ABSTRACT
Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A (6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5-8 are not associated with the reported toxicity of this plant species.
Subject(s)
Caustics , Cynanchum , Humans , Acetylcholinesterase , Australia , Glycosides/pharmacology , Pregnanes/pharmacology , Plant RootsABSTRACT
Structurally unique halimanes EBC-232 and EBC-323, isolated from the Australian rainforest plant Croton insularis, proved considerably difficult to elucidate. The two diastereomers, which consist an unusual oxo-6,7-spiro ring system fused to a dihydrofuran, were solved by unification and consultation of five in silico NMR elucidation and prediction methods [i.e., ACDLabs, olefin strain energy (OSE), DP4, DU8+ and TD DFT CD]. Structure elucidation challenges of this nature are prime test case examples for empowering future AI learning in structure elucidation.
ABSTRACT
Briarellins, a subset of C2-C11 cyclized cembranoids, were proposed to contain a C3-C14 ether or lactone bridge, similar to asbestinins. However, the total synthesis of the proposed structure of briarellin J revealed a misassignment. We revisited briarellins, computationally, with the help of a recently developed hybrid DFT/parametric method, DU8+, and revised the structures of briarellin C14-C3 ε-lactones to new structural types containing either a C14-C11 or C14-C12 lactone bridge. The original structures of briarellin and asbestinin ethers were confirmed.
Subject(s)
LactonesABSTRACT
This manuscript describes predicted NMR shifts for the limonoid natural product xylogranatin F. The 1 H and 13 C NMR shifts of four diastereomers were evaluated by GIAO and hybrid DFT/parametric DU8+ methods. The results of the 1 H and 13 C NMR calculations for both the GIAO method and the DU8+ calculations suggest the revised structure that was recently reassigned by chemical synthesis. Furthermore, we show that while DU8+ provides superior accuracy with less computation time, GIAO points to the correct structure with more distinguishable data in this case study.
Subject(s)
Density Functional Theory , Limonins/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
Total synthesis has been an effective and broadly practiced approach for structure validation (or revision) of complex natural products. It appears that computational methods for structure elucidation are gradually becoming a better alternative, being faster and more reliable, as found in the case of alstofolinine A.
Subject(s)
Biological Products/chemistry , Biological Products/chemical synthesis , Indole Alkaloids/chemistry , Indole Alkaloids/chemical synthesis , Chemistry Techniques, Synthetic , KineticsABSTRACT
Analysis of published NMR data for natural products containing the oxetane moiety, with the help of a recently developed parametric/DFT hybrid computational method DU8+, has revealed that oxetanes and related compounds constitute yet another significant challenge in structure elucidation and stereochemistry assignment, as more than 30 structures required revision. The most common pitfalls are discussed, and revised structures are suggested for 26 natural products.
Subject(s)
Biological Products/chemistry , Density Functional Theory , Ethers, Cyclic/chemistry , Models, Molecular , Molecular ConformationABSTRACT
NMR data for natural products containing the epoxy moiety have been revisited and reanalyzed with the help of a recently developed parametric/DFT hybrid computational method, DU8+. More than 20 structures needed revision, which points to challenges in NMR solution structure assignment for molecules possessing this structural feature. Among the revised structures are achicretin 2, acremine P, aromaticane I, artanomalide B, botryosphaerihydrofuran, chloroklotzchin, crithmifolide, crotodichogamoin A, emervaridone C, 9α,15-epoxyafricanane, fischambiguine B, grandilobalide B, guaianolide A, guatterfriesols A and B, juncenolide G, roscotane D, secoafricane 7, taccalonolides AJ and AF, and related compounds.
Subject(s)
Biological Products/chemistry , Ethylene Oxide/chemistry , Density Functional Theory , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
Diverse polyheterocycles are accessed via scaffolded photoassisted synthesis involving decarboxylative aromatization of the primary photoproducts from intramolecular cycloadditions of azaxylylenes and tethered heteroaromatic unsaturated pendants.
ABSTRACT
The fragmentation reaction of the radical cations of 3-aryl-5-fluoroisoxazoles formed via EI-MS is described. A new rearrangement accompanied by fluorine atom migration is discovered. A mechanistic rationale for the rearrangement supporting the existence of a fluorinated benzocyclopropenyl cation was proposed based on the experimental data and quantum chemical calculations.
ABSTRACT
The inhibitor of apoptosis protein BIRC2 regulates fundamental cell death and survival signaling pathways. Here we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2BIR2 and BIRC2BIR3, to the histone H3 tail and report the structure of the BIRC2BIR3-H3 complex. RNA-seq analysis reveals that the genes involved in interferon and defense response signaling and cell-cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell-cycle progression. We describe the structural mechanism for targeting of BIRC2BIR3 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in human immunodeficiency virus type 1-infected human CD4+ T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.
Subject(s)
Inhibitor of Apoptosis Proteins , Thiazoles , Humans , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Apoptosis/genetics , Signal Transduction/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection.