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Total Synthesis of Gramistilbenoids A, B, and C
Harmalkar, Dipesh S.,Lu, Qili,Lee, Kyeong American Chemical Society and American Society of 2018 Journal of natural products Vol.81 No.4
<P>Stilbenes are biologically active metabolites of plants that have the potential to attenuate a broad range of human diseases. Gramistilbenoids are a class of natural products with a stilbene skeleton, isolated from the bamboo orchid (<I>Arundina graminifolia</I>), and with significant cytotoxicity against cancer cell lines (NB4, A549, SHSY5Y, PC3, and MCF7). These are the first identified naturally occurring diphenylethylenes to possess a hydroxyethyl unit. However, some of these compounds are not abundant in nature, and thus, their synthesis is advantageous. This paper reports the first synthesis of gramistilbenoids A (<B>1</B>), B (<B>2</B>), and C (<B>3</B>), with overall yields of 10, 2, and 8% respectively. These natural products were synthesized using key reactions, such as Horner-Wadsworth-Emmons olefination, Stille coupling, and hydroboration-oxidation.</P> [FIG OMISSION]</BR>
Sivaraman, Aneesh,Harmalkar, Dipesh S.,Kang, Jiyoon,Choi, Yongseok,Lee, Kyeong The Royal Society of Chemistry 2019 Organic & Biomolecular Chemistry Vol.17 No.8
<P>2-Bromo-6-hydroxybenzofurans are potentially versatile intermediates for the divergent synthesis of numerous benzofuran-based natural products and their analogues. Herein we report the first one-pot strategy for the efficient synthesis of 2-bromo-6-hydroxybenzofurans. The present protocol provides shorter routes for the synthesis of moracins M, N, O and P; gramniphenols F and G; and morunigrol C using a protecting group-free approach.</P>
Vinyl-Stilbene Inhibits Human Norovirus RNA Replication by Activating Heat-Shock Factor-1
( Ahrim Lee ),( Jieun Sung ),( Dipesh S. Harmalkar ),( Hyeseul Kang ),( Hwayoung Lee ),( Kyeong Lee ),( Choongho Lee ) 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.1
Norovirus (NV) is the most common cause of viral gastroenteritis, with the potential to develop into a fatal disease in those who are immuno-compromised, and effective vaccines and treatments are still non-existent. In this study, we aimed to elucidate the molecular mechanism of the previously identified NV replication inhibitor utilizing a vinyl-stilbene backbone, AC-1858. First, we confirmed the inhibition of the NV RNA replication by a structural analog of AC-1858, AC-2288 with its exclusive cytoplasmic subcellular localization. We further validated the induction of one specific host factor, the phosphorylated form of heat shock factor (HSF)-1, and its increased nuclear localization by AC-1858 treatment. Finally, we verified the positive and negative impact of the siRNA-mediated downregulation and lentivirus-mediated overexpression of HSF-1 on NV RNA replication. In conclusion, these data suggest the restrictive role of the host factor HSF-1 in overall viral RNA genome replication during the NV life cycle.
Naik, Ravi,Ban, Hyun Seung,Jang, Kyusic,Kim, Inhyub,Xu, Xuezhen,Harmalkar, Dipesh,Shin, Seong-Ah,Kim, Minkyoung,Kim, Bo-Kyung,Park, Jaehyung,Ku, Bonsu,Oh, Sujin,Won, Misun,Lee, Kyeong American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.20
<P>Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure–activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (<B>16c</B>) as the most potent dual inhibitor. Kinetic studies revealed that compound <B>16c</B> competitively inhibited MDH1 and MDH2. Compound <B>16c</B> inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound <B>16c</B> demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2017/jmcmar.2017.60.issue-20/acs.jmedchem.7b01231/production/images/medium/jm-2017-01231h_0018.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b01231'>ACS Electronic Supporting Info</A></P>