3-Hydroxypropane-1,2-Diyl Dipalmitoleate—A Natural Compound with Dual Roles (CB1 Agonist/FAAH1 Blocker) in Inhibiting Ovarian Cancer Cell Line

Abstract

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, Conus inscriptus, 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 Rg. The compound inhibited ovarian cancer cell line, PA1 at 1.7 μM. Structural and chemical interpretation of the compound (C2) was done using FT-IR, GC-MS, ESI-MS, 1H and 13C-NMR (1 and 2D). Furthermore, a probable route for gram-scale synthesis of C2 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.

A Novel Non-Psychoactive Fatty Acid from a Marine Snail, Conus inscriptus, Signals Cannabinoid Receptor 1 (CB1) to Accumulate Apoptotic C16:0 and C18:0 Ceramides in Teratocarcinoma Cell Line PA1

“…In this paper, we report, for the first time, a marine natural compound which is a non-psychoactive fatty acid, bis(palmitoleic acid) ester of a glycerol (C2), obtained from the deep water sea snail Conus inscriptus that possesses anticancer properties. We previously reported the effect of this compound on ovarian cancer cells and using computational analysis we indicated that the compound binds to the CB1 receptor at micromolar levels [18]. Alongside binding to CB1, treatment with C2 also enhanced CB1 mRNA transcripts as well as protein expression in an ovarian cancer cell line, PA1.…”

Computational evaluation of potential ACE1 inhibitors from selected antihypertensive plants

“…A lower energy gap between the HOMO and LUMO implies high chemical reactivity, polarizability and bioactivity with a higher gap implying the opposite. This is because a wider energy gap negatively affects the electron's movement in the FMOs, which subsequently leads to a weak a nity between the ligand and the target (Sathynathan et al 2021). Hence, a smaller gap is usually preferred.…”