TYM-3-98, a novel selective inhibitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B-cell lymphomas.

AIMS: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds. MAIN METHODS: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo. KEY FINDINGS: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model. SIGNIFICANCE: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission.

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window.

Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1-/- mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg-1·d-1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1-/- mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.

Synthesis of indoles via domino reaction of N-aryl amides and ethyl diazoacetate.

A general and concise synthesis of functionalized indoles via domino reaction of N-aryl amides and ethyl diazoacetate has been developed. The methodology offers a great potential for the synthesis of biologically active and naturally occurring indole derivatives.

Copper-catalyzed multicomponent reaction: facile access to novel phosphorus amidines.

The synthesis of a novel class of phosphorus amidines via a copper-catalyzed multicomponent reaction of sulfonyl azides, alkynes and iminophosphoranes is described. The protocol is efficient and general.

Facile access to pyrazolines via domino reaction of the Huisgen zwitterions with aziridines.

A novel, efficient, and general domino reaction of 2-acylaziridines with the Huisgen zwitterions to furnish 2-pyrazoline rings is described. A possible mechanism for the domino sequence is proposed.

Copper-catalyzed multicomponent reaction: facile access to functionalized 5-arylidene-2-imino-3-pyrrolines.

The synthesis of a novel class of 2-imino-5-arylidene-3-pyrrolines via a copper-catalyzed multicomponent reaction of sulfonyl azides with alkynes and aziridines is described. The protocol is efficient and general.

Domino reaction of 3-(2-formylphenoxy)propenoates and amines: a novel synthesis of 1,4-dihydropyridines from salicaldehydes, ethyl propiolate, and amines.

A novel synthesis of Hantzsch-type N-substituted 1,4-dihydropyridines from salicaldehydes, ethyl propiolate, and amines has been developed. Salicaldehydes were treated with ethyl propiolate in the presence of N-methylmorpholine to give ethyl 3-(2-formylphenoxy)propenoates. Three equivalents of ethyl 3-(2-formylphenoxy)propenoates reacted with 1 equiv of amines under trifluoroacetic acid (TFA) catalyst to furnish the corresponding N-substituted 1,4-dihydropyridines in good to excellent yields, recovering the starting material salicaldehydes. A possible mechanism for the domino process was proposed. Furthermore, the products can be easily derived via further transformations and three of them exhibited strong fluorescence (Phif = 0.36-0.63).

Novel and efficient synthesis of iminocoumarins via copper-catalyzed multicomponent reaction.

A variety of substituted iminocoumarins are prepared in good to excellent yields via a copper-catalyzed multicomponenet reaction of sulfonyl azides, terminal alkynes, and salicylaldehydes or o-hydroxylacetophenones. The method is general, mild, versatile, and efficient. A plausible mechanism for the domino process is proposed.

A highly selective cascade approach to diverse aromatic ring systems from simple aromatic aldehydes and propiolates.

[reaction: see text] A new triethylamine-catalyzed cascade reaction of aromatic aldehydes with propiolates has been developed. This serial multi-bond-forming process furnishes diverse polycyclic aromatic hydrocarbons, including naphthalenes, phenanthrenes, benzofurans, and 2,3,9,9a-tetrahydronaphtha[2,3-b]furans. The chemical outcome of the process depends on the reaction temperature and can be tailored selectively by an appropriate choice of experimental conditions.

Parallel synthesis of strongly fluorescent polysubstituted 2,6-dicyanoanilines via microwave-promoted multicomponent reaction.

[reaction: see text] A facile parallel synthesis of polysubstituted 2,6-dicyanoanilines via microwave-promoted three-component reaction of aldehydes, ketones, and propanedinitrile in solution and also on polymer support has been developed. The screening for optical properties identified two new compounds with high fluorescence quantum yields.