QSAR, DOCKING MOLEKUL DAN SINTESIS SENYAWA TURUNAN HIDROKSIXANTON SEBAGAI ANTIKANKER DAN ANTIOKSIDAN
EMMY YUANITA, Prof. Dr. rer.nat. Harno Dwi Pranowo, M.S; Prof. Jumina, PhD; Prof. Dr. Mustofa, M.Kes, Apt
2017 | Disertasi | S3 KimiaPenelitian ini bertujuan untuk menemukan senyawa hidroksixanton yang potensial sebagai obat kemoterapi penyakit kanker dan antioksidan. Tahapan penelitian yang dilakukan adalah 1) Desain senyawa turunan hidroksixanton yang memiliki aktivitas terbaik menggunakan analisis QSAR; 2) Verifikasi aktivitas anti kanker senyawa turunan hidroksixanton hasil analisis QSAR menggunakan docking molekul terhadap C-Kit protein tirosin kinase (1T46.pdb); 3) Sintesis senyawa turunan hidroksixanton hasil kajian komputasi QSAR dan docking molekul; 4) Uji aktivitas antikanker dan antioksidan senyawa hidroksixanton. Berdasarkan hasil analisis QSAR diperoleh persamaan QSAR yaitu Log IC50 = -9,132qC1 + 28,853qC5+ 2,456qC6 -7,375qC10-5,112qC11+3,900. Model persamaan QSAR digunakan untuk mendesain senyawa turunan hidroksixanton (HX 1-11) baru sebagai bahan aktif obat antikanker, dan senyawa HX 6-11 memiliki IC50pred berkisar 0,40 - 2,01 μg/mL. Hasil analisis docking molekul terhadap C-kit reseptor protein tirosin kinase (1T46.pdb menunjukkan semua senyawa yang diusulkan dari hasil QSAR memiliki interaksi ikatan dengan ligan aktif STI-571. Sintesis senyawa HX 1-11 menghasilkan rendemen reaksi yang baik hingga sangat baik. Senyawa HX 1-5 diperoleh melalui reaksi siklodehidrasi berbagai senyawa asam dan turunan fenol dalam pereaksi Eaton menghasilkan rendemen berturut-turut yaitu 75,21; 81,96; 79,82; 74,00 dan 76,00%. Reaksi brominasi senyawa HX 1-3 menggunakan Br2 dalam asam asetat glasial membentuk senyawa HX-7, HX-9, dan HX-11 dengan rendemen 92,10; 89,10 dan 82,10%. Reaksi klorinasi menggunakan sistem pereaksi yaitu NCS (N-klorosuksinamida)/p-toluen sulfonat (p-TSA)/natrium klorida (NaCl) dalam etanol menghasilkan senyawa HX-6, HX-8, dan HX-10 dengan rendemen 81,50; 89,50 dan 81,50%. Berdasarkan nilai IC50 hasil uji secara in vitro terhadap 4 sel kanker (T47D, HeLa, HepG2, dan P388) serta penentuan nilai indeks selektivitas (IS) maka senyawa yang direkomendasikan menunjukkan hasil berbeda terhadap masing-masing sel kanker. Senyawa HX-6, HX-8, HX-9, dan HX-10 berpotensi untuk dikembangkan sebagai bahan aktif antikanker berdasarkan nilai IC50 dan IS. Aktivitas antioksidan senyawa HX 1-11 ditentukan melalui metode 2,2-difenil-2-pikrilhidrazil (DPPH). Berdasarkan nilai IC50, senyawa hidroksixanton HX 1-5 lebih direkomendasikan sebagai antioksidan (IC50 3,93-79,77 μg/mL) dengan kategori sangat kuat hingga kuat dibandingkan senyawa hidroksixanton dengan substituen halogen kloro dan bromo (HX 6-11) yang memiliki IC50 93,75 - 526,82 μg/mL dengan kategori kuat hingga lemah.
This study aims to look for new active compounds as chemotherapy drugs to treat cancer from hydroxyxanthone derivatives. The study was divided into four steps: 1) Designing the best performing activity of hydroxyxanthone derivatives using QSAR analysis; 2) Verifying the anticancer activity of the hydroxyxanthone derivatives generated from the QSAR analysis using molecular docking with tyrosine kinase protein (1T46.pdb); 3) Synthesizing the hydroxyxanthone derivatives obtained from the previous step; 4) Testing the anticancer and antioxidant activities of the prepared hydroxyxanthone derivatives. Based on the QSAR analysis, a QSAR equation describing descriptor effects on anticancer activities was formulated as: Log IC50 = -9.132qC1 + 28.853qC5+ 2.456qC6 -7.375qC10-5.112qC11+3.900. The QSAR equation model was used to design hydroxyxanthone derivatives (HX 1-11) for anticancer drug, which HX 6-11 have good activities in range IC50 pred of 0,40 - 2,01 μg/ml. The molecular docking result toward C-kit receptor of tyrosine kinase protein (IT46.pdb) revealed that all compounds suggested by the QSAR analysis had binding interaction with active ligand STI-571. Thus, it could be concluded that the compounds possess anticancer activities. Synthesis of HX1-11 was carried out to afford good to excellent yield of the expected products. Compound HX 1-5 were obtained via cyclodehydration reaction of acid derivatives and substituted phenols in Eaton reagents with yields of 75.21; 81.96; 79.82; 74.00 and 76.00% respectively. Bromination of HX 1-3 with Br2/glacial acetic acid afforded good yields of HX-7, HX-9 and HX-11 i.e. 92.10; 89.10 and 82.10% respectively. Meanwhile, chlorination of HX 1-3 using NCS/p-TSA/NaCl in ethanol produced HX-6, HX-8 and HX-10 in 81.50, 89.50 and 81.50% yield respectively. Based on the IC50 value from the in vitro test against four different cancer cells (T47D, HeLa, HepG2, and P388) and the determination of selectivity index (IS) value, the recommended derivatives for each cell was found to be different. HX6, HX-8, HX-9 and HX-10 were observed to be the main compounds that predominantly working against the cancer cells, as seen from their low IC50 and high selectivity against the cancer cells. The antioxidant activity test was performed through 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and HX 1-5 showed the excellent result with IC50 ranges between 3.93-79.77 μg/ml, which could be categorized as very strong to strong. Meanwhile, IC50 of the hydroxyxanthones with chloro and bromo substituents (HX 6-10) were 93.75-526.82 μg/ml which belonged to strong to weak category.
Kata Kunci : Antikanker, Docking, QSAR, Xanton