Solubility-Improved 10-O-Substituted SN-38 Derivatives with Antitumor Activity.

Abstract

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.

• Authors: Hisashi Doi, Tatsuya Kida, Kosuke Nishino, Masatoshi Nakatsuji, Shiho Sakamoto, Shota Shimizu, Yoshiaki Teraoka, Yasuhisa Tamura, Yosky Kataoka, Takashi Inui
• Journal: ChemMedChem (ChemMedChem) Vol. 12 Issue 20 Pg. 1715-1722 (10 20 2017) ISSN: 1860-7187 [Electronic] Germany
• PMID: 28891271 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Camptothecin (analogs & derivatives, chemistry)
• Humans
• Irinotecan
• Male
• Mice
• Molecular Structure
• Neoplasms, Experimental (drug therapy)
• Prostatic Neoplasms (drug therapy)
• Structure-Activity Relationship