Morrison Rick, Al-Rawi Jasim M A, Jennings Ian G, Thompson Philip E, Angove Michael J
Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Eur J Med Chem. 2016 Mar 3;110:326-39. doi: 10.1016/j.ejmech.2016.01.042. Epub 2016 Jan 27.
The synthesis of 6-aryl, 8- aryl, and 8-aryl-6-chloro-2-morpholino-1,3-benzoxazines with potent activity against PI3K and DNA-PK is described. Synthesis of thirty one analogues was facilitated by an improved synthesis of 3-bromo-2-hydroxybenzoic acid 13 by de-sulphonation of 3-bromo-2-hydroxy-5-sulfobenzoic acid 12 en route to 2-methylthio-substituted-benzoxazine intermediates 17-19. From this series, compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) (IC50 = 0.034 μM) was identified as a specific DNA-PK inhibitor, 170 fold more selective for DNA-PK activity compared to PI3K activity. Other compounds of the series show markedly altered selectivity for various PI3K isoforms including compound 20i (8-(naphthalen-1-yl) a potent and quite selective PI3Kδ inhibitor (IC50 = 0.64 μM). Finally, nine compounds were evaluated and showed antiproliferative activity against an NCI panel of cancer cell lines. Compound 20i (8-(naphthalen-1-yl) showed strong anti-proliferative activity against A498 renal cancer cells that warrants further investigation.
描述了具有抗PI3K和DNA-PK强效活性的6-芳基、8-芳基以及8-芳基-6-氯-2-吗啉代-1,3-苯并恶嗪的合成。通过改进3-溴-2-羟基-5-磺酸基苯甲酸12的脱磺化反应来合成3-溴-2-羟基苯甲酸13，从而促进了31种类似物的合成，该反应是通往2-甲硫基取代的苯并恶嗪中间体17-19的过程。从该系列中，化合物20k（LTURM34）（二苯并[b,d]噻吩-4-基）（IC50 = 0.034 μM）被鉴定为一种特异性DNA-PK抑制剂，与PI3K活性相比，对DNA-PK活性的选择性高170倍。该系列的其他化合物对各种PI3K亚型的选择性有明显改变，包括化合物20i（8-（萘-1-基）），一种强效且相当有选择性的PI3Kδ抑制剂（IC50 = 0.64 μM）。最后，评估了9种化合物，它们对美国国立癌症研究所（NCI）的一组癌细胞系显示出抗增殖活性。化合物20i（8-（萘-1-基））对A498肾癌细胞显示出很强的抗增殖活性，值得进一步研究。
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