Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells

Abstract

Endothelial cells (ECs) are key players in inflammation and immune responses involved in numerous pathologies. Although attempts were experimentally undertaken to prevent and control EC activation, drug leads and probes still remain necessary. Natural products (NPs) from Clusiaceous and Calophyllaceous plants were previously reported as potential candidates to prevent endothelial dysfunction. The present study aimed to identify more precisely the molecular scaffolds that could limit EC activation. Here, 13 polyphenols belonging to 5 different chemical types of secondary metabolites (i.e., mammea coumarins, a biflavonoid, a pyranochromanone acid, a polyprenylated polycyclic acylphloroglucinol (PPAP) and two xanthones) were tested on resting and cytokine-activated EC cultures. Quantitative and qualitative changes in the expression of both adhesion molecules (VCAM-1, ICAM-1, E-selectin) and major histocompatibility complex (MHC) molecules have been used to measure their pharmaceutical potential. As a result, we identified 3 mammea coumarins that efficiently reduce (up to >90% at 10 μM) both basal and cytokine-regulated levels of MHC class I, class II, MICA and HLA-E on EC surface. They also prevented VCAM-1 induction upon inflammation. From a structural point of view, our results associate the loss of the free prenyl group substituting mammea coumarins with a reduced cellular cytotoxicity but also an abrogation of their anti-inflammatory potential and a reduction of their immunosuppressive effects. A PPAP, guttiferone J, also triggers a strong immunomodulation but restricted to HLA-E and MHC class II molecules. In conclusion, mammea coumarins with a free prenyl group and the PPAP guttiferone J emerge as NPs able to drastically decrease both VCAM-1 and a set of MHC molecules and to potentially reduce the immunogenicity of the endothelium.

Homoadamantane and Adamantane Acylphloroglucinols from Hypericum hirsutum

“…The molecular formulas were determined by high-resolution electrospray ionization mass spectroscopy (ESI-HRMS), and the structures were elucidated by extensive 1D and 2D NMR spectroscopy. Substances 1-14 possess a tricyclo[4.3.1.1 3,8 ]undecane skeleton, also known as homoadamantane, whereas 15-19 exhibit a tricyclo[3.3.1.1 3,7 ]decane backbone trivially known as adamantane. Both rigid and caged ring systems themselves determine the relative configurations at the chiral centers C-1, C-3, C-5, and C-8 (homoadamantane) or C-1, C-3, C-5, and C-7 (adamantane).…”

“…Two monocyclic acylphloroglucinol derivatives, 3-geranyl-1-(2-methylpropanoyl) phloroglucinol and 3-geranyl-1-(2-methylbutanoyl)phloroglucinol have been isolated from H. linarioides Bosse [20], but until Supplementary material is available under https://doi.org/10.1055/a-1617-7573 ABSTR AC T 1 H NMR-guided fractionation of the petroleum ether extract of the aerial parts from Hypericum hirsutum yielded to the isolation of 19 polyprenylated polycyclic acylphloroglucinols. Structure elucidation based on 1D and 2D NMR spectroscopy together with high-resolution electrospray ionization mass spectroscopy revealed 14 acylphloroglucinols with a homoadamantane scaffold (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), while 5 further compounds showed an adamantane skeleton (15)(16)(17)(18)(19). Except for hookerione C (15), all isolated metabolites are hitherto unknown.…”

Targeting MHC Regulation Using Polycyclic Polyprenylated Acylphloroglucinols Isolated from Garcinia bancana

“…In these experiments, cells were treated with diluent alone, GX [ 2 – 3 (4:6)], 1 or garcinol ( 4 ) in the presence of IFNγ for 18 h before cell lysis and RNA isolation. For comparison, cells were also treated with a statin (simvastatin) or with zoledronic acid (ZA), two compounds previously reported to downregulate MHC antigens [ 17 , 34 ]. For this study, we focused on the two MHC molecules involved in both innate and adaptive immunity, namely HLA-E and MICA.…”

“…In an attempt to identify novel immune-regulatory natural products (NPs), we recently reported on the ability of guttiferone J ( 1 ), a polyprenylated polycyclic acylphloroglucinol (PPAP) isolated from a Garcinia virgata herbal extract [ 16 ], to reduce inflammation as well as immunogenicity of the endothelium by inhibiting cytokine signaling pathways [ 17 ]. For a better understanding of underlying molecular mechanisms and targets, the present study reports on the isolation, identification and biological characterization of selected PPAPs, i.e., xanthochymol ( 2 ) and guttiferone F ( 3 ) from Garcinia bancana , which, by structural analogy, may have similar effects to guttiferone J ( 1 ) or garcinol ( 4 ).…”

Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols

“…A compound like Ob-C (and likely Gt-K) which targets HSPA8, could thus be useful to regulate immunity, in addition to enhancing the effects of anticancer drugs. For example, the related compound Gt-J has been found to trigger a strong immunomodulation, inducing a marked decrease of major histocompatibility complex (MHC class II) molecules on endothelial cells [ 94 ] and the related compound Gt-F has revealed also immunoregulatory activities, downregulating the expression of several MHC molecules at the surface of human primary endothelial cells upon inflammation [ 6 ]. Altogether, this information should encourage further study of the immunoregulatory effects of Ob-C and its capacity to interact with HSPA8.…”