Dammarane Triterpenes as Potential SIRT1 Activators from the Leaves of Panax ginseng

Abstract

During a search for SIRT1 activators originating in nature, three new dammarane triterpenes, 6α,20(S)-dihydroxydammar-3,12-dione-24-ene (1), 6α,20(S),24(S)-trihydroxydammar-3,12-dione-25-ene (2), and 6α,20(S),25-trihydroxydammar-3,12-dione-23-ene (3), as well as two known triterpenes, dammar-20(22),24-diene-3β,6α,12β-triol (4) and 20(S)-ginsenoside Rg3 (5), were isolated from Panax ginseng leaves. Compounds 1 and 3-5 showed potential as SIRT1 activators, as analyzed by in vitro enzyme-based SIRT1-NAD/NADH and SIRT1-p53 luciferase cell-based assays. They were also found to increase the level of NAD(+)/NADH ratio in HEK293 cells. This study presents a new class of chemical entities that may be able to be developed as SIRT1 activators for antiaging and treatment of age-associated diseases.

Synthesis and Assay of SIRT1-Activating Compounds

“…While thesecompounds comprise diverse structural scaffolds, including flavones, stilbenes, chalcones (Howitz et al, 2003), coumarins (Dao et al, 2012), and triterpenes (Yang et al, 2014), they all appear to activate SIRT1 through a common peptide K m -lowering mechanism (Hubbard & Sinclair, 2014). In addition to natural product SIRT1 activators, Sirtris Pharmaceutics (GSK) has described the development of an expanding collection of synthetic SIRT1 activators with EC 50 values in the n M range (hundreds of times more potent natural compounds) over the past 10 years (Dai et al, 2015, 2010; Hubbard, Gomes, et al, 2013; Milne et al, 2007).…”

Four new ginsenosides from red ginseng with inhibitory activity on melanogenesis in melanoma cells

“…14,15 Recently, the oral administration of red ginseng powder was found to be an effective treatment for patients with melasma. 16 Here, four new ginsenosides, including three dammarane-type triterpenoid saponins, 20(S)-ginsenoside-Rf-1a (1), 20Z-ginsenosideRs 4 (2), 23-O-methylginsenoside-Rg 11 (3), and one oleanane-type saponin, ginsenoside-Ro-6 0 -O-butyl ester (4) were isolated from red ginseng (the steamed ginseng). We examined whether these novel ginsenosides had protective effects against melanogenesis in the a-MSH-stimulated B16 melanoma cells.…”

“…During a search for novel melanogenesis inhibitors originating from nature sources, four new ginsenosides, including three dammarane-type triterpenoid saponins, 20(S)-ginsenoside-Rf-1a (1), 20Z-ginsenoside-Rs 4 (2), 23-O-methylginsenoside-Rg 11 (3), and one oleanane-type saponin, ginsenoside-Ro-6 0 -O-butyl ester (4) were isolated from red ginseng (the steamed ginseng) to evaluate their protective effects against melanogenesis. Compounds 2 and 3 exhibited potent inhibitory effects against both melanin synthesis and tyrosinase activity in a dose-dependent manner in the a-MSH-stimulated B16 melanoma cells, and were more potent than the positive control arbutin, a well-known tyrosinase inhibitor.…”

“…It possesses various biological effects including anticancer, antitumor, antioxidative, antiaging, neurovascular modulatory and other activities. [1][2][3] Red ginseng, as one of the most common commercial ginseng, is manufactured by steaming the raw ginseng. This steaming process may lead to significant variations in the chemical constituents especially for ginsenosides which are considered to be the principal active components in ginseng.…”

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

“…We hold it is beyond the limited scope of our brief therapeutic perspectives on curcumin to review all the previous studies on nutraceuticals in schizophrenia, let alone all the other psychiatric disorders as entered in the Diagnostic Statistical Manual DSM-V for psychiatric disorders. It is perhaps fortuitous that the majority of phytochemicals: omega 3-fatty acids, vitamin D, B vitamins (B6, folate, B12), vitamin E, and carotenoids in different stages of schizophrenia exert beneficial effects in schizophrenia [81,82]. The results are it is perhaps fortuitous that the nutraceuticals exert anti-inflammatory and antioxidant effects via hitting epigenetics targets similar, albeit non-identical, to curcumin: DNA methyltransferase (DNMT), as well as Histone Acetyl-Transferase (HAT) and HDAC activities [83].…”