An efficient Selectfluor-mediated condensation of indoles and anthranilates for the synthesis of indoloquinazolinones.

Intermolecular fluorocyclization of indoles with anthranilates, which proceeded smoothly to give diverse indoloquinazolinone architectures under mild reaction conditions, has been developed. A wide range of substrates were compatible with this cyclization system. The synthetic fluorinated compounds could be modified by their conversion to various substituted quinazolinones for drug discovery. In addition, this protocol has been applied to the concise total synthesis of bioactive natural alkaloids phaitanthrins A-B, cephalanthrin A and cruciferane.

5D-QSAR studies of 1H-pyrazole derivatives as EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is highlighted as a target for anticancer treatment. Several EGFR inhibitors were approved in cancer treatment. Comparatively, 5D-QSAR is a new methodology which considers an ensemble of different induced-fit models. Based on 1H-pyrazole derivatives as EGFR inhibitors, a 5D-QSAR was studied in which the method of quasi-atomistic receptor surface modeling was used. The presented QSAR model showed contributions of the hydrogen bond acceptor, and hydrophobic and salt bridge fields to the activity. The QSAR model was statistically validated and also externally validated applying 19 compounds (test set) which were not included in the model generation process. The scramble tests were performed to further verify the robustness. Apart from exploration of the binding of 1H-pyrazole derivatives to the EGFR, the 5D-QSAR model can be helpful to design of new EGFR inhibitors. The five-dimensional quantitative structure-activity relationship (5D-QSAR) of 1H-pyrazole derivatives as EGFR inhibitors with quasi-atomistic receptor surface modeling approach is described.

Molecular dynamics-guided receptor-dependent 4D-QSAR studies of HDACs inhibitors.

Histone deacetylases (HDACs) were highlighted as a novel category of anticancer targets. Several HDACs inhibitors were approved for therapeutic use in cancer treatment. Comparatively, receptor-dependent 4D-QSAR, LQTA-QSAR, is a new approach which generates conformational ensemble profiles of compounds by molecular dynamics simulations at binding site of enzyme. This work describes a receptor-dependent 4D-QSAR studies on hydroxamate-based HDACs inhibitors. The 4D-QSAR model was generated by multiple linear regression method of QSARINS. Leave-N-out cross-validation (LNO) and Y-randomization were performed to analysis of the independent test set and to verify the robustness of the model. Best 4D-QSAR model showed the following statistics: R2 = 0.8117, Q2LOO = 0.6881, Q2LNO = 0.6830, R2Pred = 0.884. The results may be used for further virtual screening and design for novel HDACs inhibitors. The receptor dependent 4D-QSAR model was developed for the hydroxamate derivatives as HDAC inhibitors by making use of molecular dynamics simulation to obtain conformational ensemble profile for each compound. The multiple linear regression method was used to generate 4D-QSAR model with the suitable predictive ability and the excellent statistical parameters.

Synthesis and Molecular Simulation Studies of Mandelic Acid Peptidomimetic Derivatives as Aminopeptidase N Inhibitors.

BACKGROUND: The aminopeptidase N (APN) over-expressed in tumor cells plays a critical role in angiogenesis which makes the development of APN inhibitors an attractive strategy for cancer research. AIMS AND OBJECTIVES: It is clinically significant to develop potential APN inhibitors for cancer treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid peptidomimetic derivatives as APN inhibitors are reported. MATERIALS AND METHODS: Analysis of the binding mode of bestatin to APN led to the design and synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were evaluated by the spectrophotometric method. The binding mode of the target compounds with the APN binding site was studied relying on docking studies, molecular dynamics simulation experiments and binding energies calculation. RESULTS: The structures of target compounds were confirmed by IR, 1H-NMR and MS. All compounds exhibited a different range of inhibitory ability with IC50 values lying in the micromolar level. The compound 9m was found to be most potent as compared to other target derivatives. The molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important for inhibitory activities. CONCLUSION: The compound 9m might represent a promising scaffold for the further development of novel anti-cancer drugs.

Synthesis and 4D-QSAR Studies of Alanine Hydroxamic Acid Derivatives as Aminopeptidase N Inhibitors.

BACKGROUND: As a target for anticancer treatment, aminopeptidase N (APN) shows its overexpression on diverse malignant tumor cells and associates with cancer invasion, angiogenesis and metastasis. OBJECTIVE: The objective of the study was the design, synthesis and biological activity evaluation of alanine hydroxamic acid derivatives as APN inhibitors, and investigation of the binding mode of inhibitors in the APN active site. METHODS: Alanine hydroxamic acid derivatives were synthesized and evaluated for their in vitro anti-cancer activity using CCK-8 assay. Molecular docking and 4D-QSAR studies were carried out to suggest the mechanism of biological activity. RESULTS: Compared with Bestatin, compound 9b showed the best APN inhibition activity. The putative binding mode of 9b in the APN active site was also discussed. Moreover, the robust and reliable 4D-QSAR model exhibited the following statistics: R2 = 0.9352, q2 LOO = 0.8484, q2 LNO =0.7920, R2 Pred = 0.8739. CONCLUSION: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of the current scaffold would be beneficial.

Synthesis and molecular simulation study of furoic peptidomimetic derivatives as potent aminopeptodase N inhibitors.

The aminopeptidase N (APN) plays a critical role in angiogenesis and is over-expressed in tumor cells. In this paper, we report the synthesis and enzyme inhibition assay of furoic peptidomimetic compounds. These new compounds exhibit potent inhibitory ability toward APN with IC50 values lying in the micromolar level. The binding mode of inhibitors in APN active site was explained by a molecular simulation study. These data reveal that ligand coordinating with the catalytic Zn-ion is very important for inhibitory activities.

Exploring ligand dissociation pathways from aminopeptidase N using random acceleration molecular dynamics simulation.

Aminopeptidase N (APN) is a zinc-dependent ectopeptidase involved in cell proliferation, secretion, invasion, and angiogenesis, and is widely recognized as an important cancer target. However, the mechanisms whereby ligands leave the active site of APN remain unknown. Investigating ligand dissociation processes is quite difficult, both in classical simulation methods and in experimental approaches. In this study, random acceleration molecular dynamics (RAMD) simulation was used to investigate the potential dissociation pathways of ligand from APN. The results revealed three pathways (channels A, B and C) for ligand release. Channel A, which matches the hypothetical channel region, was the most preferred region for bestatin to dissociate from the enzyme, and is probably the major channel for the inner bound ligand. In addition, two alternative channels (channels B and C) were shown to be possible pathways for ligand egression. Meanwhile, we identified key residues controlling the dynamic features of APN channels. Identification of the dissociation routes will provide further mechanistic insights into APN, which will benefit the development of more promising APN inhibitors. Graphical Abstract The release pathways of bestatin inside active site of aminopeptidase N were simulated using RAMD simulation.

3D-QSAR studies on flavone-8-acetic acid derivatives of aminopeptidase N inhibitors.

The 3D-QSARs models of 29 flavone-8-acetic acid derivatives of aminopeptidase N inhibitors were generated by applying the molecular interaction fields at various 3D grid spacing. The cross-validated correlation coefficient q(2)LMO (0.6019) and conventional correlation coefficient r(2) (0.9756) were obtained at a 1.0 Å 3D grid spacing, indicating the statistical significance of this class of compounds. The calculated inhibitory activities showed a high degree of agreement with experimental values. Then, the 4 ns MD simulation of ligand-receptor complex was carried out. The stable binding mode of the compound 19b was determined.

Synthesis and antiproliferative assay of 1,3,4-oxadiazole and 1,2,4-triazole derivatives in cancer cells.

A series of new 1,3,4-oxadiazole and 1,2,4-triazole derivatives were synthesized. The structures were confirmed by IR, (1)H-NMR, and MS. The compounds were evaluated for their antiproliferative activity against K562 (human erythromyeloblastoid leukemia cell line), MDA-MB-231 (human breast adenocarcinoma cell line), HT29 (human colon adenocarcinoma grade II cell line) and HepG2 (human hepatocellular liver carcinoma cell line) in vitro. The result showed that 7 compounds displayed inhibitory activities against K562 with the inhibition rate more than 50%. Especially, compound 5f exhibited the most potent activity against K562 with 85% inhibition ratio and could be used as lead compound to search new 1,3,4-oxadiazole derivatives as antiproliferative agent.

Design, synthesis and biological evaluation of CB1 cannabinoid receptor ligands derived from the 1,5-diarylpyrazole scaffold.

The CB1 receptor belongs to the G-protein-coupled receptor superfamily. CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In this study, we report the synthesis and in vitro binding affinity assay of some 1,5-diarylpyrazole scaffold compounds. The binding results showed that some of the target compounds had an excellent potency toward the CB1 receptor with IC50 values lying at the nanomole level.

4-Chloro-N-[3-methyl-1-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)but-yl]benzamide.

In the title compound, C(14)H(16)ClN(3)O(2)S, the dihedral angle between the 4-chloro-phenyl and 1,3,4-oxadiazole rings is 67.1 (1)° and the orientation of the amide N-H and C=O bonds is anti. In the crystal, mol-ecules are linked by N-H⋯O and N-H⋯S hydrogen bonds.

(2R,3R)-N-(4-Chloro-phen-yl)-2,3-dihydr-oxy-N'-(5-phenyl-1,3,4-thia-diazol-2-yl)succinamide.

In the structure of the title compound, C(18)H(15)ClN(4)O(4)S, the dihedral angle between the two benzene rings is 1.4 (3)°. The angle between the phenyl ring and thia-diazole ring is 5.8 (4)°. The conformations of the N-H and C=O bonds are anti with respect to each other. In the crystal structure, mol-ecules are linked by inter-molecular O-H⋯N, N-H⋯O and O-H⋯O hydrogen bonds, forming a three-dimensional network.

Synthesis of 1,3,4-thiadiazole derivatives as aminopeptidase N inhibitors.

Aminopeptidase N (APN) is a zinc-dependent ectopeptidase which plays an important role in the invasion of metastatic tumors. In this study, we report the synthesis and in vitro enzyme inhibition assay of 1,3,4-thiadiazole scaffold compounds. These new compounds have potent inhibitory activities toward APN with IC50 values in the micromolar range.

1-(3-Chloro-benz-yloxy)urea.

The asymmetric unit of the crystal structure of the title compound, C(8)H(9)ClN(2)O(2), contains four independent mol-ecules. The dihedral angles between the urea N-(C=O)-N planes and the benzene rings are 83.3 (3), 87.8 (1), 89.1 (1) and 17.5 (2)° in the four mol-ecules. Extensive N-H⋯O hydrogen bonding is present in the crystal structure.

2-Benzoyl-amino-N-[5-(4-bromo-phen-yl)-1,3,4-thia-diazol-2-yl]ethanamide.

In the structure of the title compound, C(17)H(13)BrN(4)O(2)S, the dihedral angle between the two benzene rings is 38.5 (1)°; the angle between the 4-bromo-benzene and thia-diazole rings is 1.3 (1)°. The conformations of the N-H and C=O bonds are anti with respect to each other. The structure displays inter-molecular N-H⋯O and C-H⋯O hydrogen bonding, with both interactions leading to inversion dimers.

The synthesis and preliminary activity assay in vitro of peptide-like derivatives as APN inhibitors.

Both the aminopeptidase N (APN) and matrix metalloproteinase (MMP) are essential metallopeptidases in the development of tumor invasion and angiogenesis. A series of novel peptide-like derivatives were designed and synthesized as antitumor agents. Their structures were confirmed by IR, MS, and (1)H-NMR. These compounds exhibited potent inhibitory activities against APN and low activity against MMP in vitro. The derivatives with methoxy group show better activities than those with other substituted group and could be used as lead compounds for exploring new APN inhibitors in the future.

Novel aminopeptidase N inhibitors derived from 1,3,4-thiadiazole scaffold.

The aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. In this study, we report the synthesis and in vitro enzyme inhibition assay of 1,3,4-thiadiazole scaffold compounds. These new compounds have potent inhibitory activities toward APN with IC(50) values in the micromol rang.

Progress in the development of matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years. With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.

(2R)-2-Cinnamoylamino-N-[5-(4-methoxy-phen-yl)-1,3,4-thia-diazol-2-yl]propanamide.

The asymmetric unit of the title compound, C(21)H(20)N(4)O(3)S, contains two independent mol-ecules. The dihedral angles between the two benzene rings are 47.6 (1) and 30.2 (1)°, the corresponding values between the p-methoxy-benzene and thia-diazol rings are 12.3 (1) and 24.7 (1)°, respectively, for the two mol-ecules. The conformations of the N-H and C=O bonds are anti with respect to each other. The enone groups show a trans configuration. The crystal structure is stabilized by N-H⋯O and N-H⋯N inter-actions. The absolute structure could not be determined from the X-ray data but the absolute configuration has been assigned by reference to an unchanging chiral centre in the synthetic procedure.

(2R)-N-[5-(4-Chloro-phen-yl)-1,3,4-thia-diazol-2-yl]-2-(cinnamoylamino)propanamide.

In the title compound, C(20)H(17)ClN(4)O(2)S, the dihedral angle between the two benzene rings is 65.9 (1)°; the corresponding angle between the 4-chloro-phenyl and thia-diazole rings is 3.4 (8)°. The conformations of the N-H and C=O bonds are anti with respect to each other. The enone groups show a trans configuration. The structure displays intermolecular N-H⋯O, C-H⋯N, C-H⋯S and C-H⋯O hydrogen bonding.