A series of novel di- and tripeptidyl epoxyketone derivatives composed of β-amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti-proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI-H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC₅₀ values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm. In addition, all the four compounds showed anti-proliferation activities with IC₅₀ values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e. All the experimental results validated that the β-amino acid building block has the potential for the development of proteasome inhibitors.

A novel series of (S)-phenylalanine derivatives with a 2-cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors; among them, the cyclopropyl-substituted phenylalanine derivative 11h displayed the most potent DPP-4 inhibitory activity with an IC₅₀ value of 0.247 μm. In addition, molecular docking analysis of the representative compounds 11h, 11k, and 15a were performed, which not only revealed the impact of binding modes on DPP-4 inhibitory activity but also provided additional methodological values for design and optimization.

A series of novel 1,3,5-triarylpyrazoles 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t, 3u, 3v, 3w, 3x were synthesized from flavanones, arylhydrazines, and trimethyl phosphate in an one-pot procedure. Facile reaction process, easy after-reaction workshop, and good yields are the distinct characteristics of the developed protocol. The target compounds were characterized by element analysis, infrared ray (IR), ¹H NMR spectra, and electrospray ionization-mass spectrometry. The structure of representative compound 3h (C₂₃H₂₀N₂O₃, M_r = 372.42) was further confirmed by X-ray diffraction. It crystallizes in monoclinic, space group P 2₁/c, a = 8.9720(5), b = 24.5523(13), c = 8.9687(6) Å, α = 90.0000, β = 102.6417(17), γ = 90.0000°, V = 1927.76(20) ų, Z = 4, μ(MoKα) = 0.086, F(000) = 784, D_c = 1.283 g/cm³, the final R = 0.0349 and wR = 0.0844 for 1668 observed reflections (I > 2σ(I))

The design and optimization of p53–MDM2 interaction inhibitors has attracted a great deal of interest in the development of new anticancer agents. Systematical 2D-QSAR studies on 98 isoindolinone-based p53–MDM2 interaction inhibitors were carried out using linear and the non-linear mathematical methods. At first, a forward stepwise-multiple linear regression model (FS-MLR) was proposed with reasonable statistical parameters (R_train² = 0.881, Q_loo² = 0.847, R_test² = 0.854). Then, enhanced replacement method–multiple linear regression (ERM-MLR) and support vector machine regression (SVMR) were applied to set up more accurate models (ERM-MLR: R_train² = 0.914, Q_loo² = 0.894 and R_test² = 0.903; SVMR: R_train² = 0.924, Q_loo² = 0.920 and R_test² of 0.874). Furthermore, the reliability and application value of the ERM and SVMR model was also validated in virtual screening through receiver operating characteristic studies.

A series of cis-restricted 4,5-diaryl-3-aminopyrazole derivatives were synthesized and tested for their cytotoxic activity in vitro against five human cancer cell lines (K562, ECA-109, A549, SMMC-7721, and PC-3). Compounds 5a, 5b, 5d, and 6b showed potent cytotoxicity against all tested cell lines. Primary mechanism research on compound 5a indicated that it was a potent inhibitor of tubulin polymerization, arresting cell cycle in G₂/M phase. The docking research showed the conformation of 5a overlaps well with CA-4 in the crystallized protein complex, suggesting the 4,5-diaryl-3-aminopyrazoles were good mimics of CA-4.

A novel series of 2-substituted aminomethyl-9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 5a–q was synthesized via aminomethylation of 9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 4a–e with hydrochlorides of the respective amines 6a–m. The structures of these newly synthesized compounds were characterized by ¹H-NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non-small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi-drug resistant subline (KB-VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2-diethylaminomethyl-9-methyl-1,2,3,4-tetrahydrocarbazole-1-one 5c, exhibited a potential inhibitory effect against microtubule.

A series of novel arylpyrrolylmaleimides was synthesized and evaluated for their in-vitro cytotoxicity against various human cancer cell lines and their protein-kinase C inhibitory activity. Some of the compounds showed high or moderate cytotoxic activity against the tested cell lines. Compound 6b is the most promising compound against the tested cancer cell lines; 6d and 6e showed moderate protein-kinase C inhibition. Structure–activity relationships are discussed based on the experimental data obtained.