Research paperDesign, synthesis and biological evaluation of thienopyrimidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors
Graphical abstract
By rational design and modification, compound 9m showed excellent HDACs inhibitory activity, strong anti-proliferative activity against human cancer cell lines including RMPI 8226 and HCT 116. Moreover, compound 9m noticeably up-regulated the level of histone H3 acetylation at the low concentration of 0.3 μM.
Introduction
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression [1]. The acetylation status of histones is determined by two sets of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs) [2]. HDACs also interact with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 (MAT2), HDACs deacetylates p53 and modulates its effect on cell growth and apoptosis. HDAC inhibitors demonstrated prominent antitumor efficacy on broad spectrum neoplasms in preclinical and clinical studies [3], [4], [5]. This concept has been well validated by the approval of HDAC inhibitors vorinostat (suberoylanilide hydroxamic acid, SAHA) [6] and romidepsin (depsipeptide) [7] for the treatment of cutaneous T-cell lymphoma.
The thienopyrimidine fragment is widely present in antitumor agents [8], anti-inflammatory agents [9], and anti-diabetic agents [10]. In our previous studies, we reported 4-anilinothieno[2,3-d]pyrimidine derivatives as irreversible EGFR inhibitors that displayed excellent inhibitory activities against wild type and mutant EGFR (Fig. 1) [11]. CUDC-101 has been reported as a multi inhibitors against HDAC, EGFR, and HER2 for the treatment of cancer, which contains a quinazoline moiety within its structure [12]. On the basis of these observations, we attempted using substituted 4-anilinothieno[3,2-d]pyrimidine moiety as a cap group (CAP) for protein surface interactions, fixed carbon chain as a linker region, and hydroxamic acid group as a zinc binding group (ZBG) (Fig. 1). Herein, we presented the design, synthesis and biological evaluation of thienopyrimidine hydroxamic acid based derivatives as novel HDACs inhibitors. Most of these compounds showed excellent potencies against HDACs and displayed powerful anti-proliferative activities against cancer cell lines in vitro.
Section snippets
Chemistry
The synthetic route to obtain the desired thienopyrimidine-based hydroxamic acid derivatives 9a-r are shown in Scheme 1. Heated by the microwave, the thieno[3,2-d]pyrimidin-4(3H)-one 3 was obtained via the cyclization of methyl 3-aminothiophene-2-carboxylate with formamidine acetate. Then, the nitration of intermediate 3, followed by chlorination to afford 5. Coupling with various substituted anilines and then reduction of nitro group using iron/NH4Cl afforded the key intermediate 7. Treatment
Conclusion
In conclusion, based on the previous work in our laboratory, a series of thienopyrimidine-based hydroxamic acid derivatives 9a-r were designed, synthesized and evaluated as novel HDAC inhibitors. The in vitro biological evaluations indicated that most compounds exhibited excellent inhibition against recombinant HDAC enzyme activities and multiple cancer cells lines proliferation. Especially, the compounds 9e, 9m, and 9o could significantly inhibit the proliferation of RPMI 8226 and HCT 116
Chemistry
The reagents (chemicals) were commercially available and used without further purification. Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness). Column chromatography was performed on silica gel 300–400 mesh to purify the compounds. Nuclear magnetic resonance (NMR) spectra were performed on a Brucker AMX-400 (TMS as IS). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described
Acknowledgements
We gratefully acknowledge financial support from the National Natural Science Foundation of China (81620108027, 21632008, 91229204, 21472209 and 81220108025) the Major Project of Chinese National Programs for Fundamental Research and Development (2015CB910304), and National S&T Major Projects (2014ZX09507002-001 and 2014ZX09507-002-005).
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These authors contributed equally to this work.