Atherosclerosis is an inflammatory disorder of the vasculature and one of the underlying causes of CVD. Numerous preventative and therapeutic approaches are being explored to limit the morbidity and mortality of 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 patient-dependent efficacy. Currently, PCSK9 inhibitor has been attracting interests in the drug discovery of atherosclerosis treatment but, ezetimibe, a successful PCSK9 inhibitor is an expensive monoclonal antibody. Thus, exploring new PCSK9 inhibitors is crucial in overcoming this constraint. In our previous work, aaptaminoids and methyl benzoate were isolated from marine sponges Aaptos aaptos and Acanthaster plancii, respectively. These compounds enhance the transcription of the PPARγ in the luciferase assay. PPARγ agonist was hypothesized to inhibit the expression of the PCSK9 gene because the former is a transcription factor towards the latter. The synthesis of three aaptaminoids and 11 methyl benzoate derivative were carried out to address its potential as a PCSK9 inhibitor. The structure of the synthesized compound was elucidated using nuclear magnetic resonance (NMR) spectral and electron impact mass spectral (EIMS) data. The PCSK9 inhibitory activities were determined by luciferase assay. Four aaptaminoids: aaptamine, N1,N4-bisbenzylaaptamine, N4-[(3,4,5-trimethoxyl)benzyl]aaptamine, and N1-[(3,4,5-trimethoxyl)benzyl]aaptamine and one methylbenzoate derivative, N-(2,3-dihydro-1H-inden-2-yl)-2-methoxybenzamide were found to inhibit the expression of PCSK9 gene.
Key words: Aaptaminoids, benzamideindane, PCSK9, Atherosclerosis
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