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 F- or Br-labeled SN-38 derivatives for in vivo positron emission tomography studies.

Structural Modification Endows Small-Molecular SN38 Derivatives with Multifaceted Functions

“…The water solubility of compound 16 was enhanced by 17-fold in phosphate-buffered saline compared with SN38. Though the in vitro cytotoxicity of compound 16 toward prostate cancer, PC-3 cells were around half that of SN38, and compound 16 had a higher inhibitory effect on tumor growth in PC-3 tumor-bearing mice than SN38, even at lower dosage [ 33 ]. More importantly, fluoride can be tracked in cells by NMR to investigate its disposition, which deserves further study.…”

“…Compounds 45 – 51 reported by SQ Zhang and coworkers had an inhibitory effect on A549 cells and HCT-116 cells comparable to that of SN38 [ 32 ]. Compounds 52 – 57 showed slightly lower cytotoxicity toward PC-3 cells than SN38 [ 33 ]. Compound 58 was synthesized by the introduction of amino acid to SN38.…”

Effect of 23‑hydroxybetulinic acid on lung adenocarcinoma and its mechanism of action

“…23-HBA has been structurally modified to enhance its antitumor efficacy and bioavailability, resulting in >300 derivatives. Some of these derivatives have shown improved antitumor activity ( 22 ). 23-HBA can inhibit the activation of NF-κB p65 and the MAPK pathway, and reduce the secretion of inflammatory factors in mice with DSS-induced acute ulcerative colitis ( 23 ).…”

Synthesis and Biological Evaluation of 10‐Substituted Camptothecin Derivatives with Improved Water Solubility and Activity

“…In this process, SN‐38 remaining in the intestines causes intestinal inflammation, leading to diarrhea. In fact, a 10‐O‐substitution strategy was used to avoid the hepatic metabolism of 10‐O‐glucuronidation in the liver and its derivatives have been developed from the medicinal chemistry perspective to further increase the aqueous solubility and the antitumor activity [14] . Chimmitecan, a case of camptothecin 9‐position modification, was reported in 2007 [15] .…”

“…In fact, a 10-O-substitution strategy was used to avoid the hepatic metabolism of 10-O-glucuronidation in the liver and its derivatives have been developed from the medicinal chemistry perspective to further increase the aqueous solubility and the antitumor activity. [14] Chimmitecan, a case of camptothecin 9-position modification, was reported in 2007. [15] The allyl substitution at the 9 position of CPT benefits chimmitecan a salient anti-MDR activity and oral availability.…”