Publication: Olası MPGES-1 enzim inhibitörü yeni 1,2,4-triazol türevlerinin sentezi ve karakterizasyonu
Abstract
Amaç: Enflamatuvar uyarıcılara yanıt olarak PGE2'nin salınmasından sorumlu olan ve henüz FDA onayı almış bir inhibitörü bulunmayan mPGES-1 enzimi kanser tedavisinde önemli bir hedef haline gelmiştir. 4H-1,2,4-triazol yapısı pek çok biyolojik etkiden sorumlu literatürde hem antikanser hem de mPGES-1 inhibisyonu etkilerinin bildirilmesi kanser tedavisinde umut vaad etmektedir. Bu çalışmada yeni 4H-1,2,4-triazol-3-tiyoasetamit türevlerinin sentezi, karakterizasyonu ve biyolojik etkilerinin incelenmesi hedeflenmiştir. Gereç ve Yöntem: Başlangıç maddesi olan ibuprofenden hareketle sentezlenen hidrazit türevi bileşik 2, metil/ etil/ propilizotiyosiyanat ile muamele edilerek sırasıyla bileşik 3-5 sentezlenmiştir. Alkali ortamda bileşik 3-5’ten hareketle kapatılan triazol halkalarından [6-8] hareketle yeni 2-[(4H-1,2,4-triazol-3-il)sülfanil]asetamit’ler sentezlenmiştir [6a-i, 7a-i, 8a-i]. Sentezlenen bileşiklerin saflıkları kromatografik yöntemlerle belirlenmiş, yapıları ise elemental analiz çalışmalarının yanı sıra IR, 1H-NMR ve kütle spektrumları ile saptanmıştır. Biyolojik aktivite çalışmaları kapsamında antiproliferatif etkileri, mPGES-1 ve COX-1/ 2 enzim inhibisyonları değerlendirilmiş, in siliko yöntemlerle ilaç-reseptör etkileşimleri incelenmiştir. Bulgular: Çalışmada 27 adet yeni 2-[(4H-1,2,4-triazol-3-il)sülfanil]asetamit türevi bileşik %38-54 verimle sentezlenmiştir. Saflıkları ve yapıları incelenen bileşiklerin sentez ilkel maddelerinden farklı olduğu tespit edilmiştir. Hedef bileşikler anlamlı bir enzim inhibisyonu göstermezken bileşik 6a MCF-7 kanser hücre hattına karşı %65,21 inhibisyon sergileyerek en etkili antikanser ajan olarak karşımıza çıkmaktadır. Sonuç: Sentezlenen bileşikler anlamlı mPGES-1 enzim inhibisyonu göstermemesine rağmen yüksek antikanser etkiye sahip bileşik 6a, yeni antikanser etkili 1,2,4-triazol türevlerinin geliştirilmesine katkı sağlayacaktır.
Objective: The mPGES-1 enzyme, which is responsible for the release of PGE2 in response to inflammatory stimuli and has no FDA-approved inhibitor yet, has become an important target in cancer therapy. The 4H-1,2,4-triazole structure is responsible for many biological effects, and the reporting of both anticancer and mPGES-1 inhibition effects in the literature is promising in cancer treatment. In this study, it was aimed to synthesize, characterize and examine the biological effects of new 4H-1,2,4-triazole-3-thioacetamide derivatives. Material and Methods: The hydrazide derivative compound 2 synthesized from the starting material ibuprofen was treated with methyl/ ethyl/ propylisothiocyanate and compounds 3-5 were synthesized, respectively. The new 2-[(4H-1,2,4-triazol-3-yl)sulfanyl]acetamides were synthesized starting from the closed triazole rings starting from compounds 3-5 in alkaline environment. Purities of the synthesized compounds were determined by chromatographic methods, and their structures were determined by IR, 1H-NMR and mass spectra as well as elemental analysis studies. Their antiproliferative effects, mPGES-1 and COX-1/ 2 enzyme inhibitions were evaluated within the scope of biological activity studies, and drug-receptor interactions were investigated by in silico methods. Results: In the study, 27 new 2-[(4H-1,2,4-triazol-3-yl)sulfanyl]acetamide derivatives were synthesized with 38-54% yield. It was determined that the compounds whose purity and structure were examined, were different from the synthesis primitives. While the target compounds did not show a significant enzyme inhibition, compound 6a exhibited 65,21% inhibition against the MCF-7 cancer cell line, appearing as the most effective anticancer agent. Conclusion: Although none of the synthesized compounds show significant mPGES-1 enzyme inhibition, compound 6a with high anticancer effect will contribute to the development of new 1,2,4-triazole derivatives with anticancer effect.
Objective: The mPGES-1 enzyme, which is responsible for the release of PGE2 in response to inflammatory stimuli and has no FDA-approved inhibitor yet, has become an important target in cancer therapy. The 4H-1,2,4-triazole structure is responsible for many biological effects, and the reporting of both anticancer and mPGES-1 inhibition effects in the literature is promising in cancer treatment. In this study, it was aimed to synthesize, characterize and examine the biological effects of new 4H-1,2,4-triazole-3-thioacetamide derivatives. Material and Methods: The hydrazide derivative compound 2 synthesized from the starting material ibuprofen was treated with methyl/ ethyl/ propylisothiocyanate and compounds 3-5 were synthesized, respectively. The new 2-[(4H-1,2,4-triazol-3-yl)sulfanyl]acetamides were synthesized starting from the closed triazole rings starting from compounds 3-5 in alkaline environment. Purities of the synthesized compounds were determined by chromatographic methods, and their structures were determined by IR, 1H-NMR and mass spectra as well as elemental analysis studies. Their antiproliferative effects, mPGES-1 and COX-1/ 2 enzyme inhibitions were evaluated within the scope of biological activity studies, and drug-receptor interactions were investigated by in silico methods. Results: In the study, 27 new 2-[(4H-1,2,4-triazol-3-yl)sulfanyl]acetamide derivatives were synthesized with 38-54% yield. It was determined that the compounds whose purity and structure were examined, were different from the synthesis primitives. While the target compounds did not show a significant enzyme inhibition, compound 6a exhibited 65,21% inhibition against the MCF-7 cancer cell line, appearing as the most effective anticancer agent. Conclusion: Although none of the synthesized compounds show significant mPGES-1 enzyme inhibition, compound 6a with high anticancer effect will contribute to the development of new 1,2,4-triazole derivatives with anticancer effect.