15855-06-8Relevant articles and documents
Potent colchicine-site ligands with improved intrinsic solubility by replacement of the 3,4,5-trimethoxyphenyl ring with a 2-methylsulfanyl-6-methoxypyridine ring
Aramburu, Laura,Gajate, Consuelo,Medarde, Manuel,Mollinedo, Faustino,álvarez, Raquel,Peláez, Rafael,Vicente-Blázquez, Alba
, (2020)
Colchicine site antimitotic agents typically suffer from low aqueous solubilities and are formulated as phosphate prodrugs of phenolic groups. These hydroxyl groups are the aim of metabolic transformations leading to resistance. There is an urgent need for more intrinsically soluble analogues lacking these hydroxyl groups. The 3,4,5-trimethoxyphenyl ring of combretastatin A-4 is a liability in terms of solubility but it is considered essential for high cytotoxic and tubulin polymerization inhibitory (TPI) activity. We have synthesized 36 new analogues of combretastatin A-4 replacing the trimethoxyphenyl moiety with more polar pyridine based moieties, measured their aqueous solubility, and studied their anti-proliferative effects against 3 human cancer cell lines. We show here that pyridine rings can be successful replacements for the trimethoxyphenyl ring, resulting in potent and more soluble analogues. The more straightforward replacement, a 2,6-dimethoxypyridine ring led to inactive analogues, but a 2-methoxy-6-methylsulfanylpyridine moiety led to active analogues when combined with different B rings. This replacement led to potent cytotoxic activity against sensitive human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies. Cell cycle analysis also showed apoptotic responses following treatment. Docking studies suggested binding at the colchicine site of tubulin and provided a good agreement with the observed SAR. A 2-methoxy-6-methylsulfanylpyridine moiety is a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands.
COMPOUNDS AND METHODS OF USE
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Paragraph 0686, (2021/05/07)
Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X1, X2, X3, X4, X5, A, L, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
Design, synthesis and biological evaluation of sphingosine-1-phosphate receptor 2 antagonists as potent 5-FU-resistance reversal agents for the treatment of colorectal cancer
Cui, Shuxiang,Guo, Zhikun,Han, Gaitian,Liu, Shuai,Liu, Xiaochun,Luo, Dongdong,Lv, Yan,Qu, Xianjun,Tian, Xiaochen,Wan, Shengbiao,Wang, Wenyu,Yang, Shuang,Zhang, Yuhang
, (2021/08/20)
5-Fluorouracil (5-FU) and its prodrugs are the essential clinical drugs for colorectal cancer (CRC) treatment. However, the drug resistance of 5-FU has caused high mortality of CRC patients. Thus, it is urgent to develop reversal agents of 5-FU resistance. Sphingosine-1-phosphate receptor 2 (S1PR2) was proved to be a potential target for reversing 5-FU resistance, but the activity of known S1PR2 antagonists JTE-013 were weak in 5-FU-resistant cell lines. To develop more potent S1PR2 antagonists to treat 5-FU-resistant cancer, a series of JTE-013 derivatives were designed and synthesized. The most promising compound 40 could markedly reverse the resistance in 5-FU-resistant HCT116 cells and 5-FU-resistant SW620 cells via inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). The key was that compound 40 with improved pharmacokinetic properties significantly increased the inhibitory rate of 5-FU in the SW620/5-FU cells xenograft model with no observable toxicity by inhibiting the expression of DPD in tumor and liver tissues. Altogether, these results suggest that compound 40 may be a promising drug candidate to reverse 5-FU resistance in the treatment of CRC.
