02)00262‑0 12051944
    [Google Scholar]
  75. Vannini A. Volpari C. Filocamo G. Casavola E.C. Brunetti M. Renzoni D. Chakravarty P. Paolini C. Francesco d.R. Gallinari P. Steinkühler C. Marco D.S. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl. Acad. Sci. USA 2004 101 42 15064 15069 10.1073/pnas.0404603101 15477595
    [Google Scholar]
  76. Spurny R. Ramerstorfer J. Price K. Brams M. Ernst M. Nury H. Verheij M. Legrand P. Bertrand D. Bertrand S. Dougherty D.A. Esch d.I.J.P. Corringer P.J. Sieghart W. Lummis S.C.R. Ulens C. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines. Proc. Natl. Acad. Sci. USA 2012 109 44 E3028 E3034 10.1073/pnas.1208208109 23035248
    [Google Scholar]
  77. Kinoshita T. Yoshida I. Nakae S. Okita K. Gouda M. Matsubara M. Yokota K. Ishiguro H. Tada T. Crystal structure of human mono-phosphorylated ERK1 at Tyr204. Biochem. Biophys. Res. Commun. 2008 377 4 1123 1127 10.1016/j.bbrc.2008.10.127 18983981
    [Google Scholar]
  78. Chakrabarti A. Oehme I. Witt O. Oliveira G. Sippl W. Romier C. Pierce R.J. Jung M. HDAC8: A multifaceted target for therapeutic interventions. Trends Pharmacol. Sci. 2015 36 7 481 492 10.1016/j.tips.2015.04.013 26013035
    [Google Scholar]
  79. Spreafico M. Gruszka A.M. Valli D. Mazzola M. Deflorian G. Quintè A. Totaro M.G. Battaglia C. Alcalay M. Marozzi A. Pistocchi A. HDAC8: A promising therapeutic target for acute myeloid leukemia. Front. Cell Dev. Biol. 2020 8 844 10.3389/fcell.2020.00844 33015043
    [Google Scholar]
  80. Chiu C.F. Chin H.K. Huang W.J. Bai L.Y. Huang H.Y. Weng J.R. Induction of apoptosis and autophagy in breast cancer cells by a novel hdac8 inhibitor. Biomolecules 2019 9 12 824 10.3390/biom9120824 31817161
    [Google Scholar]
  81. Knethen v.A. Brüne B. Histone deacetylation inhibitors as therapy concept in sepsis. Int. J. Mol. Sci. 2019 20 2 346 10.3390/ijms20020346 30654448
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206370289250313062830
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Novel Heterocyclic Compounds Exhibit Potent Antileukemic Activity through 
Selective Induction of Apoptosis and HDAC8 Interaction in AML Cells
Bentham Science Publishers ; https://doi.org/10.2174/0118715206370289250313062830
/content/journals/acamc/10.2174/0118715206370289250313062830
/content/journals/acamc/10.2174/0118715206370289250313062830
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  • Article Type:     Research Article
Keywords: apoptosis ; histone deacetylase 8 (HDAC8) ; hematologic malignancy ; cell cycle arrest ; acute monocytic leukemia ; Heterocyclic compounds

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