Sintesis Liposom Analog Kurkumin Monoketon Sebagai Drug Delivery Pada Sel Kanker Serviks dengan Uji In Silico dan In Vitro

Fitriana Nur Hanifah, Dr. Endang Astuti, M.Si. ; Prof. Tri Joko Raharjo, M.Si., Ph.D.

2023 | Skripsi | KIMIA

Penelitian ini bertujuan untuk mengetahui interaksi dan afinitas ikatan berbagai senyawa analog kurkumin monoketon secara in silico terhadap protein p53, Bcl-2, dan EGFR; melakukan sintesis senyawa analog kurkumin monoketon dengan afinitas ikatan dan interaksi terbaik dari 6 kandidat senyawa, dan enkapsulasi dengan liposom; serta melakukan uji sitotoksisitas senyawa kurkumin, analog kurkumin, liposom kurkumin, dan liposom analog kurkumin terhadap sel HeLa. Studi in silico dilakukan dengan molecular docking terhadap 6 kandidat senyawa analog kurkumin monoketon, meliputi: (1E, 4E)-1,5-bis(4-benziloksi)-3-metoksifenil)penta-1,4-dien-3-on (A); (2E, 5E)-2,5-bis(4-benziloksi)-3-metoksibenzilidin)siklopentanon (B); (1E, 4E)-1,5-bis(4-benziloksifenil)-1,4- pentadien-3-on (C); (2E, 5E)-2,5-bis(4-benziloksibenzilidin)-siklopentanon (D); (1E, 4E)-1,5-bis(4-(dimetilamino)fenil)penta-1,4-dien-3-on (E); dan (2E, 5E)-2,5-bis(4-(dimetilamino)fenil)siklopentanon (F). Satu analog kurkumin terbaik hasil docking disintesis dari bahan benzaldehid dan keton. Sintesis dilakukan dengan metode pengadukan dan refluks melalui reaksi kondensasi aldol Claisen-Schmidt dengan katalis basa KOH 5%. Senyawa analog kurkumin hasil sintesis dikarakterisasi dengan FTIR, MS/MS, 1H-NMR dan 13C-NMR. Selanjutnya kurkumin dan senyawa tersebut dienkapsulasi dengan liposom. Liposom senyawa-senyawa tersebut dikarakterisasi dengan TEM. Senyawa beserta liposomnya diuji sitotoksisitasnya terhadap sel HeLa.

Senyawa analog kurkumin monoketon B merupakan senyawa terbaik hasil molecular docking yang memiliki interaksi spesifik pada sisi aktif protein p53, Bcl-2, dan EGFR dengan afinitas ikatan rendah dibandingkan dengan senyawa A, C, D, E, F, dan kurkumin. Senyawa B berhasil disintesis dengan produk berupa padatan kuning dan %hasil sebesar 48,06%. Enkapsulasi kurkumin dan senyawa B dengan liposom membentuk liposom unilamelar. Senyawa kurkumin, analog kurkumin monoketon hasil sintesis, liposom kurkumin, dan liposom analog kurkumin monoketon  memiliki IC50 secara berturut-turut sebesar 444,86; 68,30; 68,70; dan 74,62 ppm terhadap sel HeLa.

This study aims to determine interaction and binding affinity of various monoketone curcumin analogs to p53, Bcl-2, and EGFR proteins with in silico method; synthesize monoketone curcumin analog compound with the best bonding affinity and interactions from 6 candidate compounds, and encapsulate them with liposomes; as well as conducting cytotoxicity tests of the best curcumin compounds, curcumin analog, curcumin liposomes, and curcumin analog liposomes against HeLa cells. The in silico study was carried out by molecular docking of 6 candidate monoketone curcumin analogs, including: (1E, 4E)-1,5-bis(4-benzyloxy)-3-methoxyphenyl)penta-1,4-dien-3-one (A ); (2E, 5E)-2,5-bis(4-benzyloxy)-3-methoxybenzylidine)cyclopentanone (B); (1E, 4E)-1,5-bis(4-benzyloxphenyl)-1,4- pentadiene-3-one (C); (2E, 5E)-2,5-bis(4-benzyloxybenzylidine)-cyclopentanone (D); (1E, 4E)-1,5-bis(4-(dimethylamino)phenyl)penta-1,4-dien-3-one (E); and (2E, 5E)-2,5-bis(4-(dimethylamino)phenyl)cyclopentanone (F). The best curcumin analog as a result of docking was synthesized from benzaldehyde and ketones. Synthesis was carried out by stirring and reflux method through Claisen-Schmidt aldol condensation reaction with KOH 5% as catalyst. The synthesized curcumin analogs were characterized by FTIR, MS/MS, 1H-NMR and 13C-NMR. Furthermore, curcumin and curcumin analog was encapsulated in liposome. The liposome of these compounds were characterized by TEM. The liposome of these compounds and the compounds were tested for cytotoxicity against HeLa cells.

Monoketone curcumin analog B is the best compound as a result of molecular docking which had specific interactions on the active sites of p53, Bcl-2, and EGFR proteins with low binding affinity compared to compounds A, C, D, E, F, and curcumin. Compound B was successfully synthesized with a yellow solid product with a yield of 48,06%. Encapsulation of curcumin and compound B with liposome formed unilamellar liposomes. Curcumin compounds, monoketone curcumin analogs synthesized, curcumin liposome, and monoketone curcumin analog liposome had IC50 respectively of 444.86; 68.30; 68.70; 74.62 ppm against HeLa cells.

Kata Kunci : analog kurkumin monoketon, liposom, molecular docking, sel kanker serviks.