ABSTRACT
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Prodrugs/chemical synthesis , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Camptothecin/blood , Camptothecin/chemical synthesis , Camptothecin/chemistry , Camptothecin/pharmacokinetics , DNA Topoisomerases, Type I/metabolism , Dogs , Haplorhini , Humans , Hydrogen-Ion Concentration , Irinotecan , Mice , Mice, Nude , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Rats , Topoisomerase I Inhibitors , Transplantation, Heterologous , Water/chemistryABSTRACT
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Camptothecin/chemical synthesis , Camptothecin/chemistry , Camptothecin/pharmacology , Cell Line, Tumor , DNA Topoisomerases, Type I/metabolism , Humans , Mice , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Water soluble N-benzyltriazolium or N-benzylimidazolium salt type prodrugs of several highly lipophilic triazole or imidazole antifungals have been synthesized. They were designed to undergo an enzymatic activation followed by a self-cleavage to release a parent drug. The prodrugs such as 16 had enough chemical stability and water solubility for parenteral use and were rapidly and quantitatively converted to the active substance in human plasma.
