Dimeric benzylisoquinoline alkaloids from Thalictrum delavayi and their biological activities

Natural products perennially serve as prolific sources of drug leads and chemical probes, fueling the development of numerous therapeutics. Despite their scarcity, natural products that modulate protein function through covalent interactions with lysine residues hold immense potential to unlock new therapeutic interventions and advance our understanding of the biological processes governed by these modifications. Phloroglucinol meroterpenoids constitute one of the most expansive classes of natural products, displaying a plethora of biological activities. However, their mechanism of action and cellular targets have, until now, remained elusive. In this study, we detail the concise biomimetic synthesis, computational mechanistic insights, physicochemical attributes, kinetic parameters, molecular mechanism of action, and functional cellular targets of several phloroglucinol meroterpenoids. We harness synthetic clickable analogues of natural products to probe their disparate proteome-wide reactivity and subcellular localization through in-gel fluorescence scanning and cell imaging. By implementing sample multiplexing and a redesigned lysine-targeting probe, we streamline a quantitative activity-based protein profiling, enabling the direct mapping of global reactivity and ligandability of proteinaceous lysines in human cells. Leveraging this framework, we identify numerous lysine-meroterpenoid interactions in breast cancer cells at tractable protein sites across diverse structural and functional classes, including those historically deemed undruggable. We validate that phloroglucinol meroterpenoids perturb biochemical functions through stereoselective and site-specific modification of lysines in proteins vital for breast cancer metabolism, including lipid signaling, mitochondrial respiration, and glycolysis. These findings underscore the broad potential of phloroglucinol meroterpenoids for targeting functional lysines in the human proteome. 

Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Phloroglucinol Meroterpenoids

Sixteen new quinolizidine alkaloids (QAs), named ormosianines A–P (1–16), and 18 known congeners (17–34) were isolated from the stems and leaves of Ormosia yunnanensis. The structures were elucidated based on spectroscopic analyses and electron circular dichroism (ECD) calculations. Structurally, ormosianines A (1) and B (2) are the first examples of cytisine and Ormosia-type alkaloids with the cleavage of the piperidine ring. Results of the acetylcholinesterase (AChE) inhibitory assay revealed that the pentacycline Ormosia-type QAs, including 1, 16, 24, and 27–29, are good AChE inhibitors. Ormosianine A (1) exhibited more potent AChE inhibitory activity with an IC50 value of 1.55 μM. Molecular docking revealed that 1 might bind to the protein 1DX4, forming two hydrogen bonds with residues SER-238 and HIS-480. 

Ormosianines A-P, Structurally Diverse Quinolizidine Alkaloids with AChE Inhibitory Effects from Ormosia yunnanensis.

Alzheimer's diseases (AD) and other infectious diseases caused by drug-resistance bacteria have posed a serious threat to human lives and global health. With the aim to search for human acetylcholinesterase (hAChE) inhibitors and antibacterial agents from medicinal plants, 16 phloroglucinol oligomers, including two new phloroglucinol monomers (1a and 1b), four new phloroglucinol dimers (3a, 3b, 4b, and 5a), six new phloroglucinol trimers (6a, 6b, 7a, 7b, 8a, and 8b), and two naturally occurring phloroglucinol monomers (2a and 2b), along with two known congeners (4a and 5b), were purified from the leaves of tropic Rhodomyrtus tomentosa. The structures and absolute configurations of these new isolates were unequivocally established by comprehensive analyses of their spectroscopic data (NMR and HRESIMS), ECD calculation, and single crystal X-ray diffraction. Structurally, 3a/3b shared a rare C-5' formyl group, whereas 6a/6b possessed a unique C-7' aromatic ring. In addition, 7a/7b and 8a/8b were rare phloroglucinol trimers with a bis-furan and a C-6' hemiketal group. Pharmacologically, the mixture of 3a and 3b showed the most potent human acetylcholinesterase (hAChE) inhibitory activity with an IC50 value of 1.21 ± 0.16 μM. The molecular docking studies of 3a and 3b in the hAChE binding sites were performed, displaying good agreement with the in vitro inhibitory effects. In addition, the mixture of 3a and 3b displayed the most significant anti-MRSA (methicillin-resistant Staphylococcus aureus) with MIC and MBC values of both 0.50 μg/mL, and scanning electron microscope (SEM) studies revealed that they could destroy the biofilm structures of MRSA. The findings provide potential candidates for the further development of anti-AD and anti-bacterial agents. 

Oligomeric phloroglucinols with hAChE inhibitory and antibacterial activities from tropic Rhodomyrtus tomentosa

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Novel Triterpene Alkaloids from Buxus Sinica and Their Anti-Ache Activities

Phloroglucinols with hAChE and α-glucosidase inhibitory activities from the leaves of tropic Rhodomyrtus tomentosa.

Rhodomyrtus tomentosa fruits serve as both functional food and medicinal resources due to their rich bioactive constituents and manifold pharmacological effects. Phytochemical exploration of the R. tomentosa fruits led to the identification of eight new polymethylated phloroglucinols, designated as rhodotomentodione F (1) and rhodotomentodimers H‒N (2‒8), along with six previously described congeners (9‒14). Based on the detailed inspection of comprehensive spectroscopic data, electronic circular dichroism (ECD) simulations, and nuclear magnetic resonance (NMR) calculations, and DP4+ analyses, the structures of phloroglucinols 1‒8 were determined. Heterodimeric phloroglucinols 3‒14 exhibited human acetylcholinesterase (hAChE) inhibitory activities, with 13 exhibiting the highest potency (IC50 = 1.04 μM). Moreover, molecular docking analysis clarified the potential binding interactions between the most active phloroglucinol 13 with hAChE. In addition, phloroglucinols 11 and 12 displayed significant anti-VRE (vancomycin-resistant Enterococci) activities, with MIC values reaching as low as 1 μg/mL.

Diverse phloroglucinols with hAChE inhibitory and anti-VRE effects from Rhodomyrtus tomentosa fruits

Phloroglucinol Oligomers from Callistemon rigidus as Novel Anti-Hantavirus Replication Agents

Phytocannabinoid-like meroterpenoids from twigs and leaves of Rhododendron spinuliferum.

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