Sathynathan Christina Vijayaraghavan, Raman Lakshmi Sundaram, Vajiravelu Sivamurugan, Kumar Thirumal D, Panchatcharam Thyagarajan Sadras, Narasimhan Gopinathan, Doss George C Priya, Krishnan Mary Elizabeth Gnanambal
Department of Biotechnology, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research (SRIHER), Deemed to be University (DU), Porur, Chennai, Tamil Nadu 600 116, India.
Central Research Facility (CRF), Sri Ramachandra Institute of Higher Education and Research (SRIHER), Deemed to be University (DU), Porur, Chennai, Tamil Nadu 600 116, India.
Pharmaceuticals (Basel). 2021 Mar 12;14(3):255. doi: 10.3390/ph14030255.
Though it was once known that upregulated Cannabinoid Receptor (CB1) and downregulated Fatty Acid Amide Hydrolase (FAAH1) are associated with tumour aggressiveness and metastasis, it is now clear that upregulated CB1 levels more than a certain point cause accumulation of ceramide and directs cells to apoptosis. Hence, CB1 analogues/FAAH1 blockers are explored widely as anticancer drugs. There are reports on CB1-agonists and FAAH1-blockers separately, however, dual activities along with ovarian cancer-specific links are not established for any natural compound. With this setting, we describe for the first time the isolation of 3-hydroxypropane-1,2-diyl dipalmitoleate (564.48 Da) from a marine snail, which binds to both CB1 and FAAH1 (glide energies: -70.61 and -30.52 kcal/mol, respectively). MD simulations indicate stable compound-target interaction for a minimum of 50 nanoseconds with relative invariabilities in . The compound inhibited ovarian cancer cell line, PA1 at 1.7 μM. Structural and chemical interpretation of the compound () was done using FT-IR, GC-MS, ESI-MS, H and C-NMR (1 and 2D). Furthermore, a probable route for gram-scale synthesis of is hinted herein. With the available preliminary data, molecular mechanisms involving dual roles for this potent molecule must be elucidated to understand the possibilities of usage as an anticancer drug.
尽管人们曾经知道，上调的大麻素受体（CB1）和下调的脂肪酸酰胺水解酶（FAAH1）与肿瘤侵袭性和转移有关，但现在很清楚，CB1水平上调超过一定程度会导致神经酰胺积累并引导细胞凋亡。因此，CB1类似物/FAAH1阻滞剂作为抗癌药物被广泛探索。分别有关于CB1激动剂和FAAH1阻滞剂的报道，然而，尚未确定任何天然化合物具有双重活性以及与卵巢癌的特定联系。在此背景下，我们首次描述了从一种海洋蜗牛中分离出3-羟基丙烷-1,2-二基二棕榈油酸酯（564.48道尔顿），它与CB1和FAAH1都结合（滑行能量分别为-70.61和-30.52千卡/摩尔）。分子动力学模拟表明化合物与靶点的相互作用至少在50纳秒内稳定，相关参数相对不变。该化合物在1.7微摩尔浓度下抑制卵巢癌细胞系PA1。使用傅里叶变换红外光谱、气相色谱-质谱联用、电喷雾电离质谱、氢核磁共振和碳核磁共振（一维和二维）对该化合物进行了结构和化学解析。此外，本文还暗示了一种可能的克级合成路线。根据现有的初步数据，必须阐明这种强效分子发挥双重作用的分子机制，以了解其作为抗癌药物使用的可能性。
