ABSTRACT
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
Subject(s)
Factor IXa/antagonists & inhibitors , Isoxazoles/chemistry , Animals , Binding Sites , Blood Coagulation/drug effects , Crystallography, X-Ray , Dogs , Drug Design , Drug Evaluation, Preclinical , Factor IXa/metabolism , Half-Life , Humans , Inhibitory Concentration 50 , Isoxazoles/metabolism , Isoxazoles/pharmacology , Molecular Dynamics Simulation , Partial Thromboplastin Time , Protein Structure, Tertiary , Prothrombin Time , Rats , Structure-Activity RelationshipABSTRACT
Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B.
Subject(s)
Ciguatoxins/chemical synthesis , Ciguatoxins/chemistry , Cyclization , Ethers/chemistry , Free Radicals/chemistry , Quantum Theory , Safrole/analogs & derivatives , Safrole/chemistry , StereoisomerismABSTRACT
Ciguatera fish poisoning (CFP) is a form of food poisoning caused by the ingestion of a variety of reef fish that have accumulated trace amounts of ciguatoxins produced by dinoflagellates of the genus Gambierdiscus through the food chain. CFP affects more than 50,000 people each year. The extremely low level of the causative neurotoxins, ciguatoxins, in fish has hampered the preparation of antibodies for detecting the toxins. In this paper, we describe a thiol strategy for synthesizing a keyhole limpet hemocyanin (KLH)-conjugate (20) of the ABCDE-ring fragment of the Pacific ciguatoxins, CTX1B (1) and 54-deoxyCTX1B (4). We succeeded in producing a monoclonal antibody (3G8) against the left wings of these ciguatoxins by immunizing mice with the hapten-KLH conjugate (20) as the synthetic antigen. The most promising mAb, 3G8, does not cross-react with other related marine toxins. Sandwich enzyme-linked immunosorbent assay (ELISA) utilizing 3G8 and the previously prepared monoclonal antibody (8H4) enabled us to detect 1 specifically at less than 0.28 ng/mL.
Subject(s)
Ciguatoxins/analysis , Fishes , Food Contamination , Food Inspection/methods , Seafood/analysis , Adjuvants, Immunologic/chemistry , Animals , Antibodies, Monoclonal/metabolism , Antibody Affinity , Ciguatera Poisoning/prevention & control , Ciguatoxins/chemistry , Ciguatoxins/metabolism , Cross Reactions , Dinoflagellida/metabolism , Enzyme-Linked Immunosorbent Assay , Haptens/chemistry , Hemocyanins/chemistry , Limit of DetectionABSTRACT
Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers. We report a highly stereoselective 6-exo radical cyclization/ring-closing olefin metathesis sequence to construct the syn/trans-fused polyether system. The new method was applied to the practical synthesis of ciguatoxin CTX3C.
