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Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3- d ]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.

The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3 H )-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S -transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 μM against SjGST and 2.02 ± 0.20 μM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.

A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.

C-5 arylated 2/9-substituted pyrimido[5,4-b]indolizines were synthesized via palladium-catalyzed direct arylation. A variety of substituents on both pyrimido[5,4-b]indolizines and aryl/heteroaryl bromides are tolerated, providing rapid access to substituted pyrimido[5,4-b]indolizines in good to excellent yields.

Total synthesis of natural product marmycin A was studied. An expeditious synthetic strategy for the key fragment 8-amino-3-methylbenz[a]anthraquinone (1) was established with decarboxylative alkylation, Pd(OAc)(2)-catalyzed cyclization, aromatization, and C-N coupling as the key steps. However, final assembly of marmycin A was hampered by the failure to obtain the carbohydrate fragment 2. Instead, a small library of desmethyl analogues of marmycin A was prepared in moderate yields by using the InBr(3)-catalyzed C- and N-glycosidation reaction. The absolute configuration of these compounds was confirmed by comparison of their spectroscopic data with that reported for marmycin A, and by X-ray analysis.

Extraction and concentration at a pilot plant scale of anthocyanins and flavonoids from Perilla frutescens var. frutescens harvested in the Guangzhou area of China were investigated. The study of extraction efficiency using mineral acids and organic acids showed that 0.01 mol/L nitric acid was the most suitable to extract flavonoids from this slightly red leaf cultivar. The red extract contained 12 mg/L (as cyanidin equivalent) anthocyanins and other flavones. The multistep process included cross-flow microfiltration (CFM) with a ceramic type membrane, reverse osmosis (RO), and rotating evaporation (RE). The filtration fluxes were high and constant for CFM (150 L/h/m2 at 0.6 b) and for RO (22 L/h/m2 at 40 b). The red extract was concentrated 9.4 times by RO and then 5.4 times by RE. It contained 422 mg/L anthocyanins, representing 77% of the total extracted anthocyanin. The proportion of flavonoids was found unchanged during processing. The concentrated extract showed a pH of 2.7, and its free acidity was found to be 46% of the acidity added for extraction, because of the buffering capacity of the extract. At the concentration level reached, a crystallized deposit occurred and was identified as tartrate.