In Vitro and in Silico Study of New Biscoumarin Glycosides from Paramignya trimera against Angiotensin-Converting Enzyme 2 (ACE-2) for Preventing SARS-CoV-2 Infection.

In Vietnam, the stems and roots of the Rutaceous plant Paramignya trimera (Oliv.) Burkill (known locally as "Xáo tam phân") are widely used to treat liver diseases such as viral hepatitis and acute and chronic cirrhosis. In an effort to search for Vietnamese natural compounds capable of inhibiting coronavirus based on molecular docking screening, two new dimeric coumarin glycosides, namely cis-paratrimerin B (1) and cis-paratrimerin A (2), and two previously identified coumarins, the trans-isomers paratrimerin B (3) and paratrimerin A (4), were isolated from the roots of P. trimera and tested for their anti-angiotensin-converting enzyme 2 (ACE-2) inhibitory properties in vitro. It was discovered that ACE-2 enzyme was inhibited by cis-paratrimerin B (1), cis-paratrimerin A (2), and trans-paratrimerin B (3), with IC50 values of 28.9, 68, and 77 µM, respectively. Docking simulations revealed that four biscoumarin glycosides had good binding energies (∆G values ranging from -10.6 to -14.7 kcal/mol) and mostly bound to the S1' subsite of the ACE-2 protein. The key interactions of these natural ligands include metal chelation with zinc ions and multiple H-bonds with Ser128, Glu145, His345, Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots occur naturally in both cis- and trans-diastereomeric forms. The biscoumarin glycosides Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots hold potential for further studies as natural ACE-2 inhibitors for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Comparative metabolite analysis of Piper sarmentosum organs approached by LC-MS-based metabolic profiling.

Piper sarmentosum Roxb. (Piperaceae) is a traditional medicinal and food plant widely distributed in the tropical and subtropical regions of Asia, offering both health and culinary benefits. In this study the secondary metabolites in different organs of P. sarmentosum were identified and their relative abundances were characterized. The metabolic profiles of leaves, roots, stems and fruits were comprehensively investigated by liquid chromatography high-resolution mass spectrometry (LC-HR-MS) and the data subsequently analyzed using multivariate statistical methods. Manual interpretation of the tandem mass spectrometric (MS/MS) fragmentation patterns revealed the presence of 154 tentatively identified metabolites, mostly represented by alkaloids and flavonoids. Principle component analysis and hierarchical clustering indicated the predominant occurrence of flavonoids, lignans and phenyl propanoids in leaves, aporphines in stems, piperamides in fruits and lignan-amides in roots. Overall, this study provides extensive data on the metabolite composition of P. sarmentosum, supplying useful information for bioactive compounds discovery and patterns of their preferential biosynthesis or storage in specific organs. This can be used to optimize production and harvesting as well as to maximize the plant's economic value as herbal medicine or in food applications.

Improved Access to Potent Anticancer Tubulysins and Linker-Functionalized Payloads Via an All-On-Resin Strategy.

Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.

Assessment of metabolome diversity in black and white pepper in response to autoclaving using MS- and NMR-based metabolomics and in relation to its remote and direct antimicrobial effects against food-borne pathogens.

Piper nigrum L. (black and white peppercorn) is one of the most common culinary spices used worldwide. The current study aims to dissect pepper metabolome using 1H-NMR targeting of its major primary and secondary metabolites. Eighteen metabolites were identified with piperine detected in black and white pepper at 20.2 and 23.9 µg mg-1, respectively. Aroma profiling using HS-SPME coupled to GC-MS analysis and in the context of autoclave treatment led to the detection of a total of 52 volatiles with an abundance of ß-caryophyllene at 82% and 59% in black and white pepper, respectively. Autoclaving of black and white pepper revealed improvement of pepper aroma as manifested by an increase in oxygenated compounds' level. In vitro remote antimicrobial activity against food-borne Gram-positive and Gram-negative bacteria revealed the highest activity against P. aeruginosa (VP-MIC 16.4 and 12.9 mg mL-1) and a direct effect against Enterobacter cloacae at ca. 11.6 mg mL-1 for both white and black pepper.

Enzymatic one-step synthesis of natural 2-pyrones and new-to-nature derivatives from coenzyme A esters.

The 2-pyrone moiety is present in a wide range of structurally diverse natural products with various biological activities. The plant biosynthetic routes towards these compounds mainly depend on the activity of either type III polyketide synthase-like 2-pyrone synthases or hydroxylating 2-oxoglutarate dependent dioxygenases. In the present study, the substrate specificity of these enzymes is investigated by a systematic screening using both natural and artificial substrates with the aims of efficiently forming (new) products and understanding the underlying catalytic mechanisms. In this framework, we focused on the in vitro functional characterization of a 2-pyrone synthase Gh2PS2 from Gerbera x hybrida and two dioxygenases AtF6'H1 and AtF6'H2 from Arabidopsis thaliana using a set of twenty aromatic and aliphatic CoA esters as substrates. UHPLC-ESI-HRMSn based analyses of reaction intermediates and products revealed a broad substrate specificity of the enzymes, enabling the facile "green" synthesis of this important class of natural products and derivatives in a one-step/one-pot reaction in aqueous environment without the need for halogenated or metal reagents and protective groups. Using protein modeling and substrate docking we identified amino acid residues that seem to be important for the observed product scope.

Passiflora mucronata leaves extracts obtained from different methodologies: a phytochemical study based on cytotoxic and apoptosis activities of triterpenes and phytosterols constituents

Cancer is one of the most prevalent diseases worldwide and the natural products could be a source of bioactive compounds. Passiflora mucronata (PM) belongs to a very known vegetal genus, although, there are no studies about cytotoxic activity or isolated compounds. Different extracts from PM were obtained by liquid-liquid partition (P), Soxhlet (Sox) and supercritical fluid (SFE1-5) extraction techniques, being compared concerning their yields, chemical profile and cytotoxicity. The Sox extracts showed the highest yields (6.03%: hexane; 2.51%: dichloromethane) followed by SFE (from 4.34 to 1.63%) and partitions (1.06 and 2.26%). The hexane partition (HP) showed the best cytotoxic activity against K562 cell line (IC50 = 18.72 µg.mL-1). From HP, the following compounds were identified and analysed its cytotoxic activities: β-amyrin (IC50 = 3.92 µg.mL-1), β-sitosterol (IC50 = 3.37 µg.mL-1), stigmasterol (IC50 = 3.31 µg.mL-1) and oleanolic acid. Stigmasterol induced about 75% of K562 total apoptosis. The compounds were tested against MA-104 cell line and the selective index (SI) attributed (SI >10 for all compounds). This indicates good selectivity to K562 cell line at the expense of MA-104. This is the first time, identifying those compounds to PM .

Antibacterial and antioxidant activities and acute toxicity of Bumelia sartorum Mart., Sapotaceae, a Brazilian medicinal plant

In order to validate the Bumelia sartorum Mart., Sapotaceae, traditional use for infection diseases, this study evaluates the antibacterial activity of the stem bark fractions against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus strains by using the agar dilution method and reported as MIC (minimal inhibitory concentration). In addition, the DPPH scavenging activity of these fractions was measured and the chemical composition and acute toxicity of the active fraction were also determined. The ethyl acetate (EtOAc) extract was chemically analyzed by LC/MS, direct ionization APCI/MS, ¹H NMR and 13C-NMR. All fractions, except butanol extract, presented high antioxidant activity, especially the methanol and the EtOAc extracts, which showed EC50 values (5.67 and 5.30 µg/mL, respectively) considerably lower than the Gingko-standard EGb 761® (38.58 µg/mL). The antibacterial activity against S. aureus strains was observed in EtOAc (MIC 256-512 µg/mL), which showed a very low toxicity. The chemical study of this fraction revealed the abundant presence of polyphenolic compounds. The antibacterial and antioxidant activities reported in this paper for EtOAc extract from B. sartorum and the low toxicity of this fraction opens the possibility that it could be helpful for the developing of new antibacterial agents for treating S. aureus infections.