ABSTRACT
Tetracyclic triterpenes and steroids are pharmacologically important molecules, and acetylation could improve their bioactivities. In this study, a highly regio- and stereo-specific acetyltransferase, AmAT19, was discovered from Astragalus membranaceus. AmAT19 could selectively catalyze the 6α-OH acetylation of four tetracyclic triterpenes and steroids. The strict selectivity is associated with different orientations of the 6α/ß-OH as indicated by molecular docking. Acetylated products 1a, 3a and 4a remarkably increased the inhibitory activity against the 3-chymotrypsin-like protease (3CLpro) of SARS-CoV-2, compared to 1, 3, and 4. AmAT19 could be a promising catalyst for specific 6α-OH acetylation to expand the molecular diversity of triterpenes and steroids.
Subject(s)
Acetyltransferases/metabolism , Astragalus Plant/enzymology , Steroids/metabolism , Triterpenes/metabolism , Acetylation , CatalysisABSTRACT
Huang-Qi (Astragali Radix) is an herbal tonic widely used in China and many other countries. It is derived from the roots of Astragalus membranaceus and A. membranaceus var. mongholicus and shows potent cardiovascular protective effects. In this article, we comprehensively reviewed 189 small molecules isolated from the two Astragalus species and discussed the interspecies chemical differences. Moreover, we summarized the pharmacological activities and mechanisms of action of Huang-Qi and its major bioactive compounds for the treatment of cardiovascular diseases. This review covers 171 references published between February 1983 and March 2020.
Subject(s)
Astragalus Plant , Astragalus propinquus , China , Humans , Plant RootsABSTRACT
A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (-)-fusaspoid A (1a/1b) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.
Subject(s)
Aquatic Organisms/chemistry , Fusarium/chemistry , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Antineoplastic Agents/pharmacology , Carbon-13 Magnetic Resonance Spectroscopy , Cell Death/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indole Alkaloids/pharmacology , Models, Molecular , Proton Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
To investigate the influence of reactive oxygen species (ROS) on the secondary metabolites of the marine-derived fungus Dichotomomyces cejpii F31-1, hydrogen peroxide (H2O2) was added to the GPY culture medium. The HPLC chromatogram of the EtOAc extract of the culture broth was distinct from that of the H2O2 free GPY medium. Further study of the metabolites in the GPY medium with H2O2 resulted in the discovery of eight known compounds. Among them, (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were present in the highest concentration, while ergosterol and diketopiperazines are abundant in the H2O2 free medium. Additionally, a new compound, dichocetide D (1) containing a chlorine element and a known ergosterol (10) were isolated from the H2O2 free medium. (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) exhibited moderate cytotoxic activity against human prostate cancer cell line LNCaP-C4-2B.
Subject(s)
Antineoplastic Agents/pharmacology , Aspergillus/metabolism , Reactive Oxygen Species/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Aspergillus/drug effects , Culture Media/chemistry , Diketopiperazines/metabolism , Drug Screening Assays, Antitumor , Ergosterol/isolation & purification , Ergosterol/metabolism , Ergosterol/pharmacology , Humans , Hydrogen Peroxide/pharmacology , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Male , Melanoma/drug therapy , Mice , Molecular Structure , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Quinazolines/chemistry , Quinazolines/metabolism , Quinazolines/pharmacology , Secondary MetabolismABSTRACT
Eight previously undescribed diterpenoids, euphoroyleans A-H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A-H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 µM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking.
Subject(s)
Diterpenes , Euphorbia , ATP Binding Cassette Transporter, Subfamily B , Drug Resistance, Multiple , Molecular Docking Simulation , Molecular StructureABSTRACT
A germacrane sesquiterpenoid library containing 30 compounds (2-31) was constructed by structural modification of a major component aristolactone (1) from the traditional Chinese medicine Aristolochia yunnanensis. Compound 11 was identified as a promising anticardiac fibrosis agent by systematic screening of this library. 11 could inhibit the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagens in transforming growth factor ß 1 (TGFß1)-stimulated cardiac fibroblasts at a micromolar level and ameliorate myocardial fibrosis and heart function in abdominal aortic constriction (AAC) rats at 5 mg/kg dose. Mechanistic study revealed that 11 inhibited the TGFß/small mother against decapentaplegic (Smad) signaling pathway by targeting TGFß type I receptor (IC50 = 14.9 ± 1.6 nM). The structure-activity relationships (SARs) study indicated that the unsaturated γ-lactone ring and oxidation of C-1 were important to the activity. These findings may provide a new type of structural motif for future anticardiac fibrosis drug development.
