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1.
Org Biomol Chem ; 11(38): 6642-9, 2013 Oct 14.
Article in English | MEDLINE | ID: mdl-23989458

ABSTRACT

Here, we describe the synthesis of the first C13-N-substituted STX derivatives 4, 5, and 6 bearing a guanidine, a urea group, and an acetamide, respectively, via the fully protected saxitoxinol derivative 8. These compounds are of interest because a previous docking study of saxitoxin (STX) with voltage-gated sodium channels (NaVCh) suggested that the C13 carbamoyl group of STX interacts with residue E403 in the pore region of NaVCh. In a cell-based assay with Neuro-2a cells, the NaVCh-inhibitory activities of 4 and 5 were more than 20- to 50-fold weaker than that of decarbamoyl-STX (3), which is 10-fold less potent than STX. On the other hand, 6 was 1000 times less potent than 3. The electrostatic analysis of C13 in STX and its analogs 4-6 using EON calculations suggested that the NaVCh-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13.


Subject(s)
Guanidine/chemistry , Saxitoxin/chemical synthesis , Saxitoxin/pharmacology , Urea/chemistry , Voltage-Gated Sodium Channels/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Mice , Molecular Structure , Saxitoxin/chemistry , Structure-Activity Relationship
2.
Gan To Kagaku Ryoho ; 33(4): 479-85, 2006 Apr.
Article in Japanese | MEDLINE | ID: mdl-16612157

ABSTRACT

Three strains of human esophageal carcinoma xenografts established in our institution were tested against combination chemotherapy in vivo and in vitro. TS-1 plus cisplatin (CDDP) was shown to be an effective combination against two carcinoma strains of moderately-differentiated type. Determination of the thymidylate synthase (TS) demonstrated a higher inhibition of the enzyme by adding CDDP to 5-FU, suggesting biochemical modulation. The remaining strain of poorly-differentiated type was resistant to the combination and an attempt was made to add docetaxel (DTX) to show that the three-drug combination was effective against the strain. Combination chemotherapy including TS-1 and CDDP thus appears to be useful treatment choice for esophageal carcinoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Animals , Cisplatin/administration & dosage , Cisplatin/pharmacology , Docetaxel , Drug Combinations , Drug Synergism , Fluorouracil/administration & dosage , Fluorouracil/pharmacology , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Oxonic Acid/administration & dosage , Oxonic Acid/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacology , Succinate Dehydrogenase/antagonists & inhibitors , Taxoids/administration & dosage , Taxoids/pharmacology , Tegafur/administration & dosage , Tegafur/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Tumor Cells, Cultured/drug effects
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