Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones.

A highly efficient metal-free selective 1,4-addition reaction of difluoroenoxysilanes to chromones was developed using the low-cost and readily available HOTf as the catalyst, which is a facile and straightforward method to access valuable C2-difluoroalkylated chroman-4-one derivatives. Interestingly, the products could be readily converted to the difluorinated bioisostere of the natural product (S)-2,6-dimethylchroman-4-one and a difluorinated benzo-seven-membered heterocycle via the Schmidt rearrangement reaction. In addition, the in vitro anti-proliferative activities of these synthesized derivatives against human colon carcinoma cells (HCT116) revealed that compound 3g exhibited potent inhibitory effect on HCT116 cancer cells with an IC50 value of 6.37 µM, representing a novel lead compound for further structural optimization and biological evaluation.

Enantioselective Synthesis of Bispiro[indanedione-oxindole-cyclopropane]s through Organocatalytic [2+1] Cycloaddition.

A series of compounds featuring a novel bispiro[indanedione-oxindole-cyclopropane] moiety have been synthesized through a squaramide-catalyzed [2+1] cycloaddition reaction. The tandem Michael-alkylation reaction of 2-arylidene-1,3-indanediones with 3-bromooxindoles furnished the cycloadducts in high yields with excellent diastereo- and enantioselectivities. The ammonium ylide in the catalytic process, as a key intermediate, was revealed by the high-resolution mass spectrometry study.

Construction of ß-Quaternary α,α-Difluoroketones via Catalytic Nucleophilic Substitution of Tertiary Alcohols with Difluoroenoxysilanes.

An efficient Fe(OTf)3-catalyzed nucleophilic substitution of cyclic or acyclic tertiary alcohols with difluoroenoxysilanes is developed, which provides a facile protocol for assembling structurally diverse α,α-gem-difluoroketones featuring a quaternary carbon center in good to excellent yields under mild conditions. Moreover, the diverse product elaborations highlight the utility of this protocol, as exemplified by the preparation of valuable difluorinated tricyclic indolines.

Discovery and Biological evaluation of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors.

Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC50 = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 µM.

Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) plays a critical role in B cell receptor (BCR)-mediated signaling pathways responsible for the development and function of B cells, which makes it an attractive target for the treatment of many types of B-cell malignancies. Herein, a series of N5-substituted 6,7-dioxo-6,7-dihydropteridine-based, irreversible BTK inhibitors were reported with IC50 values ranging from 1.9 to 236.6 nM in the enzymatic inhibition assay. Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme, as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLCγ2. Overall, this series of compounds could provide a promising starting point for further development of potent BTK inhibitors for B-cell malignancy treatment.

Design, Synthesis, and Biological Evaluation of Pyrimido[4,5- d]pyrimidine-2,4(1 H,3 H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5- d]pyrimidine-2,4(1 H,3 H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFRL858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFRL858R/T790M inhibitors.

Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors.

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFRL858R/T790M (H1975 cell lines) over EGFRWT (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFRL858R/T790M. These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.

Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.

EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR(WT). Finally, the most representative compound 17d was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR(L858R/T790M) over EGFR(WT), which may play an important role in designing new classes of mutant-selective EGFR inhibitors.