Discovery of α-Obscurine Derivatives as Novel Cav3.1 Calcium Channel Blockers.

Voltage-gated calcium channels (VGCCs), particularly T-type calcium channels (TTCCs), are crucial for various physiological processes and have been implicated in pain, epilepsy, and cancer. Despite the clinical trials of TTCC blockers like Z944 and MK8998, none are currently available on the market. This study investigates the efficacy of Lycopodium alkaloids, particularly as natural product-based TTCC blockers. We synthesized eighteen derivatives from α-obscurine, a lycodine-type alkaloid, and identified five derivatives with significant Cav3.1 blockade activity. The most potent derivative, compound 7, exhibited an IC50 value of 0.19±0.03 µM and was further analyzed through molecular docking, revealing key interactions with Cav3.1. These findings provide a foundation for the structural optimization of Cav3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research.

Casuattimines A-N, fourteen new Lycopodium alkaloids from Lycopodiastrum casuarinoides with Cav3.1 channel inhibitory activity.

Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Cav3.1 channel inhibitory activities presenting IC50 values of 10.75 ± 1.02 µM, 9.33 ± 0.79 µM, and 7.14 ± 0.86 µM, respectively. The dynamics of compound 4 against the Cav3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.

Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives.

Hsp90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for cancer. Hsp90 has more recently been identified as having a significant pathogenic role in viral infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective Hsp90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 µM respectively. Direct interaction between Hsp90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell apoptosis by mitochondrial-mediated apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.

Vibsane-Type Diterpenoids: Structures, Derivatives, Bioactivities, and Synthesis.

Vibsane-type diterpenoids isolated from the genus Viburnum, are rare 6-11 membered ring polysubstituted macrocyclic diterpenoids. Since the first report of vibsane-type diterpenoids from V. odoratissimum in 1980, they have attracted the attention of scientists due to their complex structures, excellent biological activities, and great synthetic challenges. Recently, there are some notable research achievements on the discovery, synthesis, structural modification, and pharmacological mechanism of vibsane-type diterpenoids. Therefore, we will focus on these aspects to review important achievements of vibsane diterpenoids between 1980-2021.

Discovery of pseudolaric acid A as a new Hsp90 inhibitor uncovers its potential anticancer mechanism.

Pseudolaric acid A (PAA), one of the main bioactive ingredients in traditional medicine Pseudolarix cortex, exhibits remarkable anticancer activities. Yet its mechanism of action and molecular target have not been investigated and remain unclear. In this work, mechanistic study showed that PAA induced cell cycle arrest at G2/M phase and promoted cell death through caspase-8/caspase-3 pathway, demonstrating potent antiproliferation and anticancer activities. PAA was discovered to be a new Hsp90 inhibitor and multiple biophysical experiments confirmed that PAA directly bind to Hsp90. Active PAA-probe was designed, synthesized and biological evaluated. It was subsequently employed to verify the cellular interaction with Hsp90 in HeLa cells through photoaffinity labeling approach. Furthermore, NMR experiments showed that N-terminal domain of Hsp90 and essential groups in PAA are important for the protein-inhibitor recognition. Structure-activity relationship studies revealed the correlation between its Hsp90 inhibitory activity with anticancer activity. This work proposed a potential mechanism involved with the anticancer activity of PAA and will improve the appreciation of PAA as a potential cancer therapy candidate.

Copper-catalyzed amination of an α-C(sp3)-H bond in inactivated ethers to synthesize α-aminonitriles.

A copper-catalyzed functionalization of inert cyclic ethers was developed to provide α-aminonitriles via a cascade oxidation/amination/ring-opening/cyanation reaction. A series of highly versatile α-aminonitriles were obtained from primary or secondary anilines, and heterocyclic and aliphatic amines with high yields. This process features excellent functional group tolerance, a broad substrate scope, and high activity under ambient conditions.

Copper-catalyzed synthesis of α-amino nitriles through methyl transfer from DMF to aromatic amines.

A copper-catalyzed activation of C(sp3)-H bonds of DMF at room temperature was developed, which results in methyl transfer to aromatic amines for efficient synthesis of exceedingly valuable α-amino nitriles. This process features excellent functional group tolerance, a broad substrate scope, and high activity under ambient conditions.

Hydrogen bonding-promoted efficient Ru-catalyzed ring-closing metathesis of demanding homoallyl 2-(hydroxymethyl)acrylates.

An efficient hydrogen bonding-guided ring-closing metathesis (RCM) reaction of sterically demanding homoallyl 2-(hydroxymethyl)acrylates catalyzed by the Hoveyda-Grubbs 2nd generation catalyst was developed and the reaction mechanism was explored. Adding a substituent to the hydroxymethyl group in this scaffold resulted in a class of challenging RCM substrates, although usable yields could be obtained. However, substrates bearing a 1-oxygenated alkyl group on the homoallylic carbon gave excellent RCM yields, providing a practical solution. Experimental and computational evidence indicated an unusual directing effect of OHCl hydrogen bonding between the substrate and Ru catalyst, which guides Ru to interact with the electron-deficient, more hindered acrylic C[double bond, length as m-dash]C bond and thus triggers the RCM process.