A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors.
Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.
School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, People's Republic of China.
Zhenyuan
Z
Miao
Lingjian
L
Zhu
Guoqiang
G
Dong
Chunlin
C
Zhuang
Yuelin
Y
Wu
Shengzheng
S
Wang
Zizao
Z
Guo
Yang
Y
Liu
Shanchao
S
Wu
Shiping
S
Zhu
Kun
K
Fang
Jianzhong
J
Yao
Jian
J
Li
Chunquan
C
Sheng
Wannian
W
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C586836:7-cyclohexylfluorocamptothecin; D000970:Antineoplastic Agents; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin