ABSTRACT
Two series of novel benzoimidazole sulfonamides as combretastatin A-4 analogs were synthesized. The cytotoxicities of the title compounds were evaluated against five different cancer cell lines. Among the tested compounds, four compounds displayed cytotoxicities against the HCT8 cell line. Compound 6a has shown the strongest potency against the tested human tumor cell lines with an IC50 value ranging from submicromolar to micromolar level.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Stilbenes/chemical synthesis , Stilbenes/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Combretum/chemistry , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemistry , Molecular Structure , Stilbenes/chemistry , Sulfonamides/chemistryABSTRACT
Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase.
Subject(s)
Adenosine Monophosphate/chemistry , Enzyme Inhibitors/chemistry , Fructose-Bisphosphatase/antagonists & inhibitors , Fructose-Bisphosphatase/chemistry , Allosteric Site , Animals , Binding Sites , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/metabolism , Fructosediphosphates/metabolism , Fructosephosphates/metabolism , HumansABSTRACT
OBJECTIVE: To study trabecular meshwork induced glucocorticoid response protein (TIGR) gene mutation in primary open angle glaucoma (POAG), their relatives and normal controls in Chongqing. METHODS: (1) The coding sequence of TIGR was screened for sequence alterations using polymerase chain reaction (PCR) followed by single-strand conformation polymorphism (SSCP). (2) Samples corresponding to bands of altered mobility were sequenced. (3) The sequence alterations were analyzed by bioinformatics. RESULTS: (1) In 15 POAG, TIGR gene mutation was found in 5 cases. In 10 POAG relatives, 2 TIGR gene mutations were found. No TIGR gene mutation was found in 20 normal persons in Chongqing. (2) The mutation sites Ser55Thr, Asp247Stop and in 49021 c-t alteration discovered in the present study have not been reported previously. The 63155 c-t alternation has been reported as a polymorphism site previously. (3) Bioinformatics analysis indicated that the mutations in structural domain could lead to the changes in the amino acid sequence coded, second structure of protein, isoelectric point and antigen binding site. CONCLUSIONS: We found that the TIGR gene mutations is closely related to the occurrence of JOAG in Chongqing. The relatives of POAG patients may have a higher incidence of TIGR gene mutation as compared with the controls. Furthermore, after analyzed by bioinformatics, we found that the alteration of structure and biological activity of TIGR protein resulted from gene mutation may be one of the important changes that leading to the occurrence of POAG.
