ANTİKANSER İLAÇLARIN HEDEF BAZLI TASARIMINDA FARKLI MEKANİZMALARLA ETKİLİ İNDOL TÜREVLERİ

Yıl 2019, , 334 - 358, 08.09.2019

Elif Ayça Dedeoğlu Meriç Köksal

https://doi.org/10.33483/jfpau.554118

Öz

        Amaç: Bu derlemenin
amacı tübülin polimeraz, histon deasetilaz (HDAC), sirtuin (SIRT), PIM kinaz,
DNA topoizomeraz ve sigma reseptörleri gibi farklı mekanizmalarla antikanser
etkinlik gösteren doğal ve sentetik indol türevlerinin incelenmesi ve yapı-etki
ilişkileri ışığında farklı etki yolakları bağlantısının irdelenmesidir.

        Sonuç ve Tartışma: İndol
çekirdeği, birçok reseptöre ligant olarak uygunluğu ve yüksek reseptör
affinitesi sebebiyle antikanser özelliği olan ve klinikte kullanılan birçok
ilaç molekülünün iskeletini oluşturmaktadır. Bitkisel ya da marin kaynaklı elde
edilen doğal indoller üzerinde doğru modifikasyonlar veya hibrit indollerin
tasarlanması ile kanser hücreleri üzerinde seçici biyolojik hedeflere sahip
öncü moleküllerin geliştirilmesi mümkün olmuştur. Seçici biyolojik hedeflere
sahip antikanser ilaç geliştirilmesine yönelik araştırmalar ile kanser
terapilerindeki yüksek yan etki, düşük etkinlik ve ilaç direnci gibi problemler
çözülebilecektir.

Anahtar Kelimeler

antikanser, ilaç tasarım, indol

A REVIEW ON INDOLE DERIVATIVES WITH DIVERSE MECHANISM IN THE TARGET-BASED DESIGN OF ANTICANCER DRUGS

Öz

        Objective: The review article aims to evaluate
natural and synthetic indole derivatives that can act via diverse targets like
tubulin polymerase, histone deacetylases (HDACs), sirtuins, PIM kinases, DNA
topoisomerases and sigma receptors and to examine SAR studies in literature,
coordinated by their biological targets.

        Result and Discussion: Due to conformity of
versatile receptors as a ligand and high receptor affinity, indole has been
formed the skeleton of clinically used anticancer molecules. The structural
modification of natural compounds derived from plants or marine flora and
generation of hybrid indoles make the development of lead compounds, which
specifically target to the biological components possible. The studies about
development of tumor-specific targeting of anticancer drug may overcome the
problems of anticancer therapy like side effect, low potency and drug
resistance.

Anahtar Kelimeler

anticancer, drug design, indole

Kaynakça

• Jayashree, B. S., Nigam, S., Pai, A., Patel, H. K., Reddy, N. D., Kumar, N., Rao, C. M. (2015). Targets in anticancer research—A review. Indian Journal of Experimental Biology, 53(8), 489-507
• Evan, G. I., Vousden, K. H. (2001). Proliferation, cell cycle and apoptosis in cancer. Nature, 411(6835), 342-348.
• Hanahan, D., Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57-70.
• Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., Forman, D. (2011). Global cancer statistics. CA: A Cancer Journal for Clinicians, 61(2), 69-90.
• Emami, S., Dadashpour, S. (2015). Current developments of coumarin-based anti-cancer agents in medicinal chemistry. European Journal of Medicinal Chemistry, 102, 611-630.
• Sharma, S. (2009). Tumor markers in clinical practice: General principles and guidelines. Indian Journal of Medical and Paediatric Oncology: Official Journal of Indian Society of Medical & Paediatric Oncology, 30(1), 1-8.
• Olgen, S. (2018). Overview on anticancer drug design and development. Current Medicinal Chemistry, 25(15), 1704-1719.
• Queiroz, M. J. R., Abreu, A. S., Carvalho, M. S. D., Ferreira, P. M., Nazareth, N., Nascimento, M. S. J. (2008). Synthesis of new heteroaryl and heteroannulated indoles from dehydrophenylalanines: Antitumor evaluation. Bioorganic & Medicinal Chemistry, 16(10), 5584-5589.
• 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. (1988). Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. Journal of Medicinal Chemistry, 31(12), 2235-2246.
• de Sa, A., Fernando, R., Barreiro, E. J., Fraga, M., Alberto, C. (2009). From nature to drug discovery: The indole scaffold as a ‘privileged structure’. Mini Reviews in Medicinal Chemistry, 9(7), 782-793.
• Dadashpour, S., Emami, S. (2018). Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. European Journal of Medicinal Chemistry, 150, 9-29.
• Cragg, G. M., Newman, D. J. (2005). Plants as a source of anti-cancer agents. Journal of Ethnopharmacology, 100(1-2), 72-79.
• Gul, W., Hamann, M. T. (2005). Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases. Life Sciences, 78(5), 442-453.
• Almagro, L., Fernández-Pérez, F., Pedreño, M. (2015). Indole alkaloids from Catharanthus roseus: Bioproduction and their effect on human health. Molecules, 20(2), 2973-3000.
• Bradner, W. T. (2001). Mitomycin C: A clinical update. Cancer Treatment Reviews, 27(1), 35-50.
• Shabani, S. H. S., Tehrani, S. S. H., Rabiei, Z., Enferadi, S. T., Vannozzi, G. P. (2015). Peganum harmala L.’s anti-growth effect on a breast cancer cell line. Biotechnology Reports, 8, 138-143.
• Kumar, D., Rawat, D. S. (2011). Marine natural alkaloids as anticancer agents. In: K. V. Tiwari (Eds.) Opportunity, challenge and scope of natural products in medicinal chemistry, (pp. 213-268). Kerala: Research Signpost
• Lake, R. J., Blunt, J. W., Munro, M. H. G. (1989). Eudistomins from the New Zealand ascidian Ritterella sigillinoides. Australian Journal of Chemistry, 42(7), 1201-1206.
• Hutchins, S. M., Chapman, K. T. (1996). Fischer indole synthesis on a solid support. Tetrahedron Letters, 37(28), 4869-4872.
• Yun, W., Mohan, R. (1996). Heck reaction on solid support: Synthesis of indole analogs. Tetrahedron Letters, 37(40), 7189-7192.
• Howard, J., Hyman, A. A. (2003). Dynamics and mechanics of the microtubule plus end. Nature, 422(6933), 753-758.
• Ems-McClung, S. C., Walczak, C. E. (2010). Kinesin-13s in mitosis: Key players in the spatial and temporal organization of spindle microtubules. Seminars in Cell & Developmental Biology, 21(3), 276-282.
• Kaur, R., Kaur, G., Gill, R. K., Soni, R., Bariwal, J. (2014). Recent developments in tubulin polymerization inhibitors: An overview. European Journal of Medicinal Chemistry, 87, 89-124.
• Guan, Q., Han, C., Zuo, D., Li, Z., Zhang, Q., Zhai, Y., Jiang, X., Bao, K., Wu, Y., Zhang, W. (2014). Synthesis and evaluation of benzimidazole carbamates bearing indole moieties for antiproliferative and antitubulin activities. European Journal of Medicinal Chemistry, 87, 306-315.
• Woods, J. A., Hadfield, J. A., Pettit, G. R., Fox, B. W., McGown, A. T. (1995). The interaction with tubulin of a series of stilbenes based on combretastatin A-4. British Journal of Cancer, 71(4), 705-711.
• Patil, R., Patil, S. A., Beaman, K. D., Patil, S. A. (2016). Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents, an update (2013–2015). Future Medicinal Chemistry, 8(11), 1291-1316.
• Brancale, A., Silvestri, R. (2007). Indole, a core nucleus for potent inhibitors of tubulin polymerization. Medicinal Research Reviews, 27(2), 209-238.
• Del Rey, B., Ramos, A. C., Caballero, E., Inchaustti, A., Yaluff, G., Medarde, M., Arlas, A. R., San Feliciano, A. (1999). Leishmanicidal activity of combretastatin analogues and heteroanalogues. Bioorganic & Medicinal Chemistry Letters, 9(18), 2711-2714.
• Liou, J. P., Chang, Y. L., Kuo, F. M., Chang, C. W., Tseng, H. Y., Wang, C. C., Yang, Y. N., Chang J. Y., Lee, S. J., Hsieh, H. P. (2004). Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. Journal of Medicinal Chemistry, 47(17), 4247-4257.
• Gong, F., Miller, K. M. (2013). Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 750(1-2), 23–30.
• Chao, S. W., Chen, L. C., Yu, C. C., Liu, C. Y., Lin, T. E., Guh, J. H., Wang, C. Y., Hsu, K. J., Huang, W. J. (2018). Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities. European Journal of Medicinal Chemistry, 143, 792-805.
• Dokmanovic, M., Clarke, C., Marks, P. A. (2007). Histone deacetylase inhibitors: overview and perspectives. Molecular Cancer Research, 5(10), 981-989.
• Küçükoğlu, K. (2013). Histonların asetilasyonu ve Histon deasetilaz inhibitörleri. Turkiye Klinikleri Journal of Pharmacy Sciences, 2(2), 55-73.
• Verma, M., Kumar, V. (2018). Epigenetic Drugs for Cancer and Precision Medicine. In: A. Moskolev, and M. A. Vairserman (Eds.), Epigenetics of Aging and Longevity (pp. 439-451). Cambridge: Academic Press.
• Atadja, P. (2009). Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Letters, 280(2), 233-241.
• Marks, P. A. (2007). Discovery and development of SAHA as an anticancer agent. Oncogene, 26(9), 1351-1356.
• Miller, T. A., Witter, D. J., Belvedere, S. (2003). Histone deacetylase inhibitors. Journal of Medicinal Chemistry, 46(24), 5097-5116.
• Dai, Y., Guo, Y., Guo, J., Pease, L. J., Li, J., Marcotte, P. A., Keith BGlaser, K. B., Tapang, P., Daniel H Albert, D. H., Paul L Richardson, P. L., Davidsen, S. K. ., Michaelides, M. R. (2003). Indole amide hydroxamic acids as potent inhibitors of histone deacetylases. Bioorganic & Medicinal Chemistry Letters, 13(11), 1897-1901.
• Remiszewski, S. W., Sambucetti, L. C., Bair, K. W., Bontempo, J., Cesarz, D., Chandramouli, N., Chen, Ru., Cheung, M., Kennon, S. C., Dean, K., Diamantidis, G., France, D., Green, M. A., Howell, K. L., Kashi, R., Kwon, P., Lassota, P., Martin, M. S., Mou, Y., Perez, L. B., Sharma, S., Smith, T., Sorensen, E., Taplin, F., Trogani, N., Versace, R., Walker, H., Engler, S. W., Wood,A., Wu, A., Atadja, P. (2003). N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in vivo Antitumor Activity: Discovery of (2 E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1 H-indol-3-yl) ethyl] amino] methyl] phenyl]-2-propenamide (NVP-LAQ824). Journal of Medicinal Chemistry, 46(21), 4609-4624.
• Harting, K., Knöll, B. (2010). SIRT2-mediated protein deacetylation: An emerging key regulator in brain physiology and pathology. European Journal of Cell Biology, 89(2-3), 262-269.
• Kulić, A., Skerlev, S. M., Plavetıć, D. N., Belev, B., Oguić, K. S., Ivić, M., Vrbanec, D. (2014). Sirtuins in tumorigenesis. Periodicum Biologorum, 116(4), 381-386.
• Villalba, J. M., Alcaín, F. J. (2012). Sirtuin activators and inhibitors. Biofactors, 38(5), 349-359.
• Botta, G., P De Santis, L., Saladino, R. (2012). Current advances in the synthesis and antitumoral activity of SIRT1-2 inhibitors by modulation of p53 and pro-apoptotic proteins. Current Medicinal Chemistry, 19(34), 5871-5884.
• Layek, M., Kumar, Y. S., Islam, A., Karavarapu, R., Sengupta, A., Halder, D., Mukkanti, K., Pal, M. (2011). Alkynylation of N-(3-iodopyridin-2-yl) sulfonamide under Pd/C–Cu catalysis: a direct one pot synthesis of 7-azaindoles and their pharmacological evaluation as potential inhibitors of sirtuins. Medicinal Chemistry Communications, 2(6), 478-485.
• Rambabu, D., Raja, G., Sreenivas, B. Y., Seerapu, G. P. K., Kumar, K. L., Deora, G. S., Haldar D., Rao, B. V. B., Pal, M. (2013). Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3, 2′-quinazolines. Bioorganic & Medicinal Chemistry Letters, 23(5), 1351-1357.
• Medda, F., Russell, R. J., Higgins, M., McCarthy, A. R., Campbell, J., Slawin, A. M., Lane, D. P., Lain, S., Westwood, N. J. (2009). Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity. Journal of Medicinal Chemistry, 52(9), 2673-2682.
• Mahajan, S. S., Scian, M., Sripathy, S., Posakony, J., Lao, U., Loe, T. K., Leko, V., Thalhofer, A., Schuler, A. D., Bedalov, A., Simon, J. A. (2014). Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors. Journal of Medicinal Chemistry, 57(8), 3283-3294.
• Panathur, N., Gokhale, N., Dalimba, U., Koushik, P. V., Yogeeswari, P., Sriram, D. (2015). New indole–isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies. Bioorganic & Medicinal Chemistry Letters, 25(14), 2768-2772.
• Warfel, N. A., Kraft, A. S. (2015). PIM kinase (and Akt) biology and signaling in tumors. Pharmacology & Therapeutics, 151, 41-49
• Blanco-Aparicio, C., Carnero, A. (2013). Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. Biochemical Pharmacology, 85(5), 629-643.
• Cheney, I. W., Yan, S., Appleby, T., Walker, H., Vo, T., Yao, N., Hamatake, R. ,Hong, Z., Wu, J. Z. (2007). Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorganic & Medicinal Chemistry Letters, 17(6), 1679-1683.
• K Rathi, A., Syed, R., Singh, V., Shin, H. S., V Patel, R. (2017). Kinase Inhibitor Indole Derivatives as Anticancer Agents: A Patent Review. Recent Patents on Anti-cancer Drug Discovery, 12(1), 55-72.
• Akué-Gédu, R., Rossignol, E., Azzaro, S., Knapp, S., Filippakopoulos, P., Bullock, A. N., Bain, J., Cohen, P., Prudhomme, M., Anizon, F., Moreau, P. (2009). Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors. Journal of Medicinal Chemistry, 52(20), 6369-6381.
• Nishiguchi, G. A., Atallah, G., Bellamacina, C., Burger, M. T., Ding, Y., Feucht, P. H., Garciab, P. D., Hana, W., Lindvall, M., (2011). Discovery of novel 3, 5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases. Bioorganic & Medicinal Chemistry Letters, 21(21), 6366-6369.
• Wu, B., Wang, H. L., Cee, V. J., Lanman, B. A., Nixey, T., Pettus, L., Reeda, A. B., Wurza, R. P., Guerrerob, N., Sastrib, C., Winston J., Lipford, J. R., Leec M. R., Mohr, C., Kristin, L., Andrews, K. L., Taskera, A. S. (2015). Discovery of 5-(1H-indol-5-yl)-1, 3, 4-thiadiazol-2-amines as potent PIM inhibitors. Bioorganic & Medicinal Chemistry Letters, 25(4), 775-780.
• Bharate, S. B., Bharate, J. B., Khan, S. I., Tekwani, B. L., Jacob, M. R., Mudududdla, R., Yadav, R. R., Singh, B., Sharma, P. R., Maity, S., Singh B., Khan, I. A., Vishwakarma, R. A. (2013). Discovery of 3, 3′-diindolylmethanes as potent antileishmanial agents. European Journal of Medicinal Chemistry, 63, 435-443.
• More, K. N., Jang, H. W., Hong, V. S., Lee, J. (2014). Pim kinase inhibitory and antiproliferative activity of a novel series of meridianin C derivatives. Bioorganic & Medicinal Chemistry Letters, 24(11), 2424-2428.
• Lee, J., More, K. N., Yang, S. A., Hong, V. S. (2014). 3, 5-Bis (aminopyrimidinyl) indole Derivatives: Synthesis and evaluation of pim kinase ınhibitory activities. Bulletin of the Korean Chemical Society, 35(7), 2123-2129.
• Charmantray, F., Martelli, A. (2001). Interest of acridine derivatives in the anticancer chemotherapy. Current Pharmaceutical Design, 7(17), 1703-1724.
• Sherer, C., Snape, T. J. (2015). Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives. European Journal of Medicinal Chemistry, 97, 552-560.
• Pai, V. B., Nahata, M. C. (2000). Cardiotoxicity of Chemotherapeutic Agents. Drug Safety, 22(4), 263–302.
• Shi, W., Marcus, S. L., Lowary, T. L. (2011). Cytotoxicity and topoisomerase I/II inhibition of glycosylated 2-phenyl-indoles, 2-phenyl-benzo [b] thiophenes and 2-phenyl-benzo [b] furans. Bioorganic & Medicinal Chemistry, 19(1), 603-612.
• Chaniyara, R., Tala, S., Chen, C. W., Zang, X., Kakadiya, R., Lin, L. F., Chen, C. H., Chien S. I., Chou T. C., Tsai T. H., Lee T. C., Shah, A., Su, T. S. (2013). Novel antitumor indolizino [6, 7-b] indoles with multiple modes of action: DNA cross-linking and topoisomerase I and II inhibition. Journal of Medicinal Chemistry, 56(4), 1544-1563.
• Kashiwagi, H., McDunn, J. E., Simon, P. O., Goedegebuure, P. S., Xu, J., Jones, L., Chang, K., Johnston, F., Trinkaus, K., Hotchkiss, R. S., Mach, R. H., Hawkins, W. G. (2007). Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy. Molecular Cancer, 6(1), 48-60.
• Ostenfeld, M. S., Fehrenbacher, N., Høyer-Hansen, M., Thomsen, C., Farkas, T., Jäättelä, M. (2005). Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Research, 65(19), 8975-8983.
• Glennon, R. A., Ablordeppey, S. Y., Ismaiel, A. M., El-Ashmawy, M. B., Fischer, J. B., Howie, K. B. (1994). Structural features important for σ-1 receptor binding. Journal of Medicinal Chemistry, 37(8), 1214-1219.
• Yarim, M., Koksal, M., Schepmann, D., Wünsch, B. (2011). Synthesis and in vitro evaluation of novel indole‐based sigma receptors ligands. Chemical Biology & Drug Design, 78(5), 869-875.
• Heading, C. (2001). Siramesine H Lundbeck. Current Opinion in Investigational Drugs, 2(2), 266-270.
• Česen, M. H., Repnik, U., Turk, V., Turk, B. (2013). Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death & Disease, 4(10), e818.
• Abate, C., Perrone, R., Berardi, F. (2012). Classes of sigma2 (σ2) receptor ligands: Structure affinity relationship (SAR) studies and antiproliferative activity. Current Pharmaceutical Design, 18(7), 938-949.
• Xie, F., Kniess, T., Neuber, C., Deuther-Conrad, W., Mamat, C., Lieberman, B. P., Liu, B., Mach, R. H., Brust, P., Steinbach, J., Pietzsch, J., Jia, H. (2015). Novel indole-based sigma-2 receptor ligands: Synthesis, structure–affinity relationship and antiproliferative activity. Medicinal Chemistry Communications, 6(6), 1093-1103.