Physachenolide C is a Potent, Selective BET Inhibitor.
作者: Christopher J Zerio ; Jared Sivinski ; E M Kithsiri Wijeratne ; Ya-Ming Xu ; Duc T Ngo ; Andrew J Ambrose ; Luis Villa-Celis ; Niloofar Ghadirian ; Michael W Clarkson ; Donna D Zhang ; Nancy C Horton ; A A Leslie Gunatilaka ; Raimund Fromme ; Eli Chapman
A pulldown using a biotinylated natural product of interest in the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2. PCC also displays characteristics of a molecular glue, facilitating proteasome-mediated degradation of BRD3 and BRD4. Finally, PCC is more potent than other withanolide analogues and gold-standard pan-BET inhibitor (+)-JQ1 in cytotoxicity assays across five prostate cancer (PC) cell lines regardless of androgen receptor (AR)-signaling status.
2022-02-04·Carbohydrate research4区 · 化学
Sucrose esters from the calyxes of Physalis chenopodifolia.
4区 · 化学
作者: Luis Barrientos ; Ana L Pérez-Castorena ; Mahinda Martínez ; Emma Maldonado
Three new sucrose esters, physachenoses A-C (1-3) and the known withanolide, physachenolide D (4), were isolated from the calyxes of Physalis chenopodifolia Lam. Analysis of the MS, 1D and 2D NMR spectra of the new compounds allowed to determine their structures as 3'-O-dodecanoyl-2,3,4-tri-O-isobutyrylsucrose (1), 3'-O-dodecanoyl-2,4-di-O-isobutyryl-3-O-2-methylbutanoylsucrose (2), and 3'-O-dodecanoyl-2-O-isobutyryl-3-O-2-methylbutanoylsucrose (3).
2022-01-28·Molecules (Basel, Switzerland)3区 · 化学
Production and Structural Diversification of Withanolides by Aeroponic Cultivation of Plants of Solanaceae: Cytotoxic and Other Withanolides from Aeroponically Grown Physalis coztomatl.
3区 · 化学
作者: Ya-Ming Xu ; E M Kithsiri Wijeratne ; Manping X Liu ; Lijiang Xuan ; Wenqiong Wang ; A A Leslie Gunatilaka
Withanolides constitute one of the most interesting classes of natural products due to their diversity of structures and biological activities. Our recent studies on withanolides obtained from plants of Solanaceae including Withania somnifera and a number of Physalis species grown under environmentally controlled aeroponic conditions suggested that this technique is a convenient, reproducible, and superior method for their production and structural diversification. Investigation of aeroponically grown Physalis coztomatl afforded 29 withanolides compared to a total of 13 obtained previously from the wild-crafted plant and included 12 new withanolides, physacoztolides I-M (9-13), 15α-acetoxy-28-hydroxyphysachenolide C (14), 28-oxophysachenolide C (15), and 28-hydroxyphysachenolide C (16), 5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (17), 15α-acetoxy-5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (18), 28-hydroxy-5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (19), physachenolide A-5-methyl ether (20), and 17 known withanolides 3-5, 8, and 21-33. The structures of 9-20 were elucidated by the analysis of their spectroscopic data and the known withanolides 3-5, 8, and 21-33 were identified by comparison of their spectroscopic data with those reported. Evaluation against a panel of prostate cancer (LNCaP, VCaP, DU-145, and PC-3) and renal carcinoma (ACHN) cell lines, and normal human foreskin fibroblast (WI-38) cells revealed that 8, 13, 15, and 17-19 had potent and selective activity for prostate cancer cell lines. Facile conversion of the 5,6-chlorohydrin 17 to its 5,6-epoxide 8 in cell culture medium used for the bioassay suggested that the cytotoxic activities observed for 17-19 may be due to in situ formation of their corresponding 5β,6β-epoxides, 8, 27, and 28.