ABSTRACT
PURPOSE: Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11). METHODS: A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs. RESULTS: A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED(50)) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab. CONCLUSION: It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.
Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Dipeptides/therapeutic use , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Neoplasm Proteins/biosynthesis , Prodrugs/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Acetylcholinesterase/metabolism , Animals , Antineoplastic Agents/pharmacology , Camptothecin/pharmacology , Camptothecin/therapeutic use , Cell Line, Tumor , Dipeptides/pharmacology , Drug Resistance, Neoplasm , Drug Synergism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Irinotecan , Male , Mice , Mice, Nude , Prodrugs/pharmacology , Solubility , Water , Xenograft Model Antitumor AssaysABSTRACT
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
A new series of acid-stable antifungal agents having strong inhibitory activity against Candida albicans N-myristoyltransferase (CaNmt) has been developed starting from acid-unstable benzofuranylmethyl aryl ether 2. The inhibitor design is based on X-ray crystallographic analysis of a CaNmt complex with aryl ether 3. Among the new inhibitors, pyridine derivative 8b and benzimidazole derivative 8k showed clear antifungal activity in a murine systemic candidiasis model.
Subject(s)
Acyltransferases/antagonists & inhibitors , Antifungal Agents/chemical synthesis , Benzofurans/chemical synthesis , Fungal Proteins/antagonists & inhibitors , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Candida albicans/drug effects , Candida albicans/enzymology , Disease Models, Animal , Drug Design , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Models, Molecular , Structure-Activity RelationshipABSTRACT
An improved method for the synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl(3) to the neplanocin A 6'-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC(50) value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC(50) = 1.8 mg/kg/day).
