Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

To overcome drug resistance caused by ALK kinase mutations especially G1202R, two series of novel 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety were designed, synthesized and evaluated for their biological activities. Among all the target compounds, B10 efficiently inhibited the proliferation of ALK-positive Karpas299 and H2228 cells both with IC50 values of 0.07 μM. In addition, B10 exhibited remarkable enzymatic inhibitory potency with IC50 values of 4.59 nM, 2.07 nM and 5.95 nM toward ALKWT, ALKL1196M and ALKG1202R, respectively. Furthermore, B10 induced apoptosis in H2228 cell and caused cell cycle arrest in G2/M phase. Ultimately, the binding modes of B10 with ALKWT and ALKG1202R were ideally established, which further confirmed the structural basis in accordance with the SARs analysis. These results indicated that B10 was a potent ALK inhibitor for ALKG1202R mutation treatment and deserved for further investigation.

Abstract The base-induced formal [4+3] cycloaddition reaction of C,N-cyclic azomethine imines with aza-ortho-quinone methides, generated in situ, is reported. This protocol provided an efficient method for the synthesis of biologically important 1,2,4-triazepine derivatives, with a wide substrate scope and excellent functional-group tolerance, and it gives moderate to excellent yields under mild conditions. Several of the derivatives exhibited in vitro antitumor activities against the A2780 cell line in a screening of the cancer cell lines HCT-116, H2228, and A2780 by an MTT assay.

A silver(I)- and base-mediated formal [4+3] cycloaddition reaction of in situ generated 1,2-diaza-1,3-dienes with in situ formed C,N-cyclic azomethine imines has been developed. This protocol provided an efficient method for the synthesis of biologically important 1,2,4,5-tetrazepine derivatives with a wild substrate scope and excellent functional group tolerance in moderate to excellent yields.

Two series of 2-aminopyrimidine derivatives possessing triazolopiperazine or 1,4,8-triazaspiro[4.5]decan-3-one scaffolds were designed, synthesized and evaluated for their biological activity.

A novel three-component assembly of allenic alcohols, aryl iodides and 1,3-dicarbonyl compounds into 3,3-disubstituted allylic alcohols was promoted in the presence of a palladium source.

An efficient, molecular iodine-promoted MCR of alkynes and sulfonyl hydrazide for the synthesis of (E)-β-iodo vinylsulfone derivatives has been developed.

A novel and versatile method for the synthesis of 2-imidazolines has been developed via the Pd-catalyzed cyclization reaction of readily available homoallenyl oxime acetates with aryl iodides. This protocol is performed under mild reaction conditions and needs no additives or ligands.

A sensitive and highly selective method has been developed for the simultaneous determination of seven residual pharmaceuticals (paracetamol, chloramphenicol, salicylic acid, prednisone acetate, indomethacin, fenofibrate, and simvastatin) in wastewater influent and effluent. Samples were enriched by solid-phase extraction (SPE) and analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in a negative and positive switching ionization mode. Recoveries of individual pharmaceuticals in the ranges of 71.8-101.2% and 61.3-99.4% were obtained in the spiked samples of purified water and effluent matrices, respectively, at three concentration levels. Method detection limits were in the range of 1.293-36.95 ng L-1 and 0.6614-18.67 ng L-1 for the wastewater influent and effluent samples, respectively, while method quantification limits were in the range of 4.313-123.1 ng L-1 and 2.205-62.23 ng L-1 for the wastewater influent and effluent samples, respectively. The instrumental precision, calculated as relative standard deviation, ranged from 0.9 to 7.2%. The developed method was successfully applied to the analysis of wastewater samples from a wastewater treatment plant in Shenyang.