Solubility-Improved 10-O-Substituted SN-38 Derivatives with Antitumor Activity.
With the objective of improving the poor water solubility of the potent antitumor compound SN-38, 10-O-substituted SN-38 derivatives were developed by the introduction of fluoroalkyl, fluorobenzoyl, or bromobenzoyl groups. The 10-O-fluoropropyl-substituted compound 2 {(S)-4,11-diethyl-9-(3-fluoropropoxy)-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione} was found to be 17-fold more soluble than SN-38 in phosphate-buffered saline, and it exhibited a level of biological activity ≈50 % that of SN-38 in a cytotoxicity assay using the prostate cancer cell line PC-3. Five other derivatives did not show solubility improvements to the same extent, but their activities in cytotoxicity assays were nearly the same as that of SN-38. In vivo studies of 2 with PC-3 tumor-bearing mice revealed that it has higher antitumor activity than SN-38, even at lower dosage. These results will promote the medicinal chemistry application of 10-O-modifications of SN-38 and help reestablish the potential this drug. Furthermore, the inclusion of fluoro and bromo substituents means that the synthetic strategy developed here may be used to obtain 18 F- or 76 Br-labeled SN-38 derivatives for in vivo positron emission tomography studies.
['Doi|Hisashi|H|', 'Kida|Tatsuya|T|', 'Nishino|Kosuke|K|', 'Nakatsuji|Masatoshi|M|', 'Sakamoto|Shiho|S|', 'Shimizu|Shota|S|', 'Teraoka|Yoshiaki|Y|', 'Tamura|Yasuhisa|Y|', 'Kataoka|Yosky|Y|', 'Inui|Takashi|T|']
D000818:Animals D000970:Antineoplastic Agents D002166:Camptothecin D006801:Humans D000077146:Irinotecan D008297:Male D051379:Mice D015394:Molecular Structure D009374:Neoplasms, Experimental D011471:Prostatic Neoplasms D013329:Structure-Activity Relationship
SN-38 solubility PET imaging anticancer agents drug design