Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search.

SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 µM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 µM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 µM), Jurkat (IC50 = 2.2 µM), THP1 (IC50 = 3.5 µM), U937 (IC50 = 3.9 µM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.

Plantadeprate A, a Tricyclic Monoterpene Zwitterionic Guanidium, and Related Derivatives from the Seeds of Plantago depressa.

Two new alkaloids, plantadeprate A (1) and 1'-(4″-hydroxybutyl)plantagoguanidinic acid (2), along with three known compounds, were isolated from the seeds of Plantago depressa. Their structures were elucidated by physical data analyses including NMR, MS, and electronic circular dichroism (ECD) methods. Plantadeprate A (1), a monoterpene zwitterionic guanidium, possesses a unique 5/5/6-tricyclic ring system. Its absolute configuration was determined by X-ray crystallography and computational methods. Compound 1, plumbagine D (3), and plantagoguanidinic acid (4) exhibited potential antihyperglycemic properties attributed to suppression of hepatic gluconeogenesis with inhibitory rates of 8.2%, 18.5%, and 12.5% at 40 µM, respectively.

PTP1B inhibitors from stems of Angelica keiskei (Ashitaba).

Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Mosher's method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53µg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.