20-O-acylcamptothecin derivatives: evidence for lactone stabilization.
Convincing UV and NMR spectrophotometric evidence is presented which demonstrates that at physiological pH, 7.4, 20-O-acyl derivatives of camptothecin (CPT) are substantially more stable in the lactone form than the 20-OH parent. Additionally, it was determined by HPLC analysis that the lactone ring of a 20-O-ether derivative of CPT underwent endocyclic ring opening at pH > or =8.5, while the lactone ring of 20-O-acyl CPT derivatives remained unaffected. PEG (and other smaller alkyl) 20-O-acyl-CPT derivatives released native CPT at pH > 9.5, which arises from exocyclic cleavage, thus precluding isolation of any open CPT acyl PEG (or alkyl) carboxylate forms.
Zhao
H
H
Enzon, Inc., Piscataway, New Jersey 08854-3969, USA.
Lee
C
C
Sai
P
P
Choe
Y H
YH
Boro
M
M
Pendri
A
A
Guan
S
S
Greenwald
R B
RB
D000215:Acylation; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D007783:Lactones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D014197:Trees / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D011355:Prodrugs; D011092:Polyethylene Glycols; C115093:pegamotecan; D002166:Camptothecin