Cistadesertosides B-E, Four New Diastereomeric Lignan Glycosides from the Stems of Cultural Cistanche deserticola in Tarim Desert.

Four previously undescribed diastereomeric lignan glycosides, namely cistadesertosides B-E (1-4) were isolated from the stems of cultural Cistanche deserticola in Tarim desert. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including IR, HR-ESI-MS, 1D and 2D NMR, circular dichroism (CD) data and chemical degradation. The in vitro anti-inflammatory activity of the isolates was also investigated. It showed that compounds 3 and 4 exhibited potential effects with IC50 values of 21.17 µM and 26.97 µM, respectively (positive control quercetin, IC50 , 10.01 µM).

Benzylisoquinoline alkaloids with their antitumor activity from the aerial parts of Corydalis impatiens (pall.) Fisch.

Phytochemical investigation on the aerial parts of Corydalis impatiens (pall.) Fisch (Papaveraceae) resulted in the identification of four previous undescribed benzylisoquinoline alkaloids, impatienines A-D (1-4), together with 14 known analogues (5-18). The structures of these compounds were elucidated by extensive spectroscopic analysis (IR, HR-ESIMS, 1D- and 2D-NMR) as well as ECD calculations. All the compounds obtained were investigated for their inhibitory effect on the growth of A549, H1299 and HepG2 cancer cells. Compounds 7 and 15 exhibited pronounced inhibition against the A549 cancer cells with IC50 values of 6.81 µM and 3.17 µM, while the positive control cisplatin was 1.83 µM. Compounds 1-3 showed moderate inhibitory on the H1299 cancer cells. Compounds 4, 10-12, and 16 showed signiffcant activity against HepG2 cancer cells with IC50 values range of 4.41-8.75 µM.

Nitrogenous chemical constituents and their antitumor activities evaluation in vitro from the aerial parts of Corydalis impatiens (pall.) Fisch.

Four new compounds, impatienines E-H (1-4), together with 18 known ones (R)-N-methylcoclaurine (5), impatienine I (6), thalifoline (7), iseluxine (8), pisoquinoline (9), corydaldine (10), northalifoline (11), noroxyhydrastinine (12), 6,7-methylenedioxy-1(2H)-isoquinolinone (13), N-methylcorydaldine (14), oxyhydrastinine (15), corypalline (16), N-trans-feruloylmethoxytyramine (17), N-trans-feruloyldopamine (18), N-trans-feruloyltyramine (19), N-trans-sinapoyltyramine (20), N-cis-feruloyltyramine (21), N-cis-sinapoyltyramine (22) were obtained from the aerial parts of Corydalis impatiens (pall.) Fisch. Their structures were elucidated by extensive spectroscopic analysis (1D- and 2D-NMR, HR-ESIMS, IR, UV) and/or comparison with reported literature. The inhibitory effects of these isolates were also evaluated against the growth of cancer cells (A549, H1299 and HepG2). Compounds 2 and 4 showed significant inhibitory effect on HepG2 cancer cells with IC50 values of 8.62, 8.32 µM, respectively (positive control cisplatin: IC50, 6.32 µM). Compounds 22 and 4 exhibited moderate inhibitory effects against A549 cancer cells, and the IC50 values were 7.78 and 12.54 µM, respectively (positive control cisplatin: IC50, 1.83 µM).

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed. Here, a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs. A series of functional assays showed that desloratadine, an antiallergic drug, can repress proliferation in HCC cell lines, cell-derived xenograft (CDX), patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. N-myristoyl transferase 1 (NMT1) was identified as a target protein of desloratadine by drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) assays. Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo. Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3 (VILIP3) was a new substrate of NMT1 in protein N-myristoylation modification, and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC. Mechanistically, desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity, disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling. Conclusively, this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner.

Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.