Mangrove Tirucallane- and Apotirucallane-Type Triterpenoids: Structure Diversity of the C-17 Side-Chain and Natural Agonists of Human Farnesoid/Pregnane–X–Receptor

Abstract

Ten new triterpenoid compounds with structure diversity of the C-17 side-chain, including nine tirucallanes, named xylocarpols A–E (1–5) and agallochols A–D (6–9), and an apotirucallane, named 25-dehydroxy protoxylogranatin B (10), were isolated from the mangrove plants Xylocarpus granatum, Xylocarpus moluccensis, and Excoecaria agallocha. The structures of these compounds were established by HR-ESIMS and extensive one-dimensional (1D) and two-dimensional (2D) NMR investigations. The absolute configurations of 1 and 2 were unequivocally determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation; whereas those of 4, 6–8 were assigned by a modified Mosher’s method and the comparison of experimental electronic circular dichroism (ECD) spectra. Most notably, 5, 6, 7, and 9 displayed potent activation effects on farnesoid–X–receptor (FXR) at the concentration of 10.0 μM; 10 exhibited very significant agonistic effects on pregnane–X–receptor (PXR) at the concentration of 10.0 nM.

Chemistry and Biology of Novel Meliaceae Limonoids

“…Aphagranin F (9) is the C25 ethoxy analog of Piscidinol A reported previously 44 . Xylocarpol C (11) differed from previously reported xylocarpol B 47 at C24 hydroxylation and C20 configuration. Aphagranin E ( 12) is a C25 methoxy analog of compound (11).…”

“…Compounds (1501, 1502) were inactive for in vitro H 2 O 2 -induced injury in SH-SY5Y cell damage 482 . At 10 nM, compounds (76, 842) exhibited significant agonistic effect on human pregnane-X-receptor (PXR) to modulate PXR target gene CYP3A4 trans activation in HePG2 cells than positive control rifampicin 47,153 whereas compound (1220) showed activation effect. Compounds (833, 774, 549) showed strong inhibitory activities against human carboxylesterase2 (hCES2) with IC 50 values of 6.63, 11.35 and 5.05 μM, respectively 153 366 .…”

Chemistry and Biology of Novel Meliaceae Limonoids

“…Aphagranin F (9) is the C25 ethoxy analog of Piscidinol A reported previously 44 . Xylocarpol C (11) differed from previously reported xylocarpol B 47 at C24 hydroxylation and C20 configuration. Aphagranin E (12) is a C25 methoxy analog of compound (11).…”

Natural Products Targeting Liver X Receptors or Farnesoid X Receptor

“…Four tirucallanes xylocarpols E (173), agallochols A (174), B (175), and D (176) isolated from mangrove plants, activated FXR at the concentration of 10.0 µM in a luciferase reporter assay in HepG2 cells ( Jiang et al, 2018 ). Dioscoreae rhizome , also known as “Shaoyao,” acts as either a food or a traditional medicine because of its protectivity of the kidneys and liver.…”