Araştırma Makalesi
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2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI

Yıl 2023, Cilt: 47 Sayı: 2, 531 - 542, 20.05.2023

Yasmin Aljendy Hatice Oruç Demirbağ Gül Bayram Semra Utku

https://doi.org/10.33483/jfpau.1239326

Öz

Amaç: Sisplatin, klinikte kanser hastalarının tedavisinde başarılı bir şekilde kullanılmasına rağmen hastalarda rezistans gelişimi ve ciddi toksik yan etkiler görülmektedir. Bu dezavantajların önüne geçmek için bu çalışmada 2,5(6)-disübstitüebenzimidazol türevi taşıyıcı ligandlar kullanarak platin(II) komplekslerinin sentezlenmesi ve sitotoksik etkilerinin test edilmesi amaçlanmıştır.
Gereç ve Yöntem: L1-L6 taşıyıcı ligandları Philips yöntemine göre elde edilmiştir. K1-K4 kompleksleri, K2PtCl4 ve uygun ligandın ısıtılıp karıştırılması ile sentezlenmiştir. Sentez edilen L1-L6 ve K1-K4’ün kimyasal yapıları elementel analiz, İnfrared ve 1H Nükleer Manyetik Rezonans ile aydınlatılmıştır. L1-L6 taşıyıcı ligandları ve K1-K4 komplesklerinin, MTT yöntemi ile MCF-7 ve DU-145 hücre hatlarına karşı in vitro sitotoksik etkileri test edilmiştir.
Sonuç ve Tartışma: IC50 değerlerine göre 2 numaralı konumunda –CH3 sübstitüenti taşıyan ligandlar, nonsübstitüe ligandlara göre test edilen hücre hatlarında daha etkili bulunmuştur. Ayrıca 5(6) numaralı konumunda flor sübstitüe L5 ve L6 en etkili benzimidazol türevi olarak test edilmiştir. Test edilen kompleksler içerisinde K3, MCF-7 hücre hattına karşı 32.75 µM IC50 değeri ile DU-145 hücre hattında ise 18.842 µM IC50 değeri ile en etkili kompleks olarak bulunmuştur.

Anahtar Kelimeler

Benzimidazol platin(II)kompleksleri sisplatin sitotoksik aktivite

Destekleyen Kurum

Mersin Üniversitesi Bilimsel Araştırma Projeleri birimi

Proje Numarası

2019-3-TP2-3714

Teşekkür

.

Kaynakça

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INVESTIGATION OF THE ANTICANCER ACTIVITIES OF PLATIN COMPLEXES BEARING 2,5(6)-DISUBSTITUTEDBENZIMIDAZOLE DERIVATIVE LIGANDS

Yıl 2023, Cilt: 47 Sayı: 2, 531 - 542, 20.05.2023

Yasmin Aljendy Hatice Oruç Demirbağ Gül Bayram Semra Utku

https://doi.org/10.33483/jfpau.1239326

Öz

Objective: Although cisplatin is used successfully in the treatment of cancer patients in the clinic, resistance development and serious toxic side effects are seen in patients. In order to avoid these disadvantages, in this study, it was aimed to synthesize platinum(II) complexes using 2,5(6)-disubstitutedbenzimidazole derivative carrier ligands and to test their cytotoxic effects.
Material and Method: L1-L6 carrier ligands were synthesized according to the Philips method. K1-K4 complexes were synthesized by heating and mixing K2PtCl4 and the appropriate ligand. The chemical structures of synthesized L1-L6 and K1-K4 were elucidated by elemental analysis, Infrared and 1H Nuclear Magnetic Resonance. In vitro cytotoxic effects of L1-L6 carrier ligands and K1-K4 complexes against MCF-7 and DU-145 cell lines were tested by MTT method.
Result and Discussion: Ligands with –CH3 substituent in position 2 according to IC50 values were found to be more effective in tested cell lines than non-substituted ligands. Also, fluorine substituted L5 and L6 at position 5(6) were tested as the most effective benzimidazole derivatives. Among the tested complexes, it was found to be the most effective complex with an IC50 value of 32.75 µM against the K3 MCF-7 cell line and with an IC50 value of 18.842 µM in the DU-145 cell line.

Anahtar Kelimeler

Benzimidazole cisplatin cytotoxic activity platinum(II)complexes

Proje Numarası

2019-3-TP2-3714

Kaynakça

  • 1. Cancer Report, World Health Organization. (2022). https://www.who.int/news-room/fact-sheets/detail/cancer. Erişim tarihi: 15.06.2022.
  • 2. Kanser önleme çalışmaları, T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü (2020). Kanser önleme çalışmaları. https://hsgm.saglik.gov.tr/tr/kanserden-korunma/kanserden-korunmalist/kanser-%C3%B6nleme-%C3%A7al%C4%B1%C5%9Fmalar%C4%B1.html. Erişim tarihi: 15.06.2022.
  • 3. Magalhaes, L., Ferreira, L., Andricopulo, A. (2018). Recent advances and prespectives in cancer drug design. Anias da Academia Brasileira de Ciencias, 90(2), 1233-1250. [CrossRef]
  • 4. Dembic, Z. (2020). Antitumor drugs and their targets. Molecules, 25, 5776. [CrossRef]
  • 5. Peyrone, M. (1844). Über die einwirkung des ammoniaks auf platinchlorid. Annalen der Chemie und Pharmacie, 51, 1-29. [CrossRef]
  • 6. Rosenberg, B., Van Camp, L., Krigas, T. (1965). Inhibition of cell division in escherichia coli by electrolysis products from a platinum electrode. Nature, 205, 698-699. [CrossRef]
  • 7. Reed, E. (2006). Cisplatin, carboplatin, and oxaliplatin. In: B.A Chabner and D.L. Long (Eds.), Cancer Chemotherapy and Biotherapy: Principles and Practice, (pp.332-343). Philadelphia: PA Lippincott Williams and Wilkins.
  • 8. Wang, D., Lippard, S.J. (2005). Celluler processing of platinum anticanser drugs. Nature Reviews Drug Discovery, 4(4), 307-320. [CrossRef]
  • 9. Paprocka, R., Szadkowska, M., Janciauskiene, S., Kosmalski, T., Kulik, M., Basa, A. (2022). Latest developements in metal complexes as anticancer agents. Coordination Chemistry Reviews, 452, 214307. [CrossRef]
  • 10. Justin, J., Lippard, S.J. (2014). Synthetic methods for the preparation of platinum anticancer complexes. Chemical Reviews, 114, 4470-4495. [CrossRef]
  • 11. Xiong, X., Liu, L., Mao, Z., Zou, T. (2022). Approaches towards understanding the mechanism of action of metallodrugs. Coordination Chemistry Reviews, 453, 214311. [CrossRef]
  • 12. Ma, D.-L., Wu, C., Cheng, S., Lee, F., Han, Q., Leung, C. (2019). Development of Natural Product-Conjugated Metal Complexes as Cancer Therapies. International Journal of Molecular Sciences, 20(2), 341. [CrossRef]
  • 13. Peng, K., Liang, B., Liu, W., Mao, Z. (2021). What blocks more anticancer platinum complexes from experiment to clinic: Major problems and potential strategies from drug design. Coordination Chemistry Reviews, 449, 214210. [CrossRef]
  • 14. Oun, R., Moussa, Y.E., Wheate, N.J. (2018). The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Transactions, 47, 6645–6653. [CrossRef]
  • 15. Deo, K. M., Ang, D.L., McGhie, B., Rajamanickam, A., Dhiman, A., Khoury, A., Holland, J., Bjelosevic, A., Pages, B., Gordon, J., Aldrich-Wright, J.R. (2018). Platinum coordination compounds with potent anticancer activity. Coordination Chemistry Reviews, 375, 148-163. [CrossRef]
  • 16. Calvert, H. (2019). The clinical development of carboplatin–A personal perspective. Inorganica Chimica Acta, 498, 118987. [CrossRef]
  • 17. Zhao, J., Gou, S., Xu, G., Cheng, L. (2014). Antitumor platinum(II)complexes of N-monoalkyl 1R,2R-diaminocyclohexanes with 3-(nitrooxy)cyclobutane-1,1-dicarboxylate as a leaving group. European Journal of Medicinal Chemistry, 85, 408-417. [CrossRef]
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  • 19. Johnstone, T.C., Suntharalingam, K., Lippard, S.J. (2016). The next generation of platinum drugs: Targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chemical Reviews, 116(5), 3436-3486. [CrossRef]
  • 20. Ho, Y.P., Au‐Yeung, S.C., To, K.K.W. (2003). Platinum‐based anticancer agents: Innovative design strategies and biological perspectives. Medicinal Research Reviews, 235, 633-655. [CrossRef]
  • 21. Zivkovic, M.D., Rajkovic, S., Glisic, B.D., Draskovic, N.S., Djuran, M.I. (2017). Hydrolysis of the amide bond in histidine- and methionine-containing dipeptides promoted by pyrazine and pyridazine palladium(II)-aqua dimers: Comparative study with platinum(II) analogues. Bioorganic Chemistry, 72, 190-198. [CrossRef]
  • 22. Zivkovic, M.D., Rajkovic, S., Djuran, M.I. (2008). Reaction of [Pt(Gly-Gly-N,N`,O)I]- with the N-acetylate dipeptide L-methionyl-L-histidine: selective platination of the histidine side chain by intramolecular migration of the platinum(II) complex. Bioorganic Chemistry, 36(3), 161-164. [CrossRef]
  • 23. Narasimhan, B., Sharma, D., Kumar, P. (2011). Biological importance of imidazole nucleus in the new millennium. Medicinal Chemistry Research, 20, 1119-1140. [CrossRef]
  • 24. Sundberg, R.J., Martin, R.B. (1974). Interactions of histidine and other imidazole derivatives with transition metal ions in chemical and biological systems. Chemical Reviews, 74(4), 471-517. [CrossRef]
  • 25. Arora, S.S, Babbar, R. (2020). A comprehensive review on therapeutic potential of benzimidazol: a miracle scaffold. Journal of Pharmacetical Technology Research and Management, 8(1), 23-29. [CrossRef]
  • 26. Salahuddin, M.S., Mazumder A. (2017). Benzimidazoles: A biologically active compounds. Arabian Journal of Chemistry, 10, 157-173. [CrossRef]
  • 27. Khokra, S.L., Choudhary, D. (2011). Benzimidazole an important scaffold in drug discovery. Asian Journal of Biochemical and Pharmaceutical Research, 3(1), 476-486.
  • 28. Yongzhen, G., Xuben, H., Hao, F. (2021). Recent applications of benzimidazole as a privileged scaffold in drug discovery. Mini Reviews in Medicinal Chemistry, 21(11), 1367-1379. [CrossRef]
  • 29. Saral, H., Özdamar, Ö., Uçar, İ. (2017). Synthesis, structural and spectroscopic studies of two new benzimidazole derivatives: A comparative study. Journal of Molecular Structure, 1130, 46-54. [CrossRef]
  • 30. Alaqeel, S.I. (2017). Synthetic approaches to benzimidazoles from o-phenylenediamine: A literature review. Journal of Saudi Chemical Society, 21(2), 229-237. [CrossRef]
  • 31. Brishty, S.R., Hossain, J., Khandaker, M.U., Faruque, M.S.I., Osman, H., Rahman, S.M.A. (2021). A comprehensive account on recent progress in Pharmacological activities of benzimidazole derivatives. Frontiers in Pharmacology, 12, 762807. [CrossRef]
  • 32. Bansal, Y., Silakari, O. (2012). The therapeutic journey of benzimidazoles: A review. Bioorganic Medicinal Chemistry, 20(21), 6208-6236. [CrossRef]
  • 33. Vasava, M.S., Bhoi, M.N., Rathwa, S.K., Jethava, D.J., Acharya, P.T., Patel D.B., Patel, H.D. (2020). Benzimidazole: A milestone in the field of medicinal chemistry. Mini Reviews in Medicinal Chemistry, 20(7), 532-565. [CrossRef]
  • 34. Phillips, M.A. (1928). The Formation of 2-Substituted Benzimidazole. Journal of Chemical Society, 2393-2399. [CrossRef]
  • 35. Nzeyimana, A., Utku, S., Açık, L., Çelebi K.A. (2017). Synthesis, characterization and DNA ınteraction of novel platinum(II)complexes containing substituted benzimidazole ligands. Revue Roumaine de Chimie, 62, (3), 227-236.
  • 36. Valdez, J., Cedillo, R., Hernandez-Campos, A., Yepez, L., Hernandez-Luis, F., Navarrete-Vazquez, G., Tapia, A., Cortes, R. Hernandez, M., Castillo, R. (2002). Synthesis and antiparasitic activity of 1H-benzimidazole derivatives. Bioorganic Medicinal Chemistry Letters, 12(16), 2221-2224. [CrossRef]
  • 37. Zhang, Z.H, Li, J.J., Gao, Y.Z., Liu, Y.H. (2008) Synthesis of 2-substituted benzimidazoles by Iodine-mediated condensation of orthoesters with 1,2-phenylenediamines. Journal of Heterocyclic Chemistry, 44, 1509-1512. [CrossRef]
  • 38. Liu, J., Liu, Q., Xu, W., Wang, W. (2011). Expeditious and effeicient synthesis of benzoxazoles, benzimidazoles catalyzed by Ga(OTf)3 under solvent-free conditions. Chinese Journal of Chemistry, 29, 1739-1744. [CrossRef]
  • 39. Aridoss, G., Laali, K.K. (2011). Building heterocyclic systems with RC(OR)2 cabocations in recyclable bronsted acid ionic liquids: facile synthesis of 1-substituted 1H-1,2,3,4-tetrazoles, benzazoles and other ring systems with CH(OEt)3 and Et(OEt)3 in EtNH3NO3 and PMIM(SO3H) Otf. European Journal Organic Chemistry, 2827-2835. [CrossRef]
  • 40. Khaksar, S., Heydarı, A., Tajbakhsh, M., Vahdat, S.M. (2010). Lewis acid catalyst free synthesis of benzimidazoles and formamidines in 1,1,1,3,3,3-hexafluoro-2-propanol. Journal of Fluorine Chemistry, 131(12), 1377-1381. [CrossRef]
  • 41. Kim, J., Kim, J., Lee, H., Byung, M.L., Byeong, H.K. (2011). Indium-mediated one-pot benzimidazole synthesis from 2-nitroanilines or 1,2-dinitroareness with orthoesters. Tetrahedron, 67(41), 8027-8033. [CrossRef]
  • 42. Li, X., Zhang, J., Yang, Y., Hong, H., Han, L., Zhu, N. (2021). Reductive cyclization of o-phenylenediamine with CO2 and BH3NH3 to synthesize 1H-benzimidazole derivatives. Journal of Organometallic Chemistry, 122079, 954-955. [CrossRef]
  • 43. Alasmary, F.A.S, Snelling, A.M., Zain, M.E., Alafeefy, A.M., Awaad, A.S., Karodia, N. (2015). Synthesis and evaluation of selected benzimidazole derivatives as potential antimicrobial agents. Molecules, 20(8), 15206-15223. [CrossRef]
  • 44. Shaikh, A., Ravi, O., Ragini, S.P., Sadhana, N., Bathula, S.R. (2020). Benzimidazoles and benzothiazoles from styrenes and N-vinilimidazole via palladium catalysed oxidative C=C and C-N bond cleavage. Tetrahedron Letters, 61(1), 151356. [CrossRef]
  • 45. Denizot, F., Lang, R. (1986). Rapid colorimetric assay for cell growth and survival: Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. Journal of Immunological Methods, 89(2), 271-277. [CrossRef]
  • 46. International Standard. (2009). Biological evaluation of medical devices- Part 5 Test for in vitro cytotoxicity. http://nhiso.com/wp-content/uploads/2018/05/ISO-10993-5-2009.pdf. Erişim tarihi: 05 Temmuz 2022.
  • 47. Anand, K., Wakode, S. (2017). Development of drugs based on benzimidazole heterocycle: Recent advancement and inights. International Journal of Chemical Studies, 5(2), 350-362.
  • 48. Rashedy, A.A., Aboul-Enein, H.Y. (2013). Benzimidazole derivatives as potential anticacer agents. Mini Review Medicinal Chemistry, 13(3), 339-407. [CrossRef]
  • 49. Mastalarz, H., Mastalarz, A., Wietrzyk, J., Milczarek, M., Kochel, A., Regiec, A. (2020). Synthesis of platinum(II) complexes with some 1-methylnitropyrazoles and in vitro research on their cytotoxic activity. Pharmaceuticals, 13(12), 433. [CrossRef]
  • 50. Bai, L., Gao, C., Liu, Q., Yu, C., Zhang, Z., Cai, L., Yang, B., Qian, Y., Yang, J., Liao, X. (2017). Research progress in modern structure of platinum complexes. European Journal of Medicinal Chemistry, 140, 349-382. [CrossRef]
  • 51. Al-Harthy, T., Zoghaib, W., Abdel-jalil, R. (2020). Importance of flourine in benzazole compunds. Molecules, 25(20), 4677. [CrossRef]
  • 52. Wang, L., Sheng, J., Tian, H., Qian, C. (2004). An efficient procedure for the synthesis of benzimidazole derivatives using Yb (OTf)3 as catalyst under solvent-free conditions. Synthetic Communications, 34(23), 4265-4272. [CrossRef]
  • 53. Ghosh, S.P., Bhattacharjee, P., Dubey, L., Mishra, L.K. (1977). Complexes of some platinum metals with imidazole and benzimidazole. Journal of Indian Chemical Society, 54, 230-238.
  • 54. Mylonas, S., Valavanidis, A., Dimitropoulos, K., Polissiou, M., Tsiftsoglou, A.S., Vizirianakis, I.S. (1988). Synthesis, molecular structure determination, and antitumor activity of platinum (II) and palladium (II) complexes of 2-substituted benzimidazole. Journal of Inorganic Biochemistry, 34, 265-275. [CrossRef]
  • 55. Wisniewski, M.Z., Glowiak, T., Opolski, A., Wietrzyk, J. (2001). Synthesis, characterization and antiproliferative activity of the Co(II), Ni(II), Cu(II), Pd(II), and Pt(II) complexes of 2-(4-thiazolyl) benzimidazole (thiabendazole). Metal Based Drugs, 8, 189-194. [CrossRef]
  • 56. Rabiger, D.J., Joullie՜, M.M. (1964). The ionization constants, ultraviolet and infrared spectra of some substituted benzimidazoles. Journal of Organic Chemistry, 29(2), 476-482. [CrossRef]
  • 57. Callaghan, V., Goodgame, D.M.L., Tooze, R.P. (1983). Platinum and other metal complexes of 2-methyl-5-nitrobenzimidazole and metronidazole. Inorganica Chimica Acta, 78, L1-L4. [CrossRef]
Toplam 57 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Eczacılık ve İlaç Bilimleri
Bölüm Araştırma Makalesi
Yazarlar

Yasmin Aljendy 0000-0003-1701-1278

Hatice Oruç Demirbağ 0000-0002-1086-713X

Gül Bayram 0000-0002-4154-8596

Semra Utku 0000-0003-3181-9134

Proje Numarası 2019-3-TP2-3714
Erken Görünüm Tarihi 17 Mayıs 2023
Yayımlanma Tarihi 20 Mayıs 2023
Gönderilme Tarihi 19 Ocak 2023
Kabul Tarihi 21 Mart 2023
Yayımlandığı Sayı Yıl 2023 Cilt: 47 Sayı: 2

Kaynak Göster

APA Aljendy, Y., Oruç Demirbağ, H., Bayram, G., Utku, S. (2023). 2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI. Journal of Faculty of Pharmacy of Ankara University, 47(2), 531-542. https://doi.org/10.33483/jfpau.1239326
AMA Aljendy Y, Oruç Demirbağ H, Bayram G, Utku S. 2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI. Ankara Ecz. Fak. Derg. Mayıs 2023;47(2):531-542. doi:10.33483/jfpau.1239326
Chicago Aljendy, Yasmin, Hatice Oruç Demirbağ, Gül Bayram, ve Semra Utku. “2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University 47, sy. 2 (Mayıs 2023): 531-42. https://doi.org/10.33483/jfpau.1239326.
EndNote Aljendy Y, Oruç Demirbağ H, Bayram G, Utku S (01 Mayıs 2023) 2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI. Journal of Faculty of Pharmacy of Ankara University 47 2 531–542.
IEEE Y. Aljendy, H. Oruç Demirbağ, G. Bayram, ve S. Utku, “2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI”, Ankara Ecz. Fak. Derg., c. 47, sy. 2, ss. 531–542, 2023, doi: 10.33483/jfpau.1239326.
ISNAD Aljendy, Yasmin vd. “2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University 47/2 (Mayıs 2023), 531-542. https://doi.org/10.33483/jfpau.1239326.
JAMA Aljendy Y, Oruç Demirbağ H, Bayram G, Utku S. 2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI. Ankara Ecz. Fak. Derg. 2023;47:531–542.
MLA Aljendy, Yasmin vd. “2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University, c. 47, sy. 2, 2023, ss. 531-42, doi:10.33483/jfpau.1239326.
Vancouver Aljendy Y, Oruç Demirbağ H, Bayram G, Utku S. 2,5(6)-DİSÜBSTİTÜEBENZİMİDAZOL TÜREVİ LİGANDLARI TAŞIYAN PLATİN KOMPLEKSLERİNİN ANTİKANSER AKTİVİTELERİNİN ARAŞTIRILMASI. Ankara Ecz. Fak. Derg. 2023;47(2):531-42.
 Kapak Resmi İndir

Kapsam ve Amaç

Ankara Üniversitesi Eczacılık Fakültesi Dergisi, açık erişim, hakemli bir dergi olup Türkçe veya İngilizce olarak farmasötik bilimler alanındaki önemli gelişmeleri içeren orijinal araştırmalar, derlemeler ve kısa bildiriler için uluslararası bir yayım ortamıdır. Bilimsel toplantılarda sunulan bildiriler supleman özel sayısı olarak dergide yayımlanabilir. Ayrıca, tüm farmasötik alandaki gelecek ve önceki ulusal ve uluslararası bilimsel toplantılar ile sosyal aktiviteleri içerir.