Xun Ji

Design, synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors

A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC50) values of 17 compounds against EGFR wt were less than 0.020μM, and those of 12 compounds were less than 0.010μM. The IC50 values of 10 compounds against EGFR T790M/L858R were less than 0.005μM. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1μM. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1μM), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method.

Silver- and gold-mediated domino transformation: a strategy for synthesizing benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones.

We reported a strategy for the synthesis of fused heterocyclic compounds benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones via an AgSbF(6)/gold-complex catalyzed one-pot cascade transformation. The strategy is tolerant of a broad range of substrates and affords a series of intriguing fused diazepinedione heterocycles.

Gold(I)-catalyzed cascade approach for the synthesis of tryptamine-based polycyclic privileged scaffolds as α1-adrenergic receptor antagonists.

An efficient and facile gold(I)-catalyzed one-pot cascade protocol has been developed for the synthesis of tryptamine-fused polycyclic privileged structures through the treatment of substituted tryptamines and 2-ethynylbenzoic acids or 2-ethynylphenylacetic acids. This strategy features the formation of one C-C bond and two C-N bonds with high yields and broad substrate tolerance. The selected reduced target molecules are validated to perform as α1-adrenergic receptors antagonists. The most potent one, 4bh, exhibits an IC50 value of 277 nM on α1A subtype with a selectivity ratio of 15.8 over α1B subtype.

Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.

A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).

Au(I)/Ag(I)-Catalyzed Cascade Approach for the Synthesis of Benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinones

An efficient and facile Au(I)/Ag(I)-catalyzed cascade method has been developed for one-pot synthesis of the complex polycyclic heterocycles benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinone derivatives through treatment of the substituted 2-(1H-benzo[d]imidazol-2-yl)anilines with 4-pentynoic acid or 5-hexynoic acid. The strategy features a Au(I)/Ag(I)-catalyzed one-pot cascade process involving the formation of three new C-N bonds in high yields, and with broad a substrate scope.

Design, synthesis and biological evaluation of 4-anilinothieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as novel histone deacetylase inhibitors.

A series of 4-anilinothieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as novel HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10r against HDAC1, HDAC3, HDAC6 was 1.14 ± 0.03 nM, 3.56 ± 0.08 nM, 11.43 ± 0.12 nM. Compound 10r noticeably up-regulated the level of histone H3 acetylation compared to the SAHA. Most of the compounds showed the strong anti-proliferative activity against human cancer cell lines including RMPI8226 and HCT-116. The IC50 values of Compounds 10r and 10t against RPMI8226 was 2.39 ± 0.20 μM, 1.41 ± 0.44 μM, respectively, and the HCT-116 was sensitive to the compounds 10h, 10 m, 10r, 10 w with the IC50 values <1.9 μM.

Diastereoselective Michael reaction of chiral nickel(II) glycinate with nitroalkenes for asymmetric synthesis of β-substituted α,γ-diaminobutyric acid derivatives in water

We have developed the first operationally simple and environmentally benign protocol for the aqueous asymmetric Michael addition reaction of chiral nickel(II) glycinate with nitroalkenes. The reactions proceeded smoothly in the presence of TBAB (tetrabutyl ammonium bromide) in neat water at room temperature and provided good yields of β-substituted α,γ-diaminobutyric acid derivatives with excellent diastereoselectivities.

Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.

A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC(50)=0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.

Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor

A novel series of anilinoquinazoline compounds with C-6 urea-linked side chains was designed and synthesized as reversible inhibitors of epidermal growth factor receptor (EGFR) based on the structure-activity relationships (SARs) of anilinoquinazoline inhibitors. All compounds demonstrated good inhibition of EGFR wild type (EGFR wt) (IC50=0.024-1.715 μM) and inhibited proliferation of A431cell line (IC50=0.116-22.008 μM). The binding mode of compounds 8a, 8d, 8k and 8o was consistent with the biological results. Moreover, compounds 8k and 8l almost completely blocked the phosphorylation of EGFR in A431 cell line at 0.01 μM. Interestingly, all of the compounds also demonstrated moderate inhibition of EGFR/T790M/L858R (IC50=0.049-5.578 μM). In addition, compounds 8f and 8h blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (10 μM), and compound 8f was confirmed to be an irreversible inhibitor through the dilution method. Importantly, the compounds with C-6 urea-linked side chains which did not contain Michael acceptors demonstrated moderate to strong irreversible EGFR inhibition.

Design, synthesis, structure-activity relationships, and docking studies of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines as a novel series of potent and selective dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase‐4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1‐(γ‐1,2,3‐triazol substituted prolyl)‐(S)‐3,3‐difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase‐4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase‐4. Among these, compounds 7j, 7q, and 7s displayed good dipeptidyl peptidase‐4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase‐8, dipeptidyl peptidase‐9, and FAP. The possible binding modes of compounds 7j, 7q, and 7s with dipeptidyl peptidase‐4 were also explored by molecular docking simulation.