Abstract
Chemoresistance has emerged as a critical barrier in the treatment of lung cancer. The recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2, can repair topoisomerase 2-mediated DNA damage, thereby contributing to cancer cell resistance. This study reported the identification of the natural product myrtucommulone D as a selective tyrosyl-DNA phosphodiesterase 2 inhibitor and presented its first enantioselective total synthesis. The enantiomeric excess (ee) of (+)- and (‒)-myrtucommulone D was determined to be 95.3 and 95.1%, respectively. Biological experiments indicated that (+)-myrtucommulone D inhibited tyrosyl-DNA phosphodiesterase 2 with an IC50 value of 0.69 µM and exhibited significant synergistic effects with the anti-cancer drug etoposide in various human lung cancer cell lines, including non-small cell lung cancer cell line (A549), large cell lung cancer cell line (NCI-H460), small cell lung cancer cell line (NCI-H446), and etoposide resistant small cell lung cancer cell line (NCI-H446/VP). Further investigation revealed that the combination of (+)-myrtucommulone D and etoposide could induce drug-resistant cancer cell (NCI-H446/VP) apoptosis, inhibit colony formation, and potentially suppress cancer cell metastasis. The present study delineates the enantioselective total synthesis of myrtucommulone D and its role in combatting anti-tumor drug resistance as a tyrosyl-DNA phosphodiesterase 2 inhibitor.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The data that support the findings of this study are available on request from the corresponding author.
References
Carroll AR, Lamb J, Moni R, Guymer GP, Forster PI, Quinn RJ (2008) Myrtucmmulones F-I, phloroglucinols with thyrotropin-releasing hormone receptor-2 binding affinity from the seeds of Corymbia scabrida. J Nat Prod 71:1564–1568. https://doi.org/10.1021/np800247u
Charpentier M, Jauch J (2017) Metal catalysed versus organocatalysed stereoselective synthesis: the concrete case of myrtucommulones. Tetrahedron 73:6614–6623. https://doi.org/10.1016/j.tet.2017.10.011
Dean RA, Fam HK, An J, Choi K, Shimizu Y, Jones SJ, Boerkoel CF, Interthal H, Pfeifer TA (2014) Identification of a putative tdp1 inhibitor (CD00509) by in vitro and cell-based assays. J Biomol Screen 19:1372–1382. https://doi.org/10.1177/1087057114546551
Do PM, Varanasi L, Fan S, Li C, Kubacka I, Newman V, Chauhan K, Daniels SR, Boccetta M, Garrett MR, Li R, Martinez LA (2012) Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev 26:830–845. https://doi.org/10.1101/gad.181685.111
Hatano M, Goto Y, Izumiseki A, Akakura M, Ishihara K (2015) Boron tribromide-assisted chiral phosphoric acid catalyst for a highly enantioselective Diels-Alder reaction of 1,2-dihydropyridines. J Am Chem Soc 137:13472–13475. https://doi.org/10.1021/jacs.5b08693
Herzog BH, Devarakonda S, Govindan R (2021) Overcoming chemotherapy resistance in SCLC. J Thorac Oncol 16:2002–2015. https://doi.org/10.1016/j.jtho.2021.07.018
Kankanala J, Marchand C, Abdelmalak M, Aihara H, Pommier Y, Wang Z (2016) Isoquinoline-1,3-diones as selective inhibitors of tyrosyl DNA phosphodiesterase II (TDP2). J Med Chem 59:2734–2746. https://doi.org/10.1021/acs.jmedchem.5b01973
Kankanala J, Ribeiro CJA, Kiselev E, Ravji A, Williams J, Xie J, Aihara H, Pommier Y, Wang Z (2019) Novel deazaflavin analogues potently inhibited tyrosyl DNA phosphodiesterase 2 (TDP2) and strongly sensitized cancer cells toward treatment with topoisomerase II (TOP2) poison etoposide. J Med Chem 62:4669–4682. https://doi.org/10.1021/acs.jmedchem.9b00274
Kiselev E, Ravji A, Kankanla J, Xie J, Wang Z, Pommier Y (2020) Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. DNA Repair 85:102747. https://doi.org/10.1016/j.dnarep.2019.102747
Komulainen E, Pennicott L, Le Grand D, Caldecott KW (2019) Deazaflavin inhibitors of TDP2 with cellular activity can affect etoposide influx and/or efflux. ACS Chem Biol 14:1110–1114. https://doi.org/10.1021/acschembio.9b00144
Kont YS, Dutta A, Mallisetty A, Mathew J, Minas T, Kraus C, Dhopeshwarkar P, Kallakury B, Mitra S, Üren A, Adhikari S (2016) Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing. DNA Repair 43:38–47. https://doi.org/10.1016/j.dnarep.2016.04.009
Kossmann BR, Abdelmalak M, Lopez S, Tender G, Yan C, Pommier Y, Marchand C, Ivanov I (2016) Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft. Bioorg Med Chem Lett 26:3232–3236. https://doi.org/10.1016/j.bmcl.2016.05.065
Ledesma FC, El KSF, Zuma MC, Osborn K, Caldecott KW (2009) A human 5’-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461:674–678. https://doi.org/10.1038/nature08444
Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7:339–348. https://doi.org/10.15171/apb.2017.041
Marchand C, Abdelmalak M, Kankanala J, Huang SY, Kiselev E, Fesen K, Kurahashi K, Sasanuma H, Takeda S, Aihara H, Wang Z, Pommier Y (2016) Deazaflavin inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2. ACS Chem Biol 11:1925–1933. https://doi.org/10.1021/acschembio.5b01047
Nicoletti R, Ferranti P, Caira S, Misso G, Castellano M, Di Lorenzo G, Caraglia M (2014) Myrtucommulone production by a strain of Neofusicoccum australe endophytic in myrtle (Myrtus communis). World J Microbiol Biotechnol 30:1047–1052. https://doi.org/10.1007/s11274-013-1523-x
Pommier Y, Huanga SY, Gao R, Das BB, Murai J, Marchand C (2014) Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA Repair 23:114–129. https://doi.org/10.1016/j.dnarep.2014.03.020
Raoof A, Depledge P, Hamilton NM, Hamilton NS, Hitchin JR, Hopkins GV, Jordan AM, Maguire LA, McGonagle AE, Mould DP, Rushbrooke M, Small HF, Smith KM, Thomson GJ, Turlais F, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ (2013) Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II. J Med Chem 56:6352–6370. https://doi.org/10.1021/jm400568p
Ribeiro CJA, Kankanala J, Shi K, Kurahashi K, Kiselev E, Ravji A, Pommier Y, Aihara H, Wang Z (2018) New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2). Eur J Pharm Sci 118:67–79. https://doi.org/10.1016/j.ejps.2018.03.021
Ribeiro CJA, Kankanala J, Xie J, Williams J, Aihara H, Wang Z (2019) Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. Bioorg Med Chem Lett 29:257–261. https://doi.org/10.1016/j.bmcl.2018.11.044
Shaheen F, Ahmad M, Khan SN, Hussain SS, Anjum S, Tashkhodjaev B, Turgunov K, Sultankhodzhaev MN, Choudhary MI, Atta-ur-Rahman (2006) New α-glucosidase inhibitors and antibacterial compounds from Myrtus communis L. Eur J Org Chem 10:2371–2377. https://doi.org/10.1002/ejoc.200500936
Wang P, Elsayed MSA, Plescia CB, Ravji A, Redon CE, Kiselev E, Marchand C, Zeleznik O, Agama K, Pommier Y, Cushman M (2017) Synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1, tyrosyl–DNA phosphodiesterase 1 (Tdp1), and tyrosyl–DNA phosphodiesterase 2 (Tdp2). J Med Chem 60:3275–3288. https://doi.org/10.1021/acs.jmedchem.6b01565
Wiechmann K, Müller H, Huch V, Hartmann D, Werz O, Jauch J (2015) Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase. Eur J Med Chem 101:133–149. https://doi.org/10.1016/j.ejmech.2015.06.001
Wu Y, Chen M, Wang WJ, Li NP, Ye WC, Wang L (2020) Phloroglucinol derivatives from Myrtus communis ‘Variegata’ and their antibacterial activities. Chem Biodivers 17:e2000292. https://doi.org/10.1002/cbdv.202000292
Yang H, Zhu XQ, Wang W, Chen Y, Hu Z, Zhang Y, Hu DX, Yu LM, Agama K, Pommier Y, An LK (2021) The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. Bioorg Chem 111:104881. https://doi.org/10.1016/j.bioorg.2021.104881
Yu LM, Hu Z, Chen Y, Ravji A, Lopez S, Plescia CB, Yu Q, Yang H, Abdelmalak M, Saha S, Agama K, Kiselev E, Marchand C, Pommier Y, An LK (2018) Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2). Eur J Med Chem 151:777–796. https://doi.org/10.1016/j.ejmech.2018.04.024
Zeng Z, Cortés-Ledesma F, El Khamisy SF, Caldecott KW (2011) TDP2/TTRAP is the major 5′-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J Biol Chem 286:403–409. https://doi.org/10.1074/jbc.M110.181016
Zhang Y, He XZ, Yang H, Liu HY, An LK (2021) Robustadial A and B from Eucalyptus globulus Labill. and their anticancer activity as selective tyrosyl-DNA phosphodiesterase 2 inhibitors. Phyther Res 35:5282–5289. https://doi.org/10.1002/ptr.7207
Zhang Y, Yang H, Wang FT, Peng X, Liu HY, Li QJ, An LK (2022) Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities. Eur J Med Chem 238:114445. https://doi.org/10.1016/j.ejmech.2022.114445
Author information
Authors and Affiliations
Contributions
Literature search and data collection were performed by YZ. The first draft of the manuscript was written by YZ. LGX, XP, and HY commented on previous versions of the manuscript. YZ and ZW supervised the work and conceptualized the study. All authors read and approved the final manuscript.
Corresponding author
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, Y., Xiao, LG., Peng, X. et al. Synthesis of Myrtucommulone D: A Selective Inhibitor of Tyrosyl-DNA Phosphodiesterase 2 Promoting Drug Resistance Reversal in Lung Cancer Cells. Rev. Bras. Farmacogn. 34, 595–608 (2024). https://doi.org/10.1007/s43450-023-00509-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43450-023-00509-0