Yu Tang

Enteroviruses causing hand, foot, and mouth disease, including currently circulating Coxsackievirus A10 (CVA10) and Coxsackievirus A6 (CVA6), rely on KREMEN1 (KRM1) for cell entry, making the virus–KRM1 interface a potential target for antiviral intervention. We screened GLMarNP, an in-house library of about 3000 natural products and derivatives. Candidates targeting the KRM1 ectodomain were selected by blind docking, drug-likeness assessment, and scaffold diversity analysis. To enable high-throughput antiviral screening, we inserted eGFP into a full-length infectious CVA10 cDNA clone to generate a reporter virus designated eGFP-A10. The virus was rescued in HEK293T cells and produced robust fluorescence in RD cells over serial passages. Among 29 candidate compounds, LM-10 showed the strongest antiviral activity and exhibited low cytotoxicity. Mechanistically, LM-10 bound KRM1 and acted early in the viral life cycle. Molecular docking suggested that LM-10 binds the KR domain at a site overlapping the VP2 EF-loop contact region. KRM1 also acts as a DKK1 receptor to regulate Wnt/β-catenin signaling. LM-10 did not significantly affect this pathway in the TOP-GFP reporter assay or in transgenic zebrafish embryos. These findings establish a practical CVA10 reporter-virus platform and support steric blockade of the receptor interface as a potential antiviral strategy.

Liver fibrosis is a major global health challenge with limited treatment options. The marine natural product Psammaplysene D (PD) exhibits promising antifibrotic activity but suffers from significant hERG channel inhibition (>99% at 5 μM) and moderate pharmacokinetics. To address this cardiotoxicity, we employed rational optimization guided by computational toxicity prediction (ADMETlab 2.0), leading to the design and synthesis of derivatives and identification of compound C11. Patch-clamp studies confirmed C11 eliminated hERG liability (IC50 > 100 μM). C11 retained antifibrotic efficacy comparable to PD in liver fibrosis models with no observable toxicity. This work demonstrates successful separation of hERG toxicity from pharmacological activity, establishing C11 as a safe and effective lead candidate for hepatic fibrosis therapy.

We report a concise total synthesis strategy for accessing four fused tricyclic indoline-based natural products and their derivatives. The synthesis employs phosphine-catalyzed allylic alkylation as the key step to construct common precursors, which are subsequently functionalized to form the fused ring systems. Notably, the synthetic route is readily scalable, enabling the efficient preparation of a library of indoline-based alkaloids.

The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely 5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that 5-3 potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of 5-3 depends highly on FLT3-ITD expression. Mechanically, 5-3 significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound 5-3 is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that 5-3 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

The first total synthesis of epidithiodiketopiperazine (ETP) alkaloid penisuloxazin A is described. The key steps of the synthesis involve the La(III)-mediated aldol reaction to construct a benzylic alcohol, which serves as the precursor for rearrangement. Subsequently, a bioinspired Lewis acid-catalyzed rearrangement reaction facilitates sulfur migration, forming the 6/5/6 spiro-benzofuran ring system with an irregular α-β' disulfide skeleton. This synthesis produces penisuloxazin A in 14 steps from inexpensive, available materials. The method could be a general strategy for making irregular α-β' disulfide bridge ETPs, especially those with hydroxamic acids.

Plinabulin, a 2, 5-diketopiperazine-type tubulin inhibitor derived from marine natural products, is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and chemotherapy-induced neutropenia (CIN). To obtain novel 2, 5-diketopiperazine derivatives with higher biological activity, we designed and synthesized two series of 37 plinabulin derivatives at the C-ring, based on the co-crystal structure of compound 1 and tubulin. Their structures were characterized using NMR and HRMS. All compounds were screened in vitro using the lung cancer cell line NCI-H460 using the MTT method, and the compounds with better activity were further screened in BxPC-3 and HT-29 cells. The compounds 16c (IC₅₀ = 2.0, NCI-H460; IC₅₀ = 1.2 nM, BxPC-3; IC₅₀ = 1.97 nM, HT-29) and 26r (IC₅₀ = 0.96, NCI-H460; IC₅₀ = 0.66 nM, BxPC-3; IC₅₀ = 0.61 nM, HT-29) had the best activity. The cytotoxic activity of compound 26r against various tumor cell lines occurred at less than 1 nM.