Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents.

Focal adhesion kinase (FAK) is a ubiquitous intracellular non-receptor tyrosine kinase, which is involved in multiple cellular functions, including cell adhesion, migration, invasion, survival, and angiogenesis. In this study, a series of 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized according to the E-pharmacophores generated by docking a library of 667 fragments into the ATP pocket of the co-crystal complex of FAK and PF-562271 (PDB ID: 3BZ3). The 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine derivatives demonstrated excellent activity against FAK and the cell lines SMMC7721 and YY8103. 2-((2-((3-(Acetamidomethyl)phenyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylbenzamide (16c) was selected for further bioactivity evaluations in vivo, including preliminary pharmacokinetic profiling in rats and toxicity assays in mice, and tumor growth inhibition studies in a xenograft tumor model. The results showed that 16c did not affect the body weight gain of the animals up to a dose of 200 mg/kg, and significantly inhibited tumor growth with a tumor growth inhibition rate of 78.6% compared with the negative control group. Furthermore, phosphoantibody array analyses of a sample of the tumor suggested that 16c inhibited the malignant proliferation of hepatocellular carcinoma (HCC) cells through decreasing the phosphorylation in the FAK cascade.

Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor.

A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused camptothecins possess antiproliferative activity against the tested cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.