Total Synthesis of Gramistilbenoids A, B, and C

Harmalkar, Dipesh S.; Lu, Qili; Lee, Kyeong

doi:10.1021/acs.jnatprod.7b00865

Cited by 8 publications

(9 citation statements)

References 43 publications

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“…On the basis of our retrosynthetic analysis, our synthesis started with regioselective protection of the hydroxy groups of commercially available 2′,4′,6′-trihydroxyacetophenone (5) by treatment with methoxymethyl chloride (MOMCl) and N,Ndiisopropylethylamine (DIPEA) in dry dichloromethane (DCM) to give compound 6 in 90% yield. 18 O-Prenylation of compound 6 K 2 CO 3 as the base gave intermediate 7, which underwent microwave-assisted para-Claisen rearrangement to produce compound 8 in 89% yield. The selective deprotection of compound 8 under acidic conditions (2 N HCl) afforded mono-MOM-protected compound 9.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Total Synthesis of the Neuroprotective Agent Cudraisoflavone J

Harmalkar

Quan

et al. 2021

J. Nat. Prod.

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Cudraisoflavone J (1), isolated from Cudrania tricuspidata, is a potent neuroprotective compound with a chiral center. Herein, we report the first total synthesis of racemic cudraisoflavone J (1) using a Claisen rearrangement and a Suzuki coupling reaction as the key steps. Racemic secondary alcohol was kinetically resolved to give (+)-and (−)-cudraisoflavone J with up to 97 and 88% enantiomeric excess, respectively. The modified Mosher's method was used to elucidate the absolute configuration of naturally occurring cudraisoflavone J.Cudrania tricuspidata (Carr.) Bur. ex Lavallee, which is a perennial plant of the family Moraceae, is widely used in east Asia as a traditional medicine or health supplement. 1 In China, C. tricuspidata has been used in the treatment of eczema, mumps, tuberculosis, contusions, and acute arthritis since ancient times. 2 In Korea, its edible fruits have been made into juices, jams, alcoholic beverages, dietary supplements, and other health products. 3,4 The immense medicinal and economic value of C. tricuspidata has encouraged numerous studies of its phytochemical and pharmacological activities. 5−7 Flavonoids, including flavones, flavanones, and isoflavones, are considered to be the major bioactive constituents of C. tricuspidata, exhibiting notable anti-inflammatory, 8,9 antioxidative, 10 antitumor, 11 hepatoprotective, 12 neuroprotective, 13,14 and antiobesity 15,16 effects. In 2015, Lee and co-workers isolated a group of isoflavones from the fresh fruits of C. tricuspidata and found that they featured 3-hydroxy-2,2dimethyldihydropyran groups substituted on their aromatic rings, as shown in Figure 1. Among these, cudraisoflavone J had the most potent activity against 6-hydroxydopamine (6-OHDA)-induced cell death in human neuroblastoma SH-SY5Y cells, with an EC 50 value of 0.5 μM. 17 This suggested that cudraisoflavone J could be considered a candidate for further research into using it for therapeutic purposes to treat neurodegenerative diseases, such as Parkinson's disease. To the best of our knowledge, neither the total synthesis nor the

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Section: ■ Results and Discussionmentioning

confidence: 99%

Total Synthesis of the Neuroprotective Agent Cudraisoflavone J

Harmalkar

Quan

et al. 2021

J. Nat. Prod.

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“…After 24 h, the cells were incubated with serum-free media containing each compound obtained from the in-house synthesized 1697 chemical diversity library (Dongguk Univ.) and a commercial 1,102 chemical library (Selleckchem) for 4 h. The in-house library contains synthesized chemicals composed of diverse chemotypes, including phenylthiophene, biphenyl 78 , benzofuran 79 – 82 , stilbenes 83 , 84 , aryloxyacetamide 85 – 94 , and sulfonamide 27 , 95 . After incubation, luciferase activity was detected using the nanoluciferase assay system following the manufacturer’s protocol (Promega).…”

Section: Methodsmentioning

confidence: 99%

AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis

et al. 2022

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Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.

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“…Stilbenoids are widely found in plant varieties such as grapes, peanuts, sorghum, berries and spruce. [5] Due to their extensive physiological functions such as anti-cancer, antioxidation and hypolipidemic, they have received extensive attention. [6] Studies have shown that stilbenoid-maternal structure can intercept ultraviolet efficiently.…”

Section: Introductionmentioning

confidence: 99%

Ultrafast Nonadiabatic Photoisomerization Dynamics Mechanism for the UV Photoprotection of Stilbenoids in Grape Skin

Shi

Zhao

Wang

et al. 2020

Chemistry An Asian Journal

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Natural UV photoprotection plays a vital role in physiological protection. It has been reported that UVC radiation can make resveratrol (RSV) and piceatannol (PIC) accumulate in grape skin. In this work, we demonstrated that RSV and PIC could significantly absorb UVA and UVB, and confirmed their satisfactory photostability. Furthermore, we clarified the UV photoprotection mechanism of typical stilbenoids of RSV and PIC for the first time by using combined femtosecond transient absorption (FTA) spectroscopy and time-dependent density functional theory (TD-DFT) calculations. RSV and PIC can be photoexcited to the excited state after UVA and UVB absorption. Subsequently, the photoisomerized RSV and PIC quickly relax to the ground state via nonadiabatic transition from the S 1 state at a conical intersection (CI) position between potential energy surfaces (PESs) of S 1 and S 0 states. This ultrafast trans-cis photoisomerization will take place within a few tens of picoseconds. As a result, the UV energy absorbed by RSV and PIC could be dissipated by an ultrafast nonadiabatic photoisomerization process.

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Total Synthesis of Gramistilbenoids A, B, and C

Cited by 8 publications

References 43 publications

Total Synthesis of the Neuroprotective Agent Cudraisoflavone J

Total Synthesis of the Neuroprotective Agent Cudraisoflavone J

AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis

Ultrafast Nonadiabatic Photoisomerization Dynamics Mechanism for the UV Photoprotection of Stilbenoids in Grape Skin

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