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. 2017 Oct 31;22(11):1870.
doi: 10.3390/molecules22111870.

Synthesis and Structure-Activity Relationships of 4-Morpholino-7,8-Dihydro-5H-Thiopyrano[4,3-d]pyrimidine Derivatives Bearing Pyrazoline Scaffold

Qinqin Wang  1 , Xiaojing Li  2 , Chengyu Sun  3 , Binliang Zhang  4 , Pengwu Zheng  5 , Wufu Zhu  6 , Shan Xu  7
Affiliations

Synthesis and Structure-Activity Relationships of 4-Morpholino-7,8-Dihydro-5H-Thiopyrano[4,3-d]pyrimidine Derivatives Bearing Pyrazoline Scaffold

Qinqin Wang et al. Molecules. .

Abstract

Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is abnormally active in the growth and proliferation of cancer cells. The inhibition of PI3K kinase can effectively block the conduction of signaling pathways and is an ideal target for drug design. In this paper; two series of 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing pyrazoline moiety (7a-l; 8a-l) were synthesized; and their cytotoxicity in vitro were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method against four human cancer cell lines including A549; PC-3; MCF-7; and HepG2 cell lines. The activity of the most promising compound 8d against PI3Kα kinase was further evaluated. The results indicated that most of the target compounds showed moderate to excellent cytotoxicity and the most promising compound 8d showed excellent cytotoxicity against four cancer cell lines with half maximal inhibitory concentration (IC50) values of 6.02-10.27 μM. In addition; the compound 8d was found to have a moderate inhibitory activity in the PI3Kα enzyme assay. What's more; the compounds of which the substituents of benzene ring at the C-4 position are electron-withdrawing groups such as substituents (Cl; F; Br) have better activity than the compounds containing the electron donating groups (OCH₃; H). However; the exact action mechanism is not quite clear right now. Further study will be carried out to identify the exact target in near future.

Keywords: PI3Kα kinase; cytotoxicity activity; pyrazoline; synthesis; thiopyrano[4,3-d]pyrimidine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of representative compounds of two kinds of inhibitors and target compounds. Pictilisib dimethanesulfonate (GDC-0941), 4-((2-(4,6-dimorpholino-1,3,5-triazin-2-yl)hydrazono)methyl)-2,6-dimethoxyphenol (BMCL-200908069-1).
Figure 2
Figure 2
Structures and design strategy for the target compounds (7a–l and 8a–l).
Scheme 1
Scheme 1
Synthetic route of target compounds. Reagents and conditions: (a) 80% NH2NH2·H2O, EtOH, 78 °C 1 h; (b) 10% NaOH, EtOH, r.t., 24 h; (c) Na2WO4·2H2O, 30% H2O2, 20 °C, 3 h; (d) Glacial acetic acid, H2SO4; 100 °C.
Figure 3
Figure 3
Binding models of Compound 8d (shown in orange sticks) and native ligand PI103 (shown in blue sticks) with PI3Kα. The proteins are represented by green ribbon. Hydrogen bonds are showed in dashed lines (yellow).
See this image and copyright information in PMC

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