Huiming Huang

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.

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.

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 1H-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.

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.

(2R)-N-[5-(4-Chloro­phen­yl)-1,3,4-thia­diazol-2-yl]-2-(cinnamoylamino)propanamide

In the title compound, C20H17ClN4O2S, the dihedral angle between the two benzene rings is 65.9 (1)°; the corresponding angle between the 4-chlorophenyl and thiadiazole 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.

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

The asymmetric unit of the title compound, C21H20N4O3S, contains two independent molecules. The dihedral angles between the two benzene rings are 47.6 (1) and 30.2 (1)°, the corresponding values between the p-methoxybenzene and thiadiazol rings are 12.3 (1) and 24.7 (1)°, respectively, for the two molecules. 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 interactions. 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,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, C18H15ClN4O4S, the dihedral angle between the two benzene rings is 1.4 (3)°. The angle between the phenyl ring and thiadiazole 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, molecules are linked by intermolecular O—H⋯N, N—H⋯O and O—H⋯O hydrogen bonds, forming a three-dimensional network.

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

In the structure of the title compound, C17H13BrN4O2S, the dihedral angle between the two benzene rings is 38.5 (1)°; the angle between the 4-bromobenzene and thiadiazole 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 intermolecular N—H⋯O and C—H⋯O hydrogen bonding, with both interactions leading to inversion dimers.