ANTRAKİNONLARIN ANTİKANSER AJANLARI OLARAK GELİŞTİRİLMESİNE YÖNELİK GÜNCEL ARAŞTIRMALARA GENEL BİR BAKIŞ

Öz

Amaç: Bu çalışmada son yıllarda sentezlenmiş ve yüksek in vitro ve in vivo antikanser aktivite gösterdiği bulunmuş antrakinon bileşiklerine dair bazı bilimsel çalışmalar özetlenmiştir. Kanser tedavisinde daha etkili ve ilaç direncini aşabilecek yeni antrakinon türevi ilaçların tasarlanması ve geliştirilmesine katkı sunması amaçlanmıştır.   

Sonuç ve Tartışma: Antrakinonlar, doğal ve sentetik kaynaklardan elde edilebilen ve çok yönlü mekanizmalarla antikanser özelliklere sahip ayrıcalıklı bir bileşik sınıfıdır. Güçlü topoizomeraz inhibitörleri olan antrasiklinler, bu sınıfın kanser kemoterapisinde sıklıkla kullanılan üyelerini oluşturur. Literatür verileri, yapısal modifikasyonlar ile dirençli kanser hücrelerine karşı mevcut antrasiklinlerden daha iyi antiproliferatif aktivite gösteren ve antitümör ilaç adayı olabilecek yeni antrakinon bileşiklerinin geliştirilebileceğini göstermektedir.

Anahtar Kelimeler

• Antrasiklin
• antrakinon
• antikanser aktivite
• kimyasal modifikasyon

AN OVERVIEW OF CURRENT RESEARCH ON THE DEVELOPMENT OF ANTHRAQUINONES AS ANTICANCER AGENTS

Öz

Objective: In this study, some scientific studies on anthraquinone compounds that have been synthesized in recent years and have been found to have high in vitro and in vivo anticancer activity are summarized. It is aimed to contribute to the design and development of new anthraquinone derivative drugs that are more effective in cancer treatment and can overcome drug resistance.

Result and Discussion: Anthraquinones are a privileged class of compounds that can be obtained from natural and synthetic sources and have anticancer properties with versatile mechanisms. Anthracyclines, which are potent topoisomerase inhibitors, are members of this class that are frequently used in cancer chemotherapy. Literature data suggest that new anthraquinone derivatives developed through structural modifications can exhibit better antiproliferative activity against resistant cancer cells than currently existing anthracyclines and may be more effective antitumor drug candidates.

Anahtar Kelimeler

• Anthracycline
• anthraquinone
• anticancer activity
• chemical modification

Kaynakça

1. 1. Li, Y., Guo, F., Guan, Y., et al. (2020). Novel anthraquinone compounds inhibit colon cancer cell proliferation via the reactive oxygen species/JNK pathway. Molecules, 25(7), 1672. [CrossRef]
2. 2. Chua, H.M., Moshawih, S., Goh, H.P., et al. (2023). Insights into the computer-aided drug design and discovery based on anthraquinone scaffold for cancer treatment: A protocol for systematic review. Plos One, 18(9), e0290948. [CrossRef]
3. 3. Cheemalamarri, C., Batchu, U.R., Thallamapuram, N.P., et al. (2022). A review on hydroxy anthraquinones from bacteria: Crosstalk’s of structures and biological activities. Natural Product Research, 36(23), 6186-6205. [CrossRef]
4. 4. Sirazhetdinova, N.S., Savelyev, V.A., Frolova, T.S., et al. (2020). 1-Hydroxyanthraquinones containing aryl substituents as potent and selective anticancer agents. Molecules, 25(11), 2547. [CrossRef]
5. 5. Yordanova, S., Vasileva-Tonkova, E., Staneva, D., et al. (2018). Synthesis and characterization of new water soluble 9, 10-anthraquinonе and evaluation of its antimicrobial activity. Journal of Molecular Structure, 1168, 22-27. [CrossRef]
6. 6. Mishra, B.B., Kishore, N., Tiwari, V.K., et al. (2010). A novel antifungal anthraquinone from seeds of Aegle marmelos Correa (family Rutaceae). Fitoterapia, 81(2), 104-107. [CrossRef]
7. 7. Winter, R.W., Cornell, K.A., Johnson, L.L., et al. (1995). Hydroxy-anthraquinones as antimalarial agents. Bioorganic & Medicinal Chemistry Letters, 5(17), 1927-1932. [CrossRef]
8. 8. Martorell, M., Castro, N., Victoriano, M., et al. (2021). An update of anthraquinone derivatives emodin, diacerein, and catenarin in diabetes. Evidence-Based Complementary and Alternative Medicine, 2021(1), 3313419. [CrossRef]

9. 9. Li, X., Chu, S., Liu, Y., et al. (2019). Neuroprotective effects of anthraquinones from rhubarb in central nervous system diseases. Evidence-Based Complementary and Alternative Medicine, 2019(1), 3790728. [CrossRef]
10. 10. Kshirsagar, A.D., Panchal, P.V., Harle, U.N., et al. (2014). Anti-inflammatory and antiarthritic activity of anthraquinone derivatives in rodents. International Journal of Inflammation, 2014(1), 690596. [CrossRef]
11. 11. Diaz-Munoz, G., Miranda, I.L., Sartori, S.K., et al. (2018). Anthraquinones: An overview. Studies in Natural Products Chemistry, 58, 313-338. [CrossRef]
12. 12. Malik, E.M., Müller, C.E. (2016). Anthraquinones as pharmacological tools and drugs. Medicinal Research Reviews, 36(4), 705-748. [CrossRef]
13. 13. Malik, M.S., Alsantali, R.I., Jassas, R.S., et al. (2021). Journey of anthraquinones as anticancer agents–a systematic review of recent literature. RSC Advances, 11(57), 35806-35827. [CrossRef]
14. 14. Avasarala, J.R., Cross, A.H., Clifford, D.B., et al. (2003). Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. Multiple Sclerosis Journal, 9(1), 59-62. [CrossRef]
15. 15. Péan, E., Flores, B., Hudson, I., et al. (2013). The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s b-cell lymphomas: Summary of the scientific assessment of the committee for medicinal products for human use. The Oncologist, 18(5), 625-633. [CrossRef]
16. 16. Bray, F., Laversanne, M., Sung, H., et al. (2024). Global cancer statistics 2022: GLOBOCAN estimates ofincidence and mortality worldwide for 36 cancers in 185 countries. A Cancer Journal for Clinicians, 74(3), 229-263.
17. 17. De Moliner, E., Moro, S., Sarno, S., et al. (2003). Inhibition of protein kinase CK2 by anthraquinone-related compounds: A structural insight. Journal of Biological Chemistry, 278(3), 1831-1836. [CrossRef]
18. 18. Gheeya, J., Johansson, P., Chen, Q.R., et al. (2010). Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor. Cancer Letters, 293(1), 124-131. [CrossRef]
19. 19. Dey, A., Prasad, R., Barthwal, R., et al. (2022). Anthraquinone derivatives inhibit telomerase activity by interaction with G quadruplex DNA and acts as a promising anticancerous agent. The FASEB Journal, 36. [CrossRef]
20. 20. Jamshidi, S., Rostami, A., Shojaei, S., et al. (2024). Exploring natural anthraquinones as potential MMP2 inhibitors: A computational study. BioSystems, 235, 105103. [CrossRef]
21. 21. Adhikari, A., Mahar, A.S. (2016). DNA targeted anthraquinone derivatives: An important anticancer agent. International Journal of Pharmacy and Pharmaceutical Sciences, 17-25.
22. 22. Al-Otaibi, J.S., Spittle, P.T., El Gogary, T.M. (2017). Interaction of anthraquinone anti-cancer drugs with DNA: Experimental and computational quantum chemical study. Journal of Molecular Structure, 1127, 751-760. [CrossRef]
23. 23. Siddamurthi, S., Gutti, G., Jana, S.,et al. (2020). Anthraquinone: A promising scaffold for the discovery and development of therapeutic agents in cancer therapy. Future Medicinal Chemistry, 12(11), 1037-1069. [CrossRef]
24. 24. Tian, W., Wang, C., Li, D.,et al. (2020). Novel anthraquinone compounds as anticancer agents and their potential mechanism. Future Medicinal Chemistry, 12(7), 627-644. [CrossRef]
25. 25. Lin, K.W., Lin, W.H., Su, C.L., et al. (2021). Design, synthesis and antitumour evaluation of novel anthraquinone derivatives. Bioorganic Chemistry, 107, 104395. [CrossRef]
26. 26. Li, Y., Guo, F., Chen, T., et al. (2020). Design, synthesis, molecular docking, and biological evaluation of new emodin anthraquinone derivatives as potential antitumor substances. Chemistry & Biodiversity, 17(9), e2000328. [CrossRef]
27. 27. Oliveira, L.A., Nicolella, H.D., Furtado, R.A., et al. (2020). Design, synthesis, and antitumor evaluation of novel anthraquinone derivatives. Medicinal Chemistry Research, 29, 1611-1620. [CrossRef]
28. 28. Stromyer, M.L., Weader, D.J., Satyal, U., et al. (2020). Synthesis, characterization, and biological activity of anthraquinone-substituted imidazolium salts for the treatment of bladder cancer. Bladder Cancer, 6(4), 471-479. [CrossRef]
29. 29. Liu, Y., Liang, Y., Jiang, J., et al. (2019). Design, synthesis and biological evaluation of 1,4-dihydroxyanthraquinone derivatives as anticancer agents. Bioorganic & Medicinal Chemistry Letters, 29(9), 1120-1126. [CrossRef]
30. 30. Niedziałkowski, P., Czaczyk, E., Jarosz, J., et al. (2019). Synthesis and electrochemical, spectral, and biological evaluation of novel 9,10-anthraquinone derivatives containing piperidine unit as potent antiproliferative agents. Journal of Molecular Structure, 1175, 488-495. [CrossRef]
31. 31. Tian, W., Li, J., Su, Z., et al. (2019). Novel anthraquinone compounds induce cancer cell death through paraptosis. ACS Medicinal Chemistry Letters, 10(5), 732-736. [CrossRef]
32. 32. Liang, D., Su, Z., Tian, W., et al. (2020). Synthesis and screening of novel anthraquinone-quinazoline multitarget hybrids as promising anticancer candidates. Future Medicinal Chemistry, 12(2), 111-126. [CrossRef]
33. 33. Zhao, L.M., Ma, F.Y., Jin, H.S., et al. (2015). Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach. European Journal of Medicinal Chemistry, 102, 303-309. [CrossRef]
34. 34. Wu, S., Zhou, X., Li, F., et al. (2024). Novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potent human carbonic anhydrase inhibitors with antitumor activity: Synthesis, biological evaluation, and in silico analysis. International Journal of Molecular Sciences, 25(6), 3348. [CrossRef]
35. 35. Ganapathi, R.N., Ganapathi, M.K. (2013). Mechanisms regulating resistance to inhibitors of topoisomerase II. Frontiers in Pharmacology, 4, 89. [CrossRef]
36. 36. Ma, P., Mumper, R.J. (2013). Anthracycline nano-delivery systems to overcome multiple drug resistance: A comprehensive review. Nano Today, 8(3), 313-331. [CrossRef]
37. 37. Gate, L., Couvreur, P., Nguyen-Ba, G., et al. (2003). N-methylation of anthracyclines modulates their cytotoxicity and pharmacokinetic in wild type and multidrug resistant cells. Biomedicine & Pharmacotherapy, 57(7), 301-308. [CrossRef]
38. 38. Preobrazhenskaya, M.N., Tevyashova, A.N., Olsufyeva, E.N., et al. (2006). Second generation drugs-derivatives of natural antitumor anthracycline antibiotics daunorubicin, doxorubicin and carminomycin. Journal of Medical Sciences-Taipei, 26(4), 119.
39. 39. Volodina, Y.L., Tikhomirov, A.S., Dezhenkova, L.G., et al. (2021). Thiophene-2-carboxamide derivatives of anthraquinone: A new potent antitumor chemotype. European Journal of Medicinal Chemistry, 221, 113521. [CrossRef]
40. 40. Tikhomirov, A.S., Litvinova, V.A., Andreeva, D.V., et al. (2020). Amides of pyrrole-and thiophene-fused anthraquinone derivatives: A role of the heterocyclic core in antitumor properties. European Journal of Medicinal Chemistry, 199, 112294. [CrossRef]
41. 41. Litvinova, V.A., Tsvetkov, V.B., Volodina, Y.L., et al. (2025). Naphthoindole-2-carboxamides as a lipophilic chemotype of hetarene-anthraquinones potent against P-gp resistant tumor cells. European Journal of Medicinal Chemistry, 281, 117013. [CrossRef]
42. 42. Tikhomirov, A.S., Tsvetkov, V.B., Volodina, Y.L., et al. (2022). Heterocyclic ring expansion yields anthraquinone derivatives potent against multidrug resistant tumor cells. Bioorganic Chemistry, 127, 105925. [CrossRef]
43. 43. Shchekotikhin, A.E., Dezhenkova, L.G., Tsvetkov, V.B., et al. (2016). Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties. European Journal of Medicinal Chemistry, 112, 114-129. [CrossRef]
44. 44. Tikhomirov, A.S., Sinkevich, Y.B., Dezhenkova, L.G., et al. (2024). Synthesis and antitumor activity of cyclopentane-fused anthraquinone derivatives. European Journal of Medicinal Chemistry, 265, 116103. [CrossRef]
45. 45. Minotti, G., Menna, P., Salvatorelli, E., et al. (2004). Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews, 56(2), 185-229. [CrossRef]