ABSTRACT
To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys.
Subject(s)
Antineoplastic Agents , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Deoxycytidine/chemical synthesis , Deoxycytidine/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Biological Availability , Capecitabine , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Carboxylic Ester Hydrolases/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/chemistry , Deoxycytidine/pharmacokinetics , Drug Delivery Systems/methods , Drug Delivery Systems/standards , Floxuridine/blood , Floxuridine/pharmacokinetics , Fluorouracil/blood , Fluorouracil/metabolism , Fluorouracil/pharmacokinetics , Humans , Intestines/enzymology , Kinetics , Liver/enzymology , Macaca fascicularis , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms, Experimental , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/standards , Structure-Activity Relationship , Substrate Specificity , Transplantation, HeterologousABSTRACT
A novel Candida albicans chitin synthase 1 (CaChs1) inhibitor, RO-41-0986 (1) was discovered by random screening. Systematic modification led to the identification of a highly potent CaChs1 inhibitor, RO-09-3024 (2), having strong antifungal activity against Candida spp. in vitro.
