SINTESIS, UJI AKTIVITAS ANTIOKSIDAN DAN ANTIKANKER, SERTA KAJIAN PENAMBATAN MOLEKUL TURUNAN HIDROKSIXANTON TERHADAP TOPOISOMERASE II

NELA FATMASARI, Prof. Drs. Jumina, Ph.D. ; Prof. Dr. Chairil Anwar

2019 | Tesis | MAGISTER KIMIA

Telah dilakukan sintesis, uji aktivitas antioksidan dan antikanker, serta penambatan molekul turunan hidroksixanton terhadap enzim Topoisomerase II. Senyawa tersebut antara lain 1,3,8-trihidroksixanton (HX1); 1,6-dihidroksixanton (HX2); 1,5,6-trihidroksixanton (HX3); 1-hidroksi-5-kloroxanton (HX4) dan 1,6-dihidroksi-5-metilxanton (HX5). Turunan hidroksixanton diperoleh melalui reaksi asilasi Friedel-Craft dan dehidrasi antara asam-2,6-dihidroksibenzoat dengan senyawa fenolat (flouroglusinol, resorsinol, pirogalol, 2-klorofenol dan 2-metilresorsinol) menggunakan reagen Eaton (CH3SO3H/P2O5). Proses reaksi yang dilakukan berupa refluks pada 80-85 C selama 3 jam. Produk reaksi yang diperoleh kemudian dimurnikan dengan Kromatografi Lapis Tipis Preparatif (KLTP) menggunakan etil asetat:n-heksana rasio 1:1 (v/v) sebagai eluen. Konfirmasi struktur produk senyawa dilakukan menggunakan spektrometer FTIR, MS, 1H dan 13C-NMR. Uji antioksidan dilakukan terhadap turunan hidroksixanton menggunakan metode 1,1-difenil-2-pikrilhidrazin (DPPH), sedangkan uji antikanker menggunakan metode 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazoinumbromida (MTT). Proses penambatan molekul menggunakan perangkat lunak Autodock Vina. Produk turunan hidroksixanton yang diperoleh dari reaksi antara asam-2,6-dihidroksibenzoat dengan senyawa fenolat berupa padatan berwarna kuning dengan persen hasil senyawa HX1, HX2, HX3, HX4 dan HX5 masing-masing sebesar 16,12; 33,33; 10,92; 11,11 dan 19,28%. Senyawa HX1-HX5 memiliki aktivitas antioksidan dalam berbagai kategori. Senyawa HX2 dalam kategori kuat (IC50 79,68 µg/mL), HX1, HX3 dan HX5 dalam kategori sedang (IC50 159,4; 128,0 dan 276,9 µg/mL), serta HX4 dalam kategori lemah (IC50 432,9 µg/mL). Senyawa HX1-HX5 tidak bersifat selektif terhadap sel kanker uji. Senyawa HX1 paling kuat aktivitas antikankernya terhadap sel MCF-7 (IC50 45,00 µg/mL), tetapi senyawa tersebut juga besifat toksik terhadap sel Vero (IC50 67,01 µg/mL). Interaksi antara senyawa HX1 dengan Topoisomerase II pada penambatan molekul berupa ikatan hidrogen (DG F:13) dan pi-pi stacked (DA F:12 dan DC C:8).

Synthesis, antioxidant and anticancer activities evaluation as well as molecular docking of hydroxyxanthone derivatives toward Topoisomerase II have been carried out. These compounds include 1,3,8-trihydroxyxanthone (HX1); 1,6-dihydroxy-xanthone (HX2); 1,5,6-trihydroxyxanthone (HX3); 4-chloro-1-hydroxy-xanthone (HX4) and 1,6-dihydroxy-5-methylxanthone (HX5). The hydroxyxanthone derivatives were obtained through the Friedel-Craft acylation reaction and dehydration of 2,6-dihydroxybenzoic acid with phenolic compounds (phloroglucinol, resorcinol, pyrogallol, 2-chlorophenol, and 2-methyl-resorcinol) using Eaton reagents (CH3SO3H/P2O5). The reaction was conducted by reflux at 80-85 C for 3 h. The products were purified by thin layer chromatography using ethyl acetate and n-hexane 1:1 (v/v) as eluent. The chemical structures were confirmed by FTIR, MS, 1H and 13C-NMR spectrometers. Antioxidant test was conducted using 1-1-diphenylpicryl-2-hydarzyl (DPPH) method, while anticancer test was conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) method. The molecular docking process was computed by AutoDock Vina. The hydroxyxanthone derivatives were produced from the reaction between 2,6-dihydroxybenzoic acid and phenolic as yellow solids with percent yield of HX1, HX2, HX3, HX4 and HX5 were 16.12; 33.33; 10.92; 11.11 and 19.28%, respectively. The hydroxyxanthone derivatives have antioxidant activity in various categories. Compounds HX2 was in the strong category (IC50 79.68 µg/mL), compounds HX1, HX3 and HX5 were in the moderate category (IC50 159.4; 128,0 and 276.9 µg/mL), and compound HX4 was in the weak category (IC50 432.9 µg/mL). The hydroxyxanthone derivatives (HX1-HX5) were not selective towards the tested cancer cell lines. Compound HX1 has the strongest anticancer activity against MCF-7 cell (IC50 45,00 µg/mL), but the compound was also toxic to Vero cell (IC50 67.01 µg/mL). The interaction between compound HX1 and the Topoisomerase II in the molecular docking was hydrogen bond (DG F:13) and pi-pi stacked (DA F:12 and DC C:8).

Kata Kunci : asam-2,6-dihidroksibenzoat, antikanker, antioksidan, fenolat, Topoisomerase II