Total Synthesis of Grifolin, Grifolic Acid, LL-Z1272α, LL-Z1272β, and Ilicicolinic Acid A

Grabovyi, Gennadii A.; Mohr, Justin T.

doi:10.1021/acs.orglett.6b02469

Cited by 15 publications

(18 citation statements)

References 65 publications

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“…Similarly, ∆ 6′ was deduced as 6′E as shown in Figure 2. Thus, 1 is a new derivative of the co-isolated compound, grifolin (2) [6], and named grifolin B (Figure 1). The NOESY correlations from H-2 to H 2 -4 , H 3 -12 to H 2 -5 , and no observed correlation from H-2 to H 3 -12 confirmed the geometry of ∆ 2 as 2 E. Similarly, ∆ 6 was deduced as 6 E as shown in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

Polyketides and Meroterpenes from the Marine-Derived Fungi Aspergillus unguis 158SC-067 and A. flocculosus 01NT-1.1.5 and Their Cytotoxic and Antioxidant Activities

et al. 2021

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Ten secondary metabolites, including a new grifolin analog, grifolin B (1); a new homovalencic acid derivative, 12-hydroxyhomovalencic acid (7); and a compound isolated from a natural source for the first time (9), along with seven known compounds, grifolin (2), averantin (3), 7-chloroaverantin (4), 1′-O-methylaverantin (5), 7-hydroxy-2-(2-hydroxypropyl)-5-pentylchromone (6), homovalencic acid (8), and bekeleylactone E (10), were isolated from two fungal strains. The structures of 1–10 were identified by detailed analysis and comparison of their spectroscopic data with literature values. Compounds 9 and 10 showed moderate cytotoxic activity against a panel of cancer cell lines (PC-3, HCT-15, MDA-MB-231, ACHN, NCI-H23, NUGC-3), with the GI50 values ranging from 1.1 µM to 3.6 µM, whereas 1 displayed a weak 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity without cytotoxicity against all tested cell lines.

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Section: Resultsmentioning

confidence: 99%

Polyketides and Meroterpenes from the Marine-Derived Fungi Aspergillus unguis 158SC-067 and A. flocculosus 01NT-1.1.5 and Their Cytotoxic and Antioxidant Activities

et al. 2021

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“…Grifolic acid is a farnesyl phenolic compound first isolated from the mushroom Albatrellus confluens and can be totally synthesized now [ 2 ]. It has been shown that grifolin, an analog of grifolic acid, has inhibitory effects on variety of tumor cells [ 4 , 22 – 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Some natural compounds, which are isolated from botany, fungi and marine organism, are putative candidates for antitumor drugs [ 1 ]. It is well known that grifolin, one of the natural compounds isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens [ 2 ], exhibits antitumor effects on nasopharyngeal carcinoma, osteosarcoma, and gastric tumor cells [ 3 – 5 ]. Grifolic acid (the structure in Additional file 1 ) is a derivative of grifolin, but its effects on tumor cells are not well established.…”

Section: Introductionmentioning

confidence: 99%

Grifolic acid induces GH3 adenoma cell death by inhibiting ATP production through a GPR120-independent mechanism

Zhao

Zhang

Yan

et al. 2018

BMC Pharmacol Toxicol

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BackgroundGrifolic acid is a derivative of grifolin, an antitumor natural compound, and it was reported as an agonist of free fatty acid receptor GPR120. Little is known about its antitumor effects and the involvement of GPR120.MethodsGH3 cells, the rat anterior pituitary adenoma cells, were cultured and the cell death was measured by MTT assay and Annexin V/PI staining. The mitochondrial membrane potential (MMP) of GH3 cells was measured by JC-1 staining. Cellular ATP levels and the intracellular NAD/NADH ratio were measured. GPR120 expression in GH3 cells was observed by RT-PCR and Western Blot, and siRNA was used to inhibit GPR120 expression in GH3 cells.ResultsGrifolic acid dose- and time-dependently induced the necrosis of GH3 cells. Grifolic acid significantly reduced the mitochondrial membrane potential (MMP) and decreased cellular ATP levels in GH3 cells. In contrast, the MMP of isolated mitochondria was not decreased by grifolic acid. The intracellular NAD/NADH ratio was significantly increased by grifolic acid. GPR120 is expressed in GH3 cells, but GPR120 agonists such as EPA, GW9508 and TUG891 did not affect the viability of GH3 cells. Moreover, GPR120 siRNA knockdown showed no significant influence on grifolic acid-induced GH3 cell death.ConclusionGrifolic acid induces GH3 cell death by decreasing MMP and inhibiting ATP production, which may be due to the inhibition of NADH production through a GPR120-independent mechanism.Electronic supplementary materialThe online version of this article (10.1186/s40360-018-0215-4) contains supplementary material, which is available to authorized users.

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“…Diversifiable route to polysubstituted phenolic compounds: Grabovyi and Mohr (2016), West et al (2017, 2018)…”

Section: Structure‐aided Inhibitor Designmentioning

confidence: 99%

“…Grabovyi and Mohr discovered an alternative toward the total synthesis of polysubstituted phenolic natural products featuring terpenoid side chains (Scheme ). This pathway, in which the phenolic head group is introduced early in the synthesis, is advantageous because it uses accessible protecting groups (eg, methoxymethyl, tert‐butyloxycarbonyl, and tert‐butyldimethylsilyl) that are easily cleaved using HCl, ZnBr, and TBAF, respectively, and it allows the gram scale synthesis of the products in high overall yields (>50%).…”

Section: Structure‐aided Inhibitor Designmentioning

confidence: 99%

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Ebiloma

Balogun

Cueto-Díaz

et al. 2019

Medicinal Research Reviews

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The alternative oxidase (AOX) is a ubiquitous terminal oxidase of plants and many fungi, catalyzing the four‐electron reduction of oxygen to water alongside the cytochrome‐based electron transfer chain. Unlike the classical electron transfer chain, however, the activity of AOX does not generate adenosine triphosphate but has functions such as thermogenesis and stress response. As it lacks a mammalian counterpart, it has been investigated intensely in pathogenic fungi. However, it is in African trypanosomes, which lack cytochrome‐based respiration in their infective stages, that trypanosome alternative oxidase (TAO) plays the central and essential role in their energy metabolism. TAO was validated as a drug target decades ago and among the first inhibitors to be identified was salicylhydroxamic acid (SHAM), which produced the expected trypanocidal effects, especially when potentiated by coadministration with glycerol to inhibit anaerobic energy metabolism as well. However, the efficacy of this combination was too low to be of practical clinical use. The antibiotic ascofuranone (AF) proved a much stronger TAO inhibitor and was able to cure Trypanosoma vivax infections in mice without glycerol and at much lower doses, providing an important proof of concept milestone. Systematic efforts to improve the SHAM and AF scaffolds, aided with the elucidation of the TAO crystal structure, provided detailed structure‐activity relationship information and reinvigorated the drug discovery effort. Recently, the coupling of mitochondrion‐targeting lipophilic cations to TAO inhibitors has dramatically improved drug targeting and trypanocidal activity while retaining target protein potency. These developments appear to have finally signposted the way to preclinical development of TAO inhibitors.

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Total Synthesis of Grifolin, Grifolic Acid, LL-Z1272α, LL-Z1272β, and Ilicicolinic Acid A

Cited by 15 publications

References 65 publications

Polyketides and Meroterpenes from the Marine-Derived Fungi Aspergillus unguis 158SC-067 and A. flocculosus 01NT-1.1.5 and Their Cytotoxic and Antioxidant Activities

Polyketides and Meroterpenes from the Marine-Derived Fungi Aspergillus unguis 158SC-067 and A. flocculosus 01NT-1.1.5 and Their Cytotoxic and Antioxidant Activities

Grifolic acid induces GH3 adenoma cell death by inhibiting ATP production through a GPR120-independent mechanism

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

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