Abstract
Matrix metalloproteinases (MMPs) are pivotal for cancer cell migration and metastasis which are generally over-expressed in such cell types. Many drugs targeting MMPs do so by binding to the conserved catalytic domains and thus exhibit poor selectivity due to domain-similarities with other proteases. We report herein the binding of a novel compound [3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl 9Z, 12Z-octadeca-9, 12-dienoate; Mol. wt: 516.67 Da], (C1), isolated from a seagrass, Cymodocea serrulata to the unconserved hemopexin-like (PEX) domain of MMP2 (− 9.258 kcal/mol). MD simulations for 25 ns, suggest stable ligand-target binding. In addition, C1 killed an ovarian cancer cell line, PA1 at IC50: 5.8 μM (lesser than Doxorubicin: 8.6 µM) and formed micronuclei, apoptotic bodies and nucleoplasmic bridges whilst causing DNA laddering, S and G2/M phase dual arrests and MMP disturbance, suggesting intrinsic apoptosis. The molecule increased mRNA transcripts of BAX and BAD and down-regulated cell survival genes, Bcl-xL, Bcl-2, MMP2 and MMP9. The chemical and structural details of C1 were deduced through FT-IR, GC–MS, ESI–MS, 1H and 13C NMR [both 1D and 2D] spectra.
Highlights
Molecules from seagrasses [Family: Hydrocharitaceae] display chemical diversity, and demonstrate bioactivities with specificities[1,2,3]
It is clear from 13C-NMR, that the ester carbonyl carbon (C1) of cinnamoyl group appeared at 171.9 ppm and the presence of phenolic –OH at C 6 and C 7 positions is shown as a broad singlet in the range of 5.37–5.40 ppm that merges with C21, C22, C24 and C25 alkenyl protons of linoleic acid
Based on the above observation, the presence of phenolic –OH groups, alkenyl protons and aromatic protons suggests the presence of 3,4-dihydroxy cinnamoyl moiety and confirms that the carbonyl group is an ester that is connected to a glycerol moiety
Summary
Molecules from seagrasses [Family: Hydrocharitaceae] display chemical diversity, and demonstrate bioactivities with specificities[1,2,3]. Among the states in India, Tamil Nadu, located in the southeast coast, has extensive seagrass meadows comprising of 7 genera and 12 species. The present investigation deals with isolation and structure elucidation of a novel lipid class of molecule from the seagrass C. serrulata, which was identified as a glyceryl ester of 3,4-dihydroxy cinnamic and linoleic acid (assigned as C1 hereafter). We understood that C1 binds to the less conserved hemopexin-like PEX domain of MMP2 with high specificities and compactness over a period of 25 ns, in silico. The study, at this juncture, provides background information on C1 to guide future research on this molecule to understand its implications on PEX-MMP2 and usage in cancer therapies.
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