Benzyl ether-linked glucuronide derivative of 10-hydroxycamptothecin designed for selective camptothecin-based anticancer therapy.
A beta-glucuronidase-activated prodrug approach was applied to 10-hydroxycamptothecin, a Camptotheca alkaloid with promising antitumor activity but poor water solubility. We synthesized a glucuronide prodrug of 10-hydroxycamptothecin ( 7) in which glucuronic acid is connected via a self-immolative 3-nitrobenzyl ether linker to the 10-OH group of 10-hydroxycamptothecin. Compound 7 was 80 times more soluble than 10-hydroxycamptothecin in aqueous solution at pH 4.0 and was stable in human plasma. Prodrug 7 was 10- to 15-fold less toxic than the parent drug to four human tumor cell lines. In the presence of beta-glucuronidase, prodrug 7 could be activated to elicit similar cytotoxicity to the parent drug in tumor cells. Enzyme kinetic studies showed that Escherichia coli beta-glucuronidase had a quite low K m of 0.18 microM for compound 7 and exhibited 520 times higher catalytic efficiency for 7 than for 6 (a glucuronide prodrug of 9-aminocamptothecin). Molecular modeling studies predicted that compound 7 would have a higher binding affinity to human beta-glucuronidase than compound 6. Prodrug 7 may be useful for selective cancer chemotherapy by a prodrug monotherapy (PMT) or antibody-directed enzyme prodrug therapy (ADEPT) strategy.
Leu
Yu-Ling
YL
Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan. yulin@mail.chna.edu.tw
Chen
Chien-Shu
CS
Wu
Yih-Jang
YJ
Chern
Ji-Wang
JW
D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000201:enzymology; D005966:Glucuronidase / Q000737:chemistry / Q000187:drug effects; D020719:Glucuronides / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D010647:Phenyl Ethers / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D020719:Glucuronides; D010647:Phenyl Ethers; D011355:Prodrugs; C028098:10-hydroxycamptothecin; D005966:Glucuronidase; D002166:Camptothecin