Publication: Sülfonamit yapısı üzerinden sülfoniltiyoüre ve 4-tiyazolidon bileşikleri sentezi ve biyolojik etkileri
Abstract
1. ÖZET Tiyazolidin-4-on türevlerinin, antimikrobiyal, antiviral, antikanser, antikonvülsan, hipnotik, antienflamatuar, sülfoniltiyoüre türevlerinin ise antimikrobiyal, antidiyabetik, antikonvülsan, antikanser, antifibrilatör, anti-HCV etki gösterdikleri çeşitli literatürlerde bildirilmiştir. Bu çalışmada başlangıç maddesi olarak indapamid etken maddesi seçilmiştir. İndapamid bileşiğinin kuru aseton içindeki izotiyosiyanat ile potasyum karbonat varlığında verdiği reaksiyon sonucu 4-kloro-3-({[(sübstitüeamino) karbono- tiyoil]amino}sülfonil)-N-(2-metil-2,3-di-hidro-1H-indol-1-il) benzamit bileşikleri [1-20] elde edilmiştir. Bu bileşiklerin de kuru etanol içinde etil -bromoasetat ile susuz sodyum asetat varlığında reaksiyonu sonucu 4-kloro-3-({[3-(sübstitüe)-4-okso-1,3-tiyazolidin-2-iliden]amino} sülfonil)-N-(2-metil-2,3-dihidro-1H-indol-1-il) benzamit bileşiklerine [21-31] ulaşılmıştır. Bütün bileşiklerin yapıları elemental analiz, IR ve 1H-NMR ile bazı bileşiklerin ise 13C-NMR, HMBC, HR-EI kütle spektrumu ile aydınlatılmıştır. NIH (National Institutes of Health) araştırma merkezi tarafından seçilen 12, 16, 22, 26, 28 ve 30 bileşiklerinin antikanser aktivite çalışmaları in vitro ortamda incelenmiştir. Bunun için NIH tarafından lösemi, akciğer kanseri, kolon kanseri, yumurtalık kanseri, merkezi sinir sistemi kanseri, böbrek kanseri, prostat kanseri ve göğüs kanseri olmak üzere 9 kanser çeşidinden türeyen 60 farklı tümör üzerinde çalışılmıştır. 12 bileşiğinin büyüme yüzdesi, melanoma için MDA-MB-435 hücresinde % -3,70 olarak tespit edilmiştir. Sözü edilen bileşiğin ileri kanser taramaları M.Ü. Eczacılık Fakültesi Farmasötik Biyoteknoloji Anabilim Dalında çalışılmıştır. Sentezlenen bileşiklerin UMDNJ-New Jersey Medical School’da Biyokimya ve Moleküler Biyoloji bölümünde Hepatit C NS5B polimeraz enzim inhibisyonu çalışılmış, 4-kloro-3-[({[(4-florofenil) amino]karbono- tiyoil} amino) sülfonil]-N-(2-metil-2,3-dihidro-1H-indol-1-il) benzamit [13] ve 4-kloro-3-[({[(2,4-diklorofenil) amino] karbonotiyoil} amino) sülfonil]-N- (2-metil-2,3-dihidro-1H-indol-1-il) benzamit [14] bileşiklerinin her ikisinin de % 50,4 inhibisyon değerine sahip oldukları görülmüştür. Anahtar sözcükler: HCV NS5B RdRp, antikanser, sülfoniltiyoüre, indapamid, sülfoniliminotiyazolidin-4-on. 2.
Biological Evaluation and Synthesis of Sulphonylthiourea and 4-Thiazolidone Compounds Derived from Sulphonamides In the various literatures it has been reported 4-thiazolidones possess antimicrobial, antiviral, anticancer, anticonvulsant, hypnotic and antienflammatory properties. Furthermore sulfonylthiourea derivatives possess antimicrobial, antidiabetic, anticonvulsant, anticancer, antifibrillatory and anti-HCV activities. In this study, active material indapamide was chosen as the starting material. 4-Chloro-3-({[(substituted amino) carbono- thioyl]amino}sulfonyl)-N-(2-methyl-2,3-di-hydro-1H-indole-1-yl) benzamide compounds [1-20] were obtained from the reaction of indapamide with potassium carbonate and isothiocyanate in dry acetone. These compounds gave 4-chloro-3-({[3-(substituted) -4-oxo-1,3-thiazolidine-2-yliden] amino} sulfonyl)-N-(2-methyl-2,3-dihydro- 1H -indole-1-yl) benzamide compounds [21-31], with the reaction of ethyl -bromoacetate and anhydrous sodium acetate in dry ethanol. To elucidate the structures; elementary analysis, IR, and 1HNMR techniques was utilized for all; and 13C-NMR, HMBC, HR-EI mass spectrum techniques for some compounds. Anticancer activity studies of 12, 16, 22, 26, 28 and 30 compounds, were investigated by NIH on 60 different tumors that derived from 9 cancer types: lung, colon, ovarian, central nervous system, renal, prostate, breast cancer; and melanoma and leukemia. Growth percentage of compound 12 was determined to be -3,70 % for melanoma MDA-MB-435 cells. Further cancer screening for the previously mentioned compound was studied by the Pharmaceutical Biotechnology Department of Marmara University Faculty of Pharmacy. Hepatitis C NS5B polymerase activity of synthesized compounds were investigated by Biochemistry and Molecular Biology Department of UMDNJ-New Jersey Medical School. It has been shown that both 13 and 14 compounds have a 50.4 % inhibition value. HCV NS5B RdRp, anticancer, sulfonylthiourea, indapamide, sulfonylimino 4-thiazolidone.
Biological Evaluation and Synthesis of Sulphonylthiourea and 4-Thiazolidone Compounds Derived from Sulphonamides In the various literatures it has been reported 4-thiazolidones possess antimicrobial, antiviral, anticancer, anticonvulsant, hypnotic and antienflammatory properties. Furthermore sulfonylthiourea derivatives possess antimicrobial, antidiabetic, anticonvulsant, anticancer, antifibrillatory and anti-HCV activities. In this study, active material indapamide was chosen as the starting material. 4-Chloro-3-({[(substituted amino) carbono- thioyl]amino}sulfonyl)-N-(2-methyl-2,3-di-hydro-1H-indole-1-yl) benzamide compounds [1-20] were obtained from the reaction of indapamide with potassium carbonate and isothiocyanate in dry acetone. These compounds gave 4-chloro-3-({[3-(substituted) -4-oxo-1,3-thiazolidine-2-yliden] amino} sulfonyl)-N-(2-methyl-2,3-dihydro- 1H -indole-1-yl) benzamide compounds [21-31], with the reaction of ethyl -bromoacetate and anhydrous sodium acetate in dry ethanol. To elucidate the structures; elementary analysis, IR, and 1HNMR techniques was utilized for all; and 13C-NMR, HMBC, HR-EI mass spectrum techniques for some compounds. Anticancer activity studies of 12, 16, 22, 26, 28 and 30 compounds, were investigated by NIH on 60 different tumors that derived from 9 cancer types: lung, colon, ovarian, central nervous system, renal, prostate, breast cancer; and melanoma and leukemia. Growth percentage of compound 12 was determined to be -3,70 % for melanoma MDA-MB-435 cells. Further cancer screening for the previously mentioned compound was studied by the Pharmaceutical Biotechnology Department of Marmara University Faculty of Pharmacy. Hepatitis C NS5B polymerase activity of synthesized compounds were investigated by Biochemistry and Molecular Biology Department of UMDNJ-New Jersey Medical School. It has been shown that both 13 and 14 compounds have a 50.4 % inhibition value. HCV NS5B RdRp, anticancer, sulfonylthiourea, indapamide, sulfonylimino 4-thiazolidone.