First Total Synthesis of Protoapigenone and Its Analogues as Potent Cytotoxic Agents

Lin, An Shen; Nakagawa‐Goto, Kyoko; Chang, Fang Rong; Yu, Donglei; Morris‐Natschke, Susan L.; Wu, Chin Chung; Chen, Shu Li; Wu, Yang Chang; Lee, Kuo Hsiung̀

doi:10.1021/jm070363a

Cited by 56 publications

(49 citation statements)

References 17 publications

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“…The initial attempt to synthesize protected tricin proceeded through the cyclization of chalcone 5 to provide the flavanone by first refluxing in ethanol with sodium acetate, followed by several attempts at oxidative dehydrogenation using a variety of reagents; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (Shanker et al, 1983), manganese (III) acetate (Singh et al, 2005), and copper (II) acetate were all tried without success. Successful cyclization of chalcone 5 used a molar equivalent of I 2 in pyridine (Lin et al, 2007). Acetylation of the crude products (not shown in Fig.…”

Section: Synthesis Of Tricin-monolignol Cross-coupled Oligomersmentioning

confidence: 99%

Tricin, a Flavonoid Monomer in Monocot Lignification

et al. 2015

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Tricin was recently discovered in lignin preparations from wheat (Triticum aestivum) straw and subsequently in all monocot samples examined. To provide proof that tricin is involved in lignification and establish the mechanism by which it incorporates into the lignin polymer, the 49-Ob-coupling products of tricin with the monolignols (p-coumaryl, coniferyl, and sinapyl alcohols) were synthesized along with the trimer that would result from its 49-O-b-coupling with sinapyl alcohol and then coniferyl alcohol. Tricin was also found to cross couple with monolignols to form tricin-(49-O-b)-linked dimers in biomimetic oxidations using peroxidase/hydrogen peroxide or silver (I) oxide. Nuclear magnetic resonance characterization of gel permeation chromatography-fractionated acetylated maize (Zea mays) lignin revealed that the tricin moieties are found in even the highest molecular weight fractions, ether linked to lignin units, demonstrating that tricin is indeed incorporated into the lignin polymer. These findings suggest that tricin is fully compatible with lignification reactions, is an authentic lignin monomer, and, because it can only start a lignin chain, functions as a nucleation site for lignification in monocots. This initiation role helps resolve a long-standing dilemma that monocot lignin chains do not appear to be initiated by monolignol homodehydrodimerization as they are in dicots that have similar syringyl-guaiacyl compositions. The term flavonolignin is recommended for the racemic oligomers and polymers of monolignols that start from tricin (or incorporate other flavonoids) in the cell wall, in analogy with the existing term flavonolignan that is used for the lowmolecular mass compounds composed of flavonoid and lignan moieties.Lignin, a complex phenylpropanoid polymer in the plant cell wall, is predominantly deposited in the cell walls of secondary-thickened cells (Vanholme et al., 2010). It is synthesized via oxidative radical coupling reactions from three prototypical monolignols, p-coumaryl, coniferyl, and sinapyl alcohols, differentiated by their degree of methoxylation ortho to the phenolic hydroxyl group. Considered within the context of the entire polymer, the main structural features of lignin can be defined in terms of its p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) units, derived respectively from these three monolignols (Ralph, 2010). Several novel monomers, all deriving from the monolignol biosynthetic pathway, have been found to incorporate into lignin in wild-type and transgenic plants. For example, monolignol acetate, p-hydroxybenzoate, and p-coumarate ester conjugates have all been shown to incorporate into lignin polymers and are the source of naturally acylated lignins (Ralph et al., 2004;Lu and Ralph, 2008); lignins derived solely from caffeyl alcohol were found in the seed coats of both monocot and dicot plants (Chen et al., 2012a(Chen et al., , 2012b; lignins derived solely from 5-hydroxyconiferyl alcohol were found in a cactus (for example, in a member of the genera Astrop...

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Section: Synthesis Of Tricin-monolignol Cross-coupled Oligomersmentioning

confidence: 99%

Tricin, a Flavonoid Monomer in Monocot Lignification

et al. 2015

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“…For UV irradiation treatment, the cells were irradiated for 10 J/m 2 by a crosslinker (UVP CL-1000) 1 hour before analysis. WYC02 and WYC0209 were isolated and synthesized as described previously (15)(16)(17).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…1A) is a flavonoid that we previously isolated and identified from the whole plant extract of Thelypteris torresiana, a fern species native to Taiwan. This compound was originally screened for cytotoxicity function; using a colorimetric cytotoxicity assay, WYC02 showed therapeutic effects and was a lead compound for potential anticancer drug development (15)(16)(17). In previous studies, WYC02 and its more potent analog WYC0209 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

Wang

Lee

Chou

et al. 2012

Molecular Cancer Therapeutics

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DNA damage caused during cancer treatment can rapidly activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR)-dependent phosphorylation of Chk2 and Chk1 kinases, which are hallmarks of the DNA damage response (DDR). Pharmacologic inhibition of ATR causes a synthetic lethal effect on ATMor p53-defective cancers, suggesting that such inhibition is an effective way to improve the sensitivity of cancers to DNA-damaging agents. Here, both the natural compound protoapigenone (WYC02) and its synthetic derivative WYC0209 exhibited cytotoxic effects on various cancer cell lines. WYC02 causes chromosomal aberration in the mitotic spreads of Chinese hamster ovary cells. Interestingly, cancer cells did not exhibit typical DDR markers upon exposure to WYC02 and WYC0209 (WYCs). Further investigation into the molecular mechanisms of WYCs function revealed that they have a potential ability to inhibit DDR, particularly on activation of Chk1 and Fanconi anemia group D2 protein (FANCD2), but not Chk2. In this way, WYCs inhibited ATR-mediated DNA damage checkpoint and repair. Furthermore, when combined with the DNA cross-linking agent cisplatin, treatment with WYCs resulted in increased tumor sensitivity to interstrand crosslink-generating agents both in vitro and in vivo. Our results therefore especially implicate WYCs in enhancing tumor chemosensitivity when the ATR checkpoint is constitutively active in states of oncogene-driven replicative stress or tolerance to DNA-interfering agents.

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“…8,9) A commonly used methods for preparation of p-quinols is 4-substituted phenol oxidation. Among many reported oxidants for the oxidation of phenols, [10][11][12][13][14][15][16][17] hypervalent iodine(III) oxidants such as phenyliodine(III) diacetate (PIDA) and phenyliodine(III) trifluoroacetate (PIFA) are typically used [18][19][20][21] because of the non-toxic nature of hypervalent iodine(III) reagents and the method's simplicity. [22][23][24][25][26] However, this approach often gives low yields of the desired product because of competitive oligomerization, especially in the case of oxidation of 4-arylphenols.…”

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confidence: 99%

“…In contrast to the oxidation of 4-alkylphenols with stoichiometric trivalent iodine compound to yield p-quinols, [18][19][20][21] oxidation by pentavalent iodines usually takes place at the ortho position of the phenols. Ranganathan and co-workers described that N-benzoyltyrosine methyl ester was reacted with 4-tert-butyliodylbenzene in refluxing toluene to give the corresponding o-quinone in 30% yield.…”

mentioning

confidence: 99%