Bir Dizi Prodigiosin ve 1,10-Fenantrolin Türevlerinin Yeni Nesil Etkin Antikanser Tedavi Edici İlaçlar ya da Aktif Farmasötik Maddeler Olarak Tasarımı ve Yapısal İncelenmesi

Yıl 2024, Cilt: 14 Sayı: 1, 359 - 390, 15.03.2024

M. Mustafa Çetin , Sümeyye Berfin Gül

https://doi.org/10.31466/kfbd.1423254

Öz

Meme kanseri, beyin metastazı olasılığı en yüksek olan ikinci kanser türü olarak kabul edilmektedir. Bu yüzden meme kanseriyle ilgili araştırmaların çoğu beyin metastatik meme kanserinin mortalitesine yöneliktir. Ancak bu kanser türüne özgü etkili bir tedavi veya antikanser tedavi yöntemi mevcut değildir. Bu nedenle, meme kanseri ilerlemesinin modüle edilmesinde çok önemli rol oynayan HDAC ve mTOR enzimlerini inhibe edecek etkili ve yeni nesil antikanser terapötik ilaçların ve/veya aktif farmasötik maddelerin geliştirilmesi artan bir taleptir. Bu çalışmada, mTOR ve HDAC enzimlerine karşı oldukça güçlü antikanser terapötik ilaçlar ve/veya aktif farmasötik maddeler olarak bir dizi prodigiosin ve 1,10-fenantrolin türevinin yapı-aktivite ilişkisi ve in silico modellemesi incelenmiştir. Doğal ürün Ps ile karşılaştırıldığında, bu ligandlardan 20 tanesi, özellikle 2a, 6b, 13 ve 13a, HDAC1 ve/veya mTOR enzimlerine karşı –9.4 ile –7.1 kcal/mol arasında değişen çok umut verici bağlanma enerjileri ve 225 ile 569 nM arasında değişen inhibisyon sabitleri sergilemiştir. Özellikle 2a, 5, 6b, 7b ve 13 her iki enzime karşı iki taraflı etkinlik (dual action) göstermiştir. İn silico modelleme çalışmalarından elde edilen bulgular, MD simülasyonları ve Lipinski'nin beş kuralına göre ADMET çalışmasıyla da desteklenmiş olup, meme kanseri beyin metastazına sahip hastalar için olağanüstü bir terapötik potansiyel sağlamaktadır.

Anahtar Kelimeler

Antikanser tedavi edici ilaçlar/aktif farmasötik maddeler, meme kanseri beyin metastazları, mTOR, HDAC, 1, 10-fenantrolin, prodigiosin

Etik Beyan

The author declares that this study complies with Research and Publication Ethics.

Destekleyen Kurum

Kadir Has University

Proje Numarası

MMC_BAF and MMC_SEED

Teşekkür

Financial support from the Kadir Has University (MMC_BAF and MMC_SEED) is gratefully acknowledged. This research was also supported by Kadir Has University computer laboratories and facilities for the computational and molecular modeling studies. We greatly thank Prof. Kemal Yelekci and his graduate student Damla Dere from Kadir Has University and appreciate for their support to conduct our computational and molecular modeling studies on their computers as well as endless support in the discussion of the obtained results.

Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients

Öz

Breast cancer is considered as a leading cancer type with the secondary highest possibility of brain metastasis. Most research in breast cancer is currently directed into the mortality of brain metastatic breast cancer. However, there is no effective treatment or anticancer therapeutics specifically for this cancer type. Hence, development of effective and novel anticancer therapeutic drugs/APIs to inhibit HDAC and mTOR, playing very important role on modulating breast cancer progression is an increasing demand. In this study, the structure-activity relationship and in silico modeling of a series of prodigiosin and 1,10-phenanthroline derivatives as highly potent anticancer therapeutic drugs/APIs against mTOR and HDAC enzymes have been investigated. Compared to the natural product Ps, 20 of the highly potent ligands, especially 2a, 6b, 13 and 13a, have exhibited very promising binding energies ranging from –9.4 to –7.1 kcal/mol and inhibition constants ranging from 225 to 569 nM against HDAC1 and/or mTOR enzymes. Ligands 2a, 5, 6b, 7b and 13 in particular show effective dual action against both enzymes. The findings from the in silico modeling studies have also been supported with MD simulations and ADMET study with Lipinski’s rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.

Anahtar Kelimeler

Anticancer therapeutic drugs/APIs, breast cancer brain metastases, mTOR, HDAC, 1, 10-phenanthroline, prodigiosin

Etik Beyan

Statement of Conflicts of Interest The authors declare that they have no known competing financial interest and/or conflict of interest or personal relationships that could appeared to influence the work reported in this paper. Statement of Research and Publication Ethics The author declares that this study complies with Research and Publication Ethics.

Destekleyen Kurum

Kadir Has University

Proje Numarası

MMC_BAF and MMC_SEED

Teşekkür

Financial support from the Kadir Has University (MMC_BAF and MMC_SEED) is gratefully acknowledged. This research was also supported by Kadir Has University computer laboratories and facilities for the computational and molecular modeling studies. We greatly thank Prof. Kemal Yelekci and his graduate student Damla Dere from Kadir Has University and appreciate for their support to conduct our computational and molecular modeling studies on their computers as well as endless support in the discussion of the obtained results.

Kaynakça

• Akdoğan, E. D., Erman, B., and Yelekçi, K. (2011). In silico design of novel and highly selective lysine-specific histone demethylase inhibitors. Turkish Journal of Chemistry, 35(4), 523-542. https://doi.org/10.3906/kim-1102-985
• Al Shamsi, H. O., and Alrawi, S. (2018). Breast cancer screening in the United Arab Emirates: is it time to call for a screening at an earlier age. Journal of Cancer Prevention & Current Research, 9(3), 123-126. http://dx.doi.org/10.32474/OAJOM.2018.02.000131
• Bhowmick, S., AlFaris, N. A., ALTamimi, J. Z., ALOthman, Z. A., Aldayel, T. S., Wabaidur, S. M., and Islam, M. A. (2020). Screening and Analysis of Bioactive Food Compounds for Modulating the CDK2 Protein for Cell Cycle Arrest: Multi-Cheminformatics Approaches for Anticancer Therapeutics. Journal of Molecular Structure, 1216, 128316. https://doi.org/10.1016/j.molstruc.2020.128316
• Bian, X., Liang, Z., Feng, A., Salgado, E., and Shim, H. (2018). HDAC inhibitor suppresses proliferation and invasion of breast cancer cells through regulation of miR-200c targeting CRKL. Biochemical Pharmacology, 147, 30-37. https://doi.org/10.1016/j.bcp.2017.11.008
• Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., and Counter, C. M. (2014). Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature, 509(7501), 492-496. https://doi.org/10.1038/nature13180
• Butler, H. M., Hurse, A., Thursky, E., and Shulman, A. (1969). Bactericidal action of selected phenanthroline chelates and related compounds. Australian Journal of Experimental Biology and Medical Science, 47(5), 541-552. https://doi.org/10.1038/icb.1969.148
• Cetin M. M., (2017). Syntheses and characterization of copper(I) complexes for study of dynamic supramolecular ring-chain equilibria and application as photoredox catalysts. PhD Dissertation, Texas Tech University, Lubbock, TX, USA. Retrieved from https://ttu-ir.tdl.org/items/3e00e225-cd3b-41be-9348-d90b8df2f7d8
• Cetin, M. M., Hodson, R. T., Hart, C. R., Cordes, D. B., Findlater, M., Casadonte Jr, D. J., Cozzolino, A. F., and Mayer, M. F. (2017). Characterization and photocatalytic behavior of 2, 9-di(aryl)-1,10-phenanthroline copper (I) complexes. Dalton Transactions, 46(20), 6553-6569. https://doi.org/10.1039/C7DT00400A
• Cetin, M. M., Peng, W., Unruh, D., Mayer, M. F., Mechref, Y., and Yelekci, K. (2022). Design, synthesis, molecular modeling, and bioactivity evaluation of 1,10-phenanthroline and prodigiosin (Ps) derivatives and their Copper (I) complexes against mTOR and HDAC enzymes as highly potent and effective new anticancer therapeutic drugs. Frontiers in Pharmacology, 13, 980479. https://doi.org/10.3389/fphar.2022.980479
• Cetin, M. M., Shafiei‐Haghighi, S., Chen, J., Zhang, S., Miller, A. C., Unruh, D. K., Casadonte, D. J., Lohr, T. L., Marks, T. J., Mayer, M. F., Stoddart, J. F., and Findlater, M. (2020). Synthesis, structures, photophysical properties, and catalytic characteristics of 2,9‐dimesityl‐1,10‐phenanthroline (dmesp) transition metal complexes. Journal of Polymer Science, 58(8), 1130-1143. https://doi.org/10.1002/pol.20190276
• Chang, C. J. (2015). Searching for harmony in transition-metal signaling. Nature Chemical Biology, 11(10), 744-747. https://doi.org/10.1038/nchembio.1913
• Choi, J. H., Kwon, H. J., Yoon, B. I., Kim, J. H., Han, S. U., Joo, H. J., and Kim, D. Y. (2001). Expression profile of histone deacetylase 1 in gastric cancer tissues. Japanese Journal of Cancer Research, 92(12), 1300-1304. https://doi.org/10.1111/j.1349-7006.2001.tb02153.x
• Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: a Free web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Scientific Reports, 7(1). https://doi.org/10.1038/srep42717
• Danevčič, T., Borić Vezjak, M., Zorec, M., and Stopar, D. (2016). Prodigiosin - A Multifaceted Escherichia coli Antimicrobial Agent. PLoS ONE, 11(9), e0162412. https://doi.org/10.1371/journal.pone.0162412
• Dege, N., Gökce, H., Doğan, O. E., Alpaslan, G., Ağar, T., Muthu, S., Sert S. (2022). Quantum computational, spectroscopic investigations on N-(2-((2-chloro-4,5-dicyanophenyl)amino)ethyl)-4-methylbenzenesulfonamide by DFT/TD-DFT with different solvents, molecular docking and drug-likeness researches. Engineering Aspest, 638, 128311. https://doi.org/10.1016/j.colsurfa.2022.128311
• Denoyer, D., Masaldan, S., La Fontaine, S., and Cater, M. A. (2015). Targeting copper in cancer therapy:‘Copper That Cancer’. Metallomics, 7(11), 1459-1476. https://doi.org/10.1039/c5mt00149h
• Díaz-Ruiz, C., Montaner, B., and Pérez‐Tomás, R. (2001). Prodigiosin induces cell death and morphological changes indicative of apoptosis in gastric cancer cell line HGT-1. Histology and histopathology, 16(2), 415-421. https://doi.org/10.14670/hh-16.415
• Dietrich-Buchecker, C., and Sauvage, J. P. (1990). Templated synthesis of interlocked macrocyclic ligands, the catenands. Preparation and characterization of the prototypical bis-30 membered ring system. Tetrahedron, 46(2), 503-512. https://doi.org/10.1016/S0040-4020(01)85433-8
• Dwyer, F. P., Reid, I. K., Shulman, A., Laycock, G. M., and Dixson, S. (1969). The biological actions of 1,10-phenanthroline and 2,2'-bipyridine hydrochlorides, quaternary salts and metal chelates and related compounds: 1. Bacteriostatic action on selected gram-positive, gram-negative and acid-fast bacteria. Australian Journal of Experimental Biology and Medical Science, 47(2), 203-218. https://doi.org/10.1038/icb.1969.21
• Eberhardt, J., Santos-Martins, D., Tillack, A. F., and Forli, S. (2021). AutoDock Vina 1.2. 0: New Docking Methods, Expanded Force Field, and Python bindings. Journal of Chemical Information and Modeling, 61(8), 3891-3898. https://doi.org/10.1021/acs.jcim.1c00203
• Engel, J., Eckel, R., Aydemir, Ü., Aydemir, S., Kerr, J., Schlesinger-Raab, A., Dirschedl, P., and Hölzel, D. (2003). Determinants and prognoses of locoregional and distant progression in breast cancer. International Journal of Radiation Oncology*Biology*Physics, 55(5), 1186-1195. https://doi.org/10.1016/s0360-3016(02)04476-0
• Erkkila, K. E., Odom, D. T., and Barton, J. K. (1999). Recognition and Reaction of Metallointercalators with DNA. Chemical Reviews, 99(9), 2777-2796. https://doi.org/10.1021/cr9804341
• Espona-Fiedler, M., Soto-Cerrato, V., Hosseini, A., Lizcano, J. M., Guallar, V., Quesada, R., Gao, T., and Pérez-Tomás, R. (2012). Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax. Biochemical Pharmacology, 83(4), 489-496. https://doi.org/10.1016/j.bcp.2011.11.027
• Fasolo, A., and Sessa, C. (2012). Targeting mTOR Pathways in Human Malignancies. Current Pharmaceutical Design, 18(19), 2766-2777. https://doi.org/10.2174/138161212800626210
• Forman, D., Ferlay, J., Stewart, B. W., and Wild, C. P. (2014). The global and regional burden of cancer. World Cancer Report, 2014, 16-53.
• Fricker, S. P. (Ed.). (2012). Metal compounds in cancer therapy (1st ed.). Springer Science & Business Media. https://doi.org/10.1007/978-94-011-1252-9
• Ge, E. J., Bush, A. I., Casini, A., Cobine, P. A., Cross, J. R., DeNicola, G. M., Dou, Q. P., Franz, K. J., Gohil, V. M., Gupta, S., Kaler, S. G., Lutsenko, S., Mittal, V., Petris, M. J., Polishchuk, R., Ralle, M., Schilsky, M. L., Tonks, N. K., Vahdat, L. T., and Van Aelst, L. (2022). Connecting copper and cancer: from transition metal signalling to metalloplasia. Nature Reviews Cancer, 22(2), 102-113. https://doi.org/10.1038/s41568-021-00417-2
• Godone, R. L. N., Leitão, G. M., Araújo, N. B., Castelletti, C. H. M., Lima-Filho, J. L., and Martins, D. B. G. (2018). Clinical and molecular aspects of breast cancer: Targets and therapies. Biomedicine & Pharmacotherapy, 106, 14-34. https://doi.org/10.1016/j.biopha.2018.06.066
• Guo, Q., Cheng, K., Wang, X., Li, X., Yu, Y., Hua, Y., and Yang, Z. (2020). Expression of HDAC1 and RBBP4 correlate with clinicopathologic characteristics and prognosis in breast cancer. International Journal of Clinical and Experimental Pathology, 13(3), 563. PMID: 32269697; PMCID: PMC7137008. https://pubmed.ncbi.nlm.nih.gov/32269697
• Gümüş, M., Babacan, Ş. N., Demir, Y., Sert, Y., Koca, İ., Gülçin, İ. (2021). Discovery of sulfadrug–pyrrole conjugates as carbonic anhydrase and acetylcholinesterase inhibitors. Archiv der Pharmazie, 355(1), 2100242. https://doi.org/10.1002/ardp.202100242
• Halkidou, K., Gaughan, L., Cook, S., Leung, H. Y., Neal, D. E., and Robson, C. N. (2004). Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate Cancer. The Prostate, 59(2), 177-189. https://doi.org/10.1002/pros.20022
• Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674. https://doi.org/10.1016/j.cell.2011.02.013
• Hayes, D., Kohler, L., Chen, L. X., and Mulfort, K. L. (2018). Ligand Mediation of Vectorial Charge Transfer in Cu(I)diimine Chromophore–Acceptor Dyads. The Journal of Physical Chemistry Letters, 9(8), 2070-2076. https://doi.org/10.1021/acs.jpclett.8b00468
• Hayes, D., Kohler, L., Hadt, R. G., Zhang, X., Liu, C., Mulfort, K. L., and Chen, L. X. (2018). Excited state electron and energy relays in supramolecular dinuclear complexes revealed by ultrafast optical and X-ray transient absorption spectroscopy. Chemical Science, 9(4), 860-875. https://doi.org/10.1039/c7sc04055e
• Heffeter, P., Jakupec, M. A., Wilfried Körner, Wild, S., Keyserlingk, von, Leonilla Elbling, Zorbas, H., Korynevska, A., Siegfried Knasmüller, Sutterlüty, H., M. Micksche, Keppler, B. K., and Berger, W. (2006). Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24). Biochemical Pharmacology, 71(4), 426-440. https://doi.org/10.1016/j.bcp.2005.11.009
• Hindo, S. S., Frezza, M., Tomco, D., Heeg, M. J., Hryhorczuk, L., McGarvey, B. R., Dou, Q. P., and Verani, C. N. (2009). Metals in anticancer therapy: Copper(II) complexes as inhibitors of the 20S proteasome. European Journal of Medicinal Chemistry, 44(11), 4353-4361. https://doi.org/10.1016/j.ejmech.2009.05.019
• Huang, X., Hou, Y., Weng, X., Pang, W., Hou, L., Liang, Y., Wang, Y., Du, L., Wu, T., Yao, M., Wang, J., and Meng, X. (2021). Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway. Oncogenesis, 10(1), 4. https://doi.org/10.1038/s41389-020-00295-7
• Hussain, A., AlAjmi, M. F., Rehman, M. T., Amir, S., Husain, F. M., Alsalme, A., Siddiqui, M. A., AlKhedhairy, A. A., and Khan, R. A. (2019). Copper(II) complexes as potential anticancer and Nonsteroidal anti-inflammatory agents: In vitro and in vivo studies. Scientific Reports, 9(1), 1-17. https://doi.org/10.1038/s41598-019-41063-x
• Jo, S., Kim, T., Iyer, V. G., and Im, W. (2008). CHARMM-GUI: A web-based graphical user interface for CHARMM. Journal of Computational Chemistry, 29(11), 1859-1865. https://doi.org/10.1002/jcc.20945
• Kang, S., Cetin, M. M., Jiang, R., Clevenger, E. S., and Mayer, M. F. (2014). Synthesis of Metalated Pseudorotaxane Polymers with Full Control over the Average Linear Density of Threaded Macrocycles. Journal of the American Chemical Society, 136(36), 12588-12591. https://doi.org/10.1021/ja507167k
• Kawai, H., Li, H., Avraham, S., Jiang, S., and Avraham, H. K. (2003). Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α. International Journal of Cancer, 107(3), 353-358. https://doi.org/10.1002/ijc.11403
• Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W. A., Williams, R. L., and Shokat, K. M. (2006). A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. Cell, 125(4), 733-747. https://doi.org/10.1016/j.cell.2006.03.035
• Kohler, L., Hadt, R. G., Hayes, D., Chen, L. X., and Mulfort, K. L. (2017). Synthesis, structure, and excited state kinetics of heteroleptic Cu (I) complexes with a new sterically demanding phenanthroline ligand. Dalton Transactions, 46(38), 13088-13100. https://doi.org/10.1039/C7DT02476B
• Kohler, L., Hayes, D., Hong, J., Carter, T. J., Shelby, M. L., Fransted, K. A., Chen, L. X., and Mulfort, K. L. (2016). Synthesis, structure, ultrafast kinetics, and light-induced dynamics of CuHETPHEN chromophores. Dalton Transactions, 45(24), 9871-9883. https://doi.org/10.1039/c6dt00324a
• Kölbl, A. C., Andergassen, U., and Jeschke, U. (2015). The role of glycosylation in breast cancer metastasis and cancer control. Frontiers in oncology, 5, 219. https://doi.org/10.3389/fonc.2015.00219
• Krusche, C. A., Wülfing, P., Kersting, C., Vloet, A., Böcker, W., Kiesel, L., Beier, H. M., and Alfer, J. (2005). Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Research and Treatment, 90, 15-23. https://doi.org/10.1007/s10549-004-1668-2
• Kufareva, I., and Abagyan, R. (2012). Methods of protein structure comparison. Homology Modeling: Methods in Molecular Biology, 857, 231-257. https://doi.org/10.1007/978-1-61779-588-6_10
• Leone, J. P., and Leone, B. A. (2015). Breast cancer brain metastases: the last frontier. Experimental Hematology & Oncology, 4(1), 1-10.
• Li, Y. (2020). Copper homeostasis: Emerging target for cancer treatment. IUBMB Life, 72(9), 1900-1908. https://doi.org/10.1002/iub.2341
• Lin, S., Kemmner, W., Grigull, S., and Schlag, P. M. (2002). Cell surface α2, 6-sialylation affects adhesion of breast carcinoma cells. Experimental Cell Research, 276(1), 101-110. https://doi.org/10.1006/excr.2002.5521
• Lippard, S. J., and Berg, J. M. (1994). Principles of Bioinorganic Chemistry. University Science Books. https://doi.org/10.1016/0307-4412(95)90685-1
• Lobanov, M. Yu., Bogatyreva, N. S., and Galzitskaya, O. V. (2008). Radius of gyration as an indicator of protein structure compactness. Molecular Biology, 42(4), 623-628. https://doi.org/10.1134/S0026893308040195
• Lu, Y., and Liu, W. (2020). Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer. Journal of Medicinal Chemistry, 63(24), 15094-15114. https://doi.org/10.1021/acs.jmedchem.0c00913
• Lumme, P., Elo, H., and Jänne, J. (1984). Antitumor activity and metal complexes of the first transition series. Trans-bis(salicylaldoximato)copper(II) and related copper(II) complexes, a novel group of potential antitumor agents. Inorganica Chimica Acta, 92(4), 241-251. https://doi.org/10.1016/s0020-1693(00)80045-6
• MacLeod, R. A. (1952). The toxicity of o-phenanthroline for lactic acid bacteria. Journal of Biological Chemistry, 197(2), 751-761. https://doi.org/10.1016/S0021-9258(18)55631-3
• Maiese, K. (Ed.). (2016). Molecules to medicine with mTOR: translating critical pathways into novel therapeutic strategies. Academic Press. https://doi.org/10.1016/C2014-0-03321-7
• Marzano, C., Pellei, M., Tisato, F., and Santini, C. (2009). Copper complexes as anticancer agents. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 9(2), 185-211. https://doi.org/10.2174/187152009787313837
• Marzano, C., Trevisan, A., Giovagnini, L., and Fregona, D. (2002). Synthesis of a new platinum(II) complex: anticancer activity and nephrotoxicity in vitro. Toxicology in Vitro, 16(4), 413-419. https://doi.org/10.1016/s0887-2333(02)00022-x
• Min, K. N., Joung, K. E., Kim, D. K., and Sheen, Y. Y. (2012). Anti-cancer effect of IN-2001 in MDA-MB-231 human breast cancer. Biomolecules & Therapeutics, 20(3), 313. https://doi.org/10.4062/biomolther.2012.20.3.313
• Molinaro, C., Martoriati, A., Pelinski, L., and Cailliau, K. (2020). Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II. Cancers, 12(10), 2863. https://doi.org/10.3390/cancers12102863
• Montaner, B., Navarro, S., Piqué, M., Vilaseca, M., Martinell, M., Giralt, E., Gil, J., and Pérez-Tomás, R. (2000). Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. British Journal of Pharmacology, 131(3), 585-593. https://doi.org/10.1038/sj.bjp.0703614
• Montaner, B., and Pérez-Tomás, R. (2001). Prodigiosin-induced apoptosis in human colon cancer cells. Life Sciences, 68(17), 2025-2036. https://doi.org/10.1016/s0024-3205(01)01002-5
• Montaner, B., and Pérez-Tomás, R. (2003). The Prodigiosins: A New Family of Anticancer Drugs. Current Cancer Drug Targets, 3(1), 57-65. https://doi.org/10.2174/1568009033333772
• Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., and Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry, 19(14), 1639-1662. https://doi.org/10.1002/(sici)1096-987x(19981115)19:14%3C1639::aid-jcc10%3E3.0.co;2-b
• Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., and Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785-2791. https://doi.org/10.1002/jcc.21256
• Müller, B. M., Jana, L., Kasajima, A., Lehmann, A., Prinzler, J., Budczies, J., Winzer, K.-J., Dietel, M., Weichert, W., and Denkert, C. (2013). Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer - overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer, 13(1). https://doi.org/10.1186/1471-2407-13-215
• Pangeni, R. P., Channathodiyil, P., Huen, D. S., Eagles, L. W., Johal, B. K., Pasha, D., Hadjistephanou, N., Nevell, O., Davies, C. L., Adewumi, A. I., Khanom, H., Samra, I. S., Buzatto, V. C., Chandrasekaran, P., Shinawi, T., Dawson, T. P., Ashton, K. M., Davis, C., Brodbelt, A. R., Jenkinson, M. D., Bièche, I., Latif, F., Darling, J. L., Warr, T. J., and Morris, M. R. (2015). The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain. Clinical epigenetics, 7(1), 57. PMID: 26052355; PMCID: PMC4457099. https://doi.org/10.1186/s13148-015-0089-x
• Pereira, G. R. C., Vieira, B. D. A. A., and De Mesquita, J. F. (2021). Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis. PloS ONE, 16(2), e0247841. https://doi.org/10.1371/journal.pone.0247841
• Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R. D., Kalé, L., and Schulten, K. (2005). Scalable molecular dynamics with NAMD. Journal of Computational Chemistry, 26(16), 1781-1802. https://doi.org/10.1002/jcc.20289
• Porta, C., Paglino, C., and Mosca, A. (2014). Targeting PI3K/Akt/mTOR Signaling in Cancer. Frontiers in Oncology, 4(64). https://doi.org/10.3389/fonc.2014.00064
• Que, E. L., Domaille, D. W., and Chang, C. J. (2008). Metals in neurobiology: probing their chemistry and biology with molecular imaging. Chemical Reviews, 108(5), 1517-1549. https://doi.org/10.1021/cr078203u
• Ranford, J. D., Sadler, P. J., and Tocher, D. A. (1993). Cytotoxicity and antiviral activity of transition-metal salicylato complexes and crystal structure of bis (diisopropylsalicylato)(1, 10-phenanthroline) copper (II). Journal of the Chemical Society, Dalton Transactions, (22), 3393-3399. https://doi.org/10.1039/dt9930003393
• Rapoport, H., and Holden, K. G. (1960). The synthesis of prodigiosin. Journal of the American Chemical Society, 82(20), 5510-5511. https://doi.org/10.1021/ja01505a056
• Rostami, R., Mittal, S., Rostami, P., Tavassoli, F., and Jabbari, B. (2016). Brain metastasis in breast cancer: a comprehensive literature review. Journal of Neuro-oncology, 127, 407-414. https://doi.org/10.1007/s11060-016-2075-3
• Ruijter, A. J. D., GENNIP, A. H. V., Caron, H. N., Kemp, S., and KUILENBURG, A. B. V. (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemical Journal, 370(3), 737-749. https://doi.org/10.1042/bj20021321
• Saha, D., Uday Sandbhor, K. Shirisha, Subhash Padhyé, Deobagkar, D. N., Anson, C. E., and Powell, A. K. (2004). A novel mixed-ligand antimycobacterial dimeric copper complex of ciprofloxacin and phenanthroline. Bioorganic & Medicinal Chemistry Letters, 14(12), 3027-3032. https://doi.org/10.1016/j.bmcl.2004.04.043
• Schmittel, M., Lüning, U., Meder, M., Ganz, A., Michel, C., and Herderich, M. (1997). Synthesis of sterically encumbered 2, 9-diaryl substituted phenanthrolines. Key building blocks for the preparation of mixed (bis-heteroleptic) phenanthroline copper (I) complexes. Heterocyclic Communications, 3(6), 493-498. https://doi.org/10.1515/HC.1997.3.6.493
• Senese, S., Zaragoza, K., Minardi, S., Muradore, I., Ronzoni, S., Passafaro, A., Bernard, L., Giulio Draetta, Alcalay, M., Seiser, C., and Chiocca, S. (2007). Role for Histone Deacetylase 1 in Human Tumor Cell Proliferation. Molecular and Cellular Biology, 27(13), 4784-4795. https://doi.org/10.1128/mcb.00494-07
• Seto, E., and Yoshida, M. (2014). Erasers of Histone Acetylation: The Histone Deacetylase Enzymes. Cold Spring Harbor Perspectives in Biology, 6(4), a018713-a018713. https://doi.org/10.1101/cshperspect.a018713
• Shouksmith, A. E., Gawel, J. M., Nabanita Nawar, Sina, D., Raouf, Y. S., Bukhari, S., He, L., Johns, A. E., Pimyupa Manaswiyoungkul, Olaoye, O. O., Cabral, A. D., Abootaleb Sedighi, Elvin, and Gunning, P. T. (2019). Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia. ACS Medicinal Chemistry Letters, 11(1), 56-64. https://doi.org/10.1021/acsmedchemlett.9b00471
• Siegel, R. L., Miller, K. D., and Jemal, A. (2020). Cancer statistics, 2020. CA: A Cancer Journal for Clinicians, 70(1), 7-30. https://doi.org/10.3322/caac.21590
• Sinnokrot, M. O., and Sherrill, C. D. (2004). Substituent Effects in π-π Interactions:  Sandwich and T-Shaped Configurations. Journal of the American Chemical Society, 126(24), 7690-7697. https://doi.org/10.1021/ja049434a
• Solomon, E. I., Sundaram, U. M., and Machonkin, T. E. (1996). Multicopper Oxidases and Oxygenases. Chemical Reviews, 96(7), 2563-2606. https://doi.org/10.1021/cr950046o
• Soto-Cerrato, V., Llagostera, E., Montaner, B., Scheffer, G. L., and Perez-Tomas, R. (2004). Mitochondria-mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin. Biochemical Pharmacology, 68(7), 1345-1352. https://doi.org/10.1016/j.bcp.2004.05.056
• Studio D. Dassault Systemes BIOVIA, Discovery Studio Modelling Environment, Release 4.5. Accelrys Software Inc., 2015. https://www.3ds.com/products/biovia/discovery-studio
• Tang, Z., Ding, S., Huang, H., Luo, P., Qing, B., Zhang, S., and Tang, R. (2017). HDAC1 triggers the proliferation and migration of breast cancer cells via upregulation of interleukin-8. Biological Chemistry, 398(12), 1347-1356. https://doi.org/10.1515/hsz-2017-0155
• Uba, A. I., and Yelekçi, K. (2018). Identification of potential isoform-selective histone deacetylase inhibitors for cancer therapy: A combined approach of structure-based virtual screening, ADMET prediction and molecular dynamics simulation assay. Journal of Biomolecular Structure and Dynamics, 36(12), 3231-3245. https://doi.org/10.1080/07391102.2017.1384402
• Walsh, C. T., Garneau-Tsodikova, S., and Howard-Jones, A. R. (2006). Biological formation of pyrroles: nature's logic and enzymatic machinery. Natural Product Reports, 23(4), 517-531. https://doi.org/10.1039/B605245M
• Wang, Z., Li, B., Zhou, L., Yu, S., Su, Z., Song, J., Sun, Q., Sha, O., Wang, X., Jiang, W., Willert, K., Wei, L., Carson, D. A., and Lu, D. (2016). Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 113(46), 13150-13155. https://doi.org/10.1073/pnas.1616336113
• Weichert, W. (2009). HDAC expression and clinical prognosis in human malignancies. Cancer Letters, 280(2), 168-176. https://doi.org/10.1016/j.canlet.2008.10.047
• Wild, C. (2014). World Cancer Report 2014 (pp. 482-494). C. P. Wild, & B. W. Stewart (Eds.). Geneva, Switzerland: World Health Organization.
• World Health Organization. (2023, July 12). Breast cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/breast-cancer
• Yao, D., Jiang, J., Zhang, H., Huang, Y., Huang, J., and Wang, J. (2021). Design, synthesis and biological evaluation of dual mTOR/HDAC6 inhibitors in MDA-MB-231 cells. Bioorganic & Medicinal Chemistry Letters, 47, 128204. https://doi.org/10.1016/j.bmcl.2021.128204
• Zhang, C. X., and Lippard, S. J. (2003). New metal complexes as potential therapeutics. Current Opinion in Chemical Biology, 7(4), 481-489. https://doi.org/10.1016/s1367-5931(03)00081-4
• Zhang, X., Bi, C., Fan, Y., Cui, Q., Chen, D., Xiao, Y., and Dou, Q. P. (2008). Induction of tumor cell apoptosis by taurine Schiff base copper complex is associated with the inhibition of proteasomal activity. International Journal of Molecular Medicine, 22(5), 677-682. https://doi.org/10.3892/ijmm_00000072
• Zhang, Z., Bi, C., Fan, Y., Zhang, N., Deshmukh, R., Yan, X., Lv, X., Zhang, P., Zhang, X., and Dou, Q. P. (2014). l-Ornithine Schiff base–copper and –cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells. JBIC Journal of Biological Inorganic Chemistry, 20(1), 109-121. https://doi.org/10.1007/s00775-014-1219-1
• Zhang, Z., Bi, C., Schmitt, S. M., Fan, Y., Dong, L., Zuo, J., and Dou, Q. P. (2012). 1, 10-Phenanthroline promotes copper complexes into tumor cells and induces apoptosis by inhibiting the proteasome activity. JBIC Journal of Biological Inorganic Chemistry, 17, 1257-1267. https://doi.org/10.1007/s00775-012-0940-x
• Zhong, W., Tang, Y., Zampella, G., Wang, X., Yang, X., Hu, B., Wang, J., Xiao, Z., Wei, Z., Chen, H., Luca De Gioia, and Liu, X. (2010). A rare bond between a soft metal (FeI) and a relatively hard base (RO−, R = phenolic moiety). Inorganic Chemistry Communications, 13(9), 1089-1092. https://doi.org/10.1016/j.inoche.2010.06.026
• Zoroddu, M. A., Anna, S., Pogni, R., & Riccardo Basosi. (1996). An electron spin resonance study and antimicrobial activity of copper(II)-phenanthroline complexes. Journal of Inorganic Biochemistry, 63(4), 291-300. https://doi.org/10.1016/0162-0134(96)00015-3
• Zuo, J., Bi, C., Fan, Y., Buac, D., Nardon, C., Daniel, K. G., and Dou, Q. P. (2013). Cellular and computational studies of proteasome inhibition and apoptosis induction in human cancer cells by amino acid Schiff base–copper complexes. Journal of Inorganic Biochemistry, 118, 83-93. https://doi.org/10.1016/j.jinorgbio.2012.10.006