Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-d]pyrimidine Derivatives as Mnk and HDAC Inhibitors.

Kun Xing,Linxiang Zhao,Jian Zhang,Tong Tong,Dan Liu,Yu Han

doi:10.3390/molecules25184318

Kun Xing, Linxiang Zhao + Show 4 more

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https://doi.org/10.3390/molecules25184318

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Abstract

Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound A12 displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound A12 exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-d]pyrimidine framework and hydroxamic acid motif of compound A12 were essential for maintaining the activity of HDAC and Mnk. These result indicated that A12 was a potent Mnk /HDAC inhibitor and will be further researched.

Highlights

Histone deacetylase (HDAC) plays an important role in regulating the acetylation level of histones or non-histone proteins, it can regulate cell proliferation, differentiation and apoptosis [1].The abnormal changes in histone acetylation levels often induce the expression of oncogene.targeting HDAC could be a strategy to treat cancer
The synthesis route of A01 and A07 is described in Scheme 1
The results showed that when the zinc-binding motif (ZBG) was hydroxamic acid motif, the inhibitory against Mnks and HDACs through a linker with different length and rigidity to obtain the compounds A01–A12

Summary

Introduction

Histone deacetylase (HDAC) plays an important role in regulating the acetylation level of histones or non-histone proteins, it can regulate cell proliferation, differentiation and apoptosis [1].The abnormal changes in histone acetylation levels often induce the expression of oncogene.targeting HDAC could be a strategy to treat cancer. Histone deacetylase (HDAC) plays an important role in regulating the acetylation level of histones or non-histone proteins, it can regulate cell proliferation, differentiation and apoptosis [1]. The abnormal changes in histone acetylation levels often induce the expression of oncogene. Targeting HDAC could be a strategy to treat cancer. HDAC inhibitors can inhibit cell growth and differentiation by increasing histone and non-histone acetylation levels in tumor cells, and further promote apoptosis. HDAC inhibitors show promising therapeutic effects in hematological cancers, but they show poor effect in solid tumors. Vorinostat has an unsatisfactory effect on breast cancer, colorectal cancer, non-small cell lung cancer and thyroid cancer [2]. Romidepsin, belisestat and pabistil are not effective in solid tumors [3]

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