Discovery of natural product derivative triptolidiol as a direct NLRP3 inhibitor by reducing K63-specific ubiquitination.

Background And Purpose: NLRP3 is up-regulated in inflammatory and autoimmune diseases. The development of NLRP3 inhibitors is challenged by the identification of compounds with distinct mechanisms of action avoiding side effects and toxicity. Triptolide is a natural product with multiple anti-inflammatory activities, but a narrow therapeutic window.

Design, synthesis, and biological evaluation of 3, 5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting inhibitors against microtubule and kinases.

Combination therapy of kinases inhibitors and chemotherapeutics targeting tubulin dynamics is an important strategy to improve therapeutic efficacy and overcome the resistance to single-target drug therapies. Inspired by this, we report herein the rational design of 3,5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting molecules that are capable of inhibiting tubulin and kinases simultaneously. Among them, 8g showed excellent antiproliferative activities toward a panel of cancer cell lines.

Total Syntheses of Daphnezomine L-type and Secodaphniphylline-type Alkaloids via Late-Stage C-N Bond Activation.

Here, we report the first total syntheses of daphnezomine L-type alkaloids daphnezomine L methyl ester and calyciphylline K via late-stage C-N bond activation. The first synthesis of secodaphniphylline-type alkaloid caldaphnidine D was also achieved via a similar strategy. Other key transformations employed in our synthesis were a facile vicinal diol olefination and an efficient radical cyclization cascade.

Small molecule RHP1 promotes root hair tip growth by acting upstream of the RHD6-RSL4-dependent transcriptional pathway and ROP signaling in plants.

Root hairs are single-cell projections in the root epidermis. The presence of root hairs greatly expands the root surface, which facilitates soil anchorage and the absorption of water and nutrients. Root hairs are also the ideal system to study the mechanism of polar growth.

Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J.

Ever since Hirata's report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described.

A Concise Total Synthesis of (-)-Himalensine A.

The daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (-)-himalensine A, which was accomplished in 14 steps.

Gallic acid disruption of Aβ aggregation rescues cognitive decline of APP/PS1 double transgenic mouse.

Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aβ aggregation and neurotoxicity.

Stereoselective Synthesis of the ABC Ring System of Aspterpenacids.

Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also contain a sterically encumbered isopropyl trans-hydrindane motif and a cyclopropane motif bearing two quaternary centers, which make them remarkably challenging synthetic targets. Herein, we report the successful construction of the key highly substituted ABC ring system in a stereoselective manner.

Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure-activity relationship studies.

Owning to the promising neuroprotective profile and the ability to cross the blood-brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure-activity relationship studies for Alzheimer's disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model.

Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2.

A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.

Design, synthesis and biological evaluation of di-substituted cinnamic hydroxamic acids bearing urea/thiourea unit as potent histone deacetylase inhibitors.

A novel class of di-substituted cinnamic hydroxamic acid derivatives containing urea or thiourea unit was designed, synthesized and evaluated as HDAC inhibitors. All tested compounds demonstrated significant HDAC inhibitory activities and anti-proliferative effects against diverse human tumor cell lines. Among them, 7l exhibited most potent pan-HDAC inhibitory activity, with an IC50 value of 130 nM.

[Research progresses of the PARP inhibitors for the treatment of cancer].

The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development.

Design, synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors.

Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI50 values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC50 value of 0.

Discovery and mechanism study of SIRT1 activators that promote the deacetylation of fluorophore-labeled substrate.

SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate.