IN SILICO DOCKING STUDIES OF GALLIC ACID STRUCTURAL ANALOGUES AS BCL-XL INHIBITOR IN CANCER

Objective: Apoptosis, or programed cell death, forms an important part of the cellular regulation machinery. The Bcl-2 protein family, comprisingproapoptotic and antiapoptotic members, forms an important part of the cells internal apoptotic pathway. Overexpression of the antiapoptoticmembers of the family in a number of cancer cell lines renders them immune to apoptosis and the ability to survive under conditions of cellular stress.Inhibition of the antiapoptotic members of the Bcl-2 family like Bcl-XL is, therefore, an interesting target for the development of anticancer therapy.Methods: The structure of antiapoptotic Bcl-XL receptor (1YSG) was taken from PDB database. The 23-dimensional structure of gallic acid analogswas designed. The Lipinski properties of gallic acid analogs were calculated using molsoft. Docking studies have been carried out through Autodock4.0 software.Results: Molecular docking analysis with gallic acid and their structural analogs showed propyl gallate, benzyl gallate, diallyl gallate, phenyl ethylgallate, and allyl gallate are more interactive and binding strongly than gallic acid at active site of Bcl-XL.Conclusion: Further these five compounds should be considered as potential candidates for Bcl-XL inhibitor.Keywords: Apoptosis, Bcl-2, Antiapoptotic Bcl-XL receptor, Gallic acid, Docking studies

INHIBITION OF CARSINOGENESIS BY SEED AND SOYBEAN MEAL EXTRACT IN COLON OF MICE: APOPTOSIS AND DYSPLASIA

Objective: Colon cancer is a major public health problem. Soybean has demonstrated chemopreventive and anticancer. Here, we have investigatedthe effect of a standardized seed and soybean meal extract (SE) with content of lunasin, here named grobogan extract (GE) and SE. They are botanicaldrug substance in experimental models of colon cancer in vivo.Methods: The effect of GE and SE was examined on the preneoplastic lesions (aberrant crypt foci), polyps and tumors induced by the carcinogenicagent azoxymethane (10 mg/kg) and dextran sodium sulfate 2% as well as in a xenograft model of colon cancer in mice.Results: GE and SE increased apoptosis (p=0.001). GE (150 mg/kg) has the highest impact level of apoptosis (p=0.009). GE and SE decreased dysplasia(p=0.024). GE (200 mg/kg) has the highest impact level of dysplasia (p=0.002), and SE (200 mg/kg) has the second impact level of dysplasia (p=0.003).Conclusions: GE and SE inhibition of colon carcinogenesis with increased level of apoptosis and decrease level of dysplasia.Keywords:Soybean, Lunasin, Colon cancer, Azoxymethane, Dextran sodium sulfate, Apoptosis, Dysplasia

PHENYLPROPANOIDS, EUGENOL SCAFFOLD, AND ITS DERIVATIVES AS ANTICANCER

ABSTRACTEugenol (EU) is a phenylpropene, an allyl chain-substituted guaiacol. EU is a member of the phenylpropanoids class of chemical compounds. It is acolorless to pale yellow oily liquid extracted from certain essential oils especially from clove oil. Further, chemopreventive agents might be used singlyor in combination with chemotherapy or radiotherapy for the more effective treatment of cancer by enhancing the efficacy of these modalities withminimal side effects and toxicity. Considering that EU scaffold may be a prospective chemopreventive agent, its potent antitumor ability to interferewith solid cancer cell growth and its molecular mechanism were evaluated as an initiative toward the development of a novel strategy for cancertreatment. This review article will conduct that EU as the antiproliferative activity and molecular mechanism of the EU induced apoptosis against thecancer cells and animal models.Keywords: Eugenol, Derivatives of eugenol, Scaffold, Anticancer, Phenylpropanoids

ANTIOXIDATIVE ACTIVITY AND PHYTOCHEMISTRY PROFILE OF HIBISCUS SABDARIFFA HERB EXTRACTS

Objective: Hibiscus sabdariffa, known as Roselle, is a widely-cultivated herb in Indonesia and has been consumed as an herbal drink due to its medicinal properties. The purpose of this research is to identify the antioxidant activity and phytochemical profile of Hibiscus sabdariffa. Methods: The Hibiscus sabdariffa samples were extracted and macerated with three different organic solvents: ethyl acetate, ethanol, and n-hexane. These extracts were then analyzed using thin layer chromatography (TLC) and phytochemical tests to identify the extracts’ secondary metabolites. The extracts’ antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Results: The phytochemistry tests were positive for glycosides, alkaloids, steroids, triterpenoids, tannins, and flavonoids. The TLC analysis revealed that the extracts containing two to three organic compounds. The ethanol Hibiscus sabdariffa extracts with an IC50 value 103.63 ppm showed stronger antioxidant activity than the ethyl acetate extract. Conclusion: Ethanol Hibiscus sabdariffa extracts may be a potential source of natural antioxidant

IDENTIFICATION OF FGFR INHIBITOR AS ST2 RECEPTOR/INTERLEUKIN-1 RECEPTOR-LIKE 1 INHIBITOR IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE DUE TO EXPOSURE TO E-CIGARETTES BY NETWORK PHARMACOLOGY AND MOLECULAR DOCKING PREDICTION

Objective: This study was designed to search for candidate drugs that act on IL-33 and ST2, which was carried out using a bioinformatics approach. Methods: We first analyzed Network Electronic Cigarette Smokes Predictions of therapeutic targets by Cytoscape. We collected from the Swiss TargetPrediction database [http://www. swisstargetprediction. ch/] by inputting each compound structure of the electronic cigarette smoke in SDF format. The target protein data is then supplemented with UniProt ID data to uniform protein identity. We then identified COPD Related Targets in Humans by Cytoscape. Subsequently, we identified key receptors in the pathogenesis of COPD. All target proteins that have a significant role in the pathogenesis of COPD exposed to cigarette smoke will be known from the combination of this network. Results: Based on the validation results of the protein receptor for ST2, a protein is used as a receptor with PDB ID: 1IRA. After analyzed by PyMol software, a protein with PDB ID 1IRA it has no missing residue in its sequenceDrug candidates analyzed by the structural similarity with the native ligand using PubChem and DRUGBANK analysis are follow: N-acetylmannosamine, Aceneuramic acid, Ceramide AP, Ceramide NP, Hg9a-9, Nonanoyl-N-hydroxyethylglucamide, N-Acetyl-2-deoxy-2-amino-galactose, N-Acetyllactosamine, MLi/2,6-dimethyl-4-[6-[5-[1-methylcyclopropyl] oxy-1H-indazol-3-yl] pyrimidin-4-yl] morpholine, Terazosin, BMS-911543, NAG Inhibitor, FGFR Inhibitor/sodium; 2-amino-5-[1-methoxy-2-methylindolizine-3-carbonyl] benzoate. After docking, the smallest or more negative binding affinity values are obtained. The stronger the FGFR Inhibitor ligand showed the interaction with the Receptor with a binding affinity value of-9.0 kcal/mol with mode/position 0, and RMSD 0.0. The second smallest binding affinity value is the NAG ligand with a-8.5 kcal/mol with mode/position 0 and RMSD 0.0. Conclusion: The findings revealed that FGFR Inhibitor was a suitable repurposing medication for anti-COPD development via the IL-33/ST-2 signaling pathway

MOLECULAR DOCKING STUDIES OF OPENED-CHAIN ANALOGUES OF ANTIMYCIN A ASCASPASES INHIBITORS OF APOPTOSIS IN COLORECTAL CANCER 3

Objective: Studies of open-chain analogues of antimycin A as caspase inhibitors of apoptosis by molecular docking approach through computeraideddrug design. The noveltyof this studyis finding the potentialantimycinA33 analogues which structurally modified against caspases.Methods: In finding potential caspase inhibitor of apoptosis in colorectal cancer (CRC) by in silico approach has been utilized. Protein structure ofcaspase has been downloaded from Protein Data Bank (1SHJ). The minimized of caspase was ready for molecular docking analysis. Analogues ofantimycin A as lead compounds were designed and assessed using Molsoft drug-likeness. Both protein and lignan derivatives were docked withAutodock 4.2. The best docking score was shown by the lowest binding energy.3Results: Analogues of antimycin A has been done by evaluating their physicochemical properties as lead compounds. From this assessment, itshowed that analogue 2 (AMD2), intermediate amide 4 (AMD4) showed good compounds to be drug-likeness by following Lipinski's rule of five(RO5), while intermediate amide 3 (AMD3) and antimycin A3 (AMY3) showed cannot followed in Lipinski's RO5. From molecular docking result, themost favorable binding of caspase was AMD4 and AMD2 based on its energy that AMD4 (−7.34 kcal/mol) has the best binding interaction comparedto AMD2 (−7.33 kcal/mol), AMY3 (−7.26 kcal/mol), and AMD3 (−5.23 kcal/mol), respectively.3Conclusion: This studies demonstrated that the opened-chain analogues of antimycin AAMD2 and AMD4 as a promising candidates of caspaseinhibitor of apoptosis in CRC.Keywords: Open-chain analogue, Antimycin A3, Caspase, Apoptosis, Anticolorectal cancer.3

PHYTOCHEMICAL ANALYSIS AND ANTIOXIDANT PROPERTIES BY DPPH RADICAL SCAVENGER ACTIVITY OF RUELLIA BRITTONIANA FLOWER

Objective: The genus Ruellia has been widely used in traditional and Ayurvedic medicine as an antioxidant. This study seeks to examine the antioxidant activity of the species Ruellia brittoniana. Methods: In this study, Ruellia brittoniana flowers were acquired from Depok, West Java, Indonesia. The flowers were cleaned and ground to form a powder, then dissolved in hexane, ethanol and ethyl acetate solvents. These three extracts were then tested for phytochemicals and thin layer chromatography (TLC) analysis. Ethanol and ethyl acetate extracts were also analyzed for antioxidants using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Results: Phytochemical results from the three extracts proved that Ruellia brittoniana contains flavonoids, alkaloids, tannins, glycosides and triterpenes. These results are comparable to the results from TLC analysis, which showed the samples contained 4–5 chemical components. Furthermore, the best antioxidant activity resulted from the ethyl acetate extract of the Ruellia brittoniana flower with an IC50 value of 68.42 ppm. Conclusion: An ethyl acetate extract from the Ruellia brittoniana flower can be used as a natural source of additional antioxidants

PHYTOCHEMISTRY AND ANTIOXIDANT ACTIVITY OF SOURSOP (ANNONA MURICATA) LEAVES

Objective: Soursop (Annona muricata) is a tropical plant which has been utilized as a folk medicine to treat many diseases including cancer, inflammation and parasitic infection. In this study, we investigated its phytochemistry properties and antioxidant activity against free radicals. Methods: Annona muricata leaves were extracted in three different solvents: ethanol, ethyl acetate and n-hexane. Afterwards, a phytochemistry test and the thin layer chromatography (TLC) method were used to evaluate bioactive compounds contained in the three different extracts. Antioxidant activity from the semi-polar (ethyl acetate) and polar (ethanol) solvents were evaluated by the DPPH (1,1-diphenyl-2-picrylhydrazyl) method, and the antioxidant activity is expressed by IC50 value. The results were compared to ascorbic acid as a positive control. Results: The phytochemistry test showed that the extracts were positive for flavonoids, steroids, alkaloids, glycosides and tannins. Moreover, TLC analysis revealed that there were three chemical compounds contained in the extracts. The results from the DPPH method were that ethanolic extract was shown to have the most potent antioxidant activity with an IC50 value of 35.51 ppm. Conclusion: The ethanolic extract of Annona muricata could be developed as the next promising natural antioxidant source

SYNTHESIS, CHARACTERIZATION, AND IN VITRO ANTIMALARIAL ACTIVITY OF DIHYDROXYLATION DERIVATIVES OF TRICLOSAN

Objective: The emergence of malaria as a global health problem over the past few decades, accompanied by the rise of chemoresistant strains ofPlasmodium falciparum, has emphasized the need for the discovery of new therapeutic drugs against this disease. In this study, enantiomericallyenriched (enantioenriched) analogs of triclosan were synthesized and evaluated for antimalarial activity against P. falciparum cultures.Methods: Enantioselective dihydroxylation of the olefin in amide seven was performed efficiently using chiral quinine ligand (DHQ)2PHAL to yieldenantioenriched dihydroxy propionamide derivative (+)-1 in moderate yields. In a similar way, the chiral quinidine ligand (DHQD)2PHAL was used asstereoselectivity agent yielded the desired enantioenriched (−)-1. The enantioenriched products were used for further in vitro assay, and accordingly thepercent enantiomeric excess (% ee) was not determined. The structures of compounds were proven by spectral data (1H NMR, 13C NMR, and mass spectra).Results: The phenol moiety at the C1 position of triclosan was chemically substituted with a methoxy group, in conjunction with an introducedstereocenter in a 2,3-dihydroxy-propionamide group at C2’ position. Unmodified triclosan inhibited the P. falciparum cultures with an IC50 value of27.2 μM. By contrast, the triclosan analogs, compounds (+)-1 and (−)-1, inhibited the P. falciparum cultures with IC50 values of 0.034 and 0.028 μM,respectively.Conclusion: Collectively, our preliminary in vitro results suggest that these triclosan analogs have potent antimalarial activity and represent apromising new treatment strategy on further development

MOLECULAR DOCKING OF ANTIMYCIN A3 ANALOGS AND ITS AROMATIC SEGMENTS AS INHIBITORS OF APOPTOSIS PROTEIN MARKER BCL-XL AND MCL-1

  Objective: Apoptosis is an important cellular process that causes the death of damaged cells. Its malfunction can lead to cancer development and poor response to conventional chemotherapy. Cellular proteins from the B-cell lymphoma 2 (BCL-2) family are crucial for apoptosis. Breast cancer is the most commonly diagnosed cancer among women worldwide. The aim of this work was to design using in silico docking antimycin A3, antimycin analogs, and its aromatic segments as inhibitors of Bcl-xl and Mcl-1.Methods: In silico molecular docking approach has been utilized to find the potential anticancer from antimycin A3 analogs and its aromatic segments. Antimycin A3 analogs and its aromatic segments were modeled into three-dimensional (3D) structures using Marvin Sketch. Based on Protein Data Bank, 3ZLN for Bcl-xl, and 5IEZ for Mcl-1 were selected as apoptosis protein marker from BCL-2 family. Geometry optimization and minimization of energy 3D structure of antimycin A3 analogs and segments (ligands) using the AutoDock software. Docking process and amino acid residue analysis were executed using AutoDock software. The best docking score was shown by the lowest binding energy and also checked with Lipinski rule of five.Results: In silico molecular docking showed antimycin A3 analogs, amide 5 and aromatic segment 14 have the best interaction and activity for Bcl-xl receptor inhibition. Moreover, amide 5 and segment 15 showed the best interaction and activity for Mcl-1 receptor inhibition.Conclusion: Our results clearly demonstrate that amide 5, segment 14, and segment 15 of antimycin A3 analog have a strong inhibitory activity against Bcl-xl and Mcl-1, and should be further developed as a promising candidate for the new anti-apoptosis agents.Â