#TITLE_ALTERNATIVE#

• Main Author: KURNIAWAN NIM : 30715008 , FRANSISKA
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/27396
• Institution: Institut Teknologi Bandung

Cancer is a disease related to the abnormal growth of cell. The potency of <br /> <br /> <br /> <br /> porphyrin compounds as anticancer agents have already known due to their affinity <br /> <br /> <br /> <br /> to the DNA, however, the study about their interaction with the non-DNA target is <br /> <br /> <br /> <br /> still limited. The purpose of present research was to obtain porphyrin derivatives <br /> <br /> <br /> <br /> as a candidate of anticancer and information about their interaction to the non- <br /> <br /> <br /> <br /> DNA target. Five known porphyrin derivatives and three novel porphyrin <br /> <br /> <br /> <br /> derivatives bearing bis(3,4-ethylcarboxymethylenoxy) phenyl (BECP) as mesosubstituent were used to study their interaction with their targets (in silico study), <br /> <br /> <br /> <br /> synthesized, and tested their cytotoxicity activity against cancer cell line. Three <br /> <br /> <br /> <br /> novel porphyrins with meso-susbituent of BECP were designed as candidates of <br /> <br /> <br /> <br /> radiopharmaceutical ligand and their interactions with the targets after being <br /> <br /> <br /> <br /> labeled with rhenium (Re) and technetium (Tc) were studied by in silico. The <br /> <br /> <br /> <br /> interactions of porphyrin derivatives with protein target of cancer such as spleen <br /> <br /> <br /> <br /> tyrosin kinase, epidermal growth factor receptor, carbonic anhydrase IX (CAIX), <br /> <br /> <br /> <br /> and REV-ERB&#946;were then analyzed after performing molecular docking with <br /> <br /> <br /> <br /> AutoDock 4.2 and molecular dynamic simulation with Gromacs2016. The <br /> <br /> <br /> <br /> simulations showed that studied porphyrins have affinity to the targets and the <br /> <br /> <br /> <br /> interactions were dominated by hydrophobic interactions. Re- and Tc-porphyrin <br /> <br /> <br /> <br /> also have affinity to the targets although the porphyrins have been already labeled. <br /> <br /> <br /> <br /> For each protein target, the porphyrin with best affinity was determined and the <br /> <br /> <br /> <br /> free binding energy between the best porphyrin-target complex was also calculated <br /> <br /> <br /> <br /> by MM/PBSA method. The toxicity of all porphyrins were also predicted by using <br /> <br /> <br /> <br /> ADMET Predictor v 8.1. In general, it was predicted that porphyrin derivatives are <br /> <br /> <br /> <br /> cardiotoxic, hepatotoxic, and toxic to reproduction system, however, they are not <br /> <br /> <br /> <br /> mutagenic, and their carcinogenicity level were not high. All porphyrin derivatives <br /> <br /> <br /> <br /> were successfully synthesized by Adler method, and they were characterized by <br /> <br /> <br /> <br /> UV/Vis, <br /> <br /> <br /> <br /> 1 <br /> <br /> <br /> <br /> H-NMR, <br /> <br /> <br /> <br /> 13 <br /> <br /> <br /> <br /> C-NMR, and LRMS MALDI-TOF. The reaction pathway in this <br /> <br /> <br /> <br /> Adler method was also studied by in silico study and it was known that the keystep <br /> <br /> <br /> <br /> of the reaction is the first step when the aldehyde reacts with pyrrole based on the <br /> <br /> <br /> <br /> reactivity of the aldehyde. The cytotoxicity activities of all porphyrin derivatives <br /> <br /> <br /> <br /> were tested by MTT assay against cancer cell (HeLa, WIDR, MCF-7, T47D, and <br /> <br /> <br /> <br /> HepG2 cell lines) and normal cell (Vero cell line). The in vitro test results showed <br /> <br /> <br /> <br /> iv <br /> <br /> <br /> <br /> that all studied porphyrins have good affinity against cancer cell, having higher <br /> <br /> <br /> <br /> affinity to the cancer cell than to that of the normal cell, and they are categorized <br /> <br /> <br /> <br /> as marginally active compound with the IC50 < 5 mM. Based on these results, it can <br /> <br /> <br /> <br /> be concluded that all studied porphyrins were potential as an anticancer agents, <br /> <br /> <br /> <br /> and porphyrins bearing bis(3,4-ethylcarboxymethylenoxy) phenyl (BECP) as mesosubstituent have better potential as a radiopharmaceutical ligand kit after the ester <br /> <br /> <br /> <br /> groups of BECP were hydrolyzed. <br />