ABSTRACT
Atherosclerosis is an inflammatory disorder of the vasculature and one of the underlying causes of cardiovasculardiseases. Numerous preventative and therapeutic approaches are being explored to limit the morbidity and mortalityof this disease. Nevertheless, some of the treatments cost greatly and contributed to various side effects; for example,statin therapy is associated with substantial residual cardiovascular risk as well as issues such as tolerability and patientdependent efficacy. Currently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been attractinginterests in the drug discovery of atherosclerosis treatment, but ezetimibe, a successful PCSK9 inhibitor, is an expensivemonoclonal antibody. Thus, exploring new PCSK9 inhibitors is crucial in overcoming this constraint. In the previouswork, aaptaminoids and methyl benzoate were isolated from marine sponges Aaptos aaptos and Acanthaster planci,respectively. These compounds enhance the transcription of the peroxisome proliferator-activated receptor gamma(PPARγ) in the luciferase assay. PPARγ agonist was hypothesized to inhibit the expression of the PCSK9 gene becausethe former is a transcription factor toward the latter. The synthesis of three aaptaminoids and 11 methyl benzoatederivative was carried out to address its potential as a PCSK9 inhibitor. The structure of the synthesized compound waselucidated using nuclear magnetic resonance spectral and electron impact mass spectral data. The PCSK9 inhibitoryactivities were determined by luciferase assay. Four aaptaminoids, such as aaptamine, N1,N4-bisbenzylaaptamine,N4-[(3,4,5-trimethoxy)benzyl]aaptamine, and N1-[(3,4,5-trimethoxy)benzyl]aaptamine, and one benzamide derivative,N-(2,3-dihydro-1H-inden-2-yl)-2-methoxybenzamide, were found to inhibit the expression of PCSK9 gene.
ABSTRACT
Objective: To investigate phenolics, fatty acids composition and biological activities of various extracts and fractions of Malaysian Aaptos aaptos. Methods: Fatty acid methyl ester was analyzed by gas chromatography-flame ionization detector. Antioxidant activity was determined using 2,2-diphenyl-picrylhydrazyl radical scavenging assay and total phenolics content by Folin-Ciocalteu procedure. Vero cells viability was evaluated using methyl thiazole tetrazolium and the inactivation of herpes simplex virus type 1 by neutral red uptake assay. p-Hydroxybenzamide isolated by column chromatography was characterized by utilizing nuclear magnetic resonance spectroscopy and electron impact mass spectrometry. Results: The chloroform, ethyl acetate and methanol extracts of Aaptos aaptos produced higher portions of straight-chain saturated fatty acid, while hexane extract mainly consisted of unsaturated fatty acid. The five majors of fatty acid methyl ester were identified as behenic acid, cis-10-heptadecenoic acid and cis-10-pentadecenoic acids, palmitic acid and tricosanoic acid. In addition, among all organic extracts, chloroform extract inactivated herpes simplex virus type 1 while exhibited weak cytotoxic activity against normal Vero cells and also exhibited strong cytotoxic activity on HL-60, MCF-7, K562, CEM-SS and WEHI-3B cells. A phenolic compound, p-hydroxybenzamide was also isolated from the sponge. Conclusions: Aaptos aaptos could be a source to derive the potential antiviral and anticancer agents. However, further studies are needed to determine the mechanism involved in the process.