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. 2019 Sep 20;24(19):3422.
doi: 10.3390/molecules24193422.

Design, Synthesis, and Biological Evaluation of Novel Thienopyrimidine Derivatives as PI3Kα Inhibitors

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Free PMC article

Design, Synthesis, and Biological Evaluation of Novel Thienopyrimidine Derivatives as PI3Kα Inhibitors

Lide Yu et al. Molecules. .
Free PMC article

Abstract

Three series of novel thienopyrimidine derivatives 9a-l, 15a-l, and 18a-h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 µM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC50 of 9.47 ± 0.63 µM. In addition, docking studies of compounds 9a and 15a were also investigated.

Keywords: PI3Kα inhibitor; Pyrazole; Thienopyrimidine.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of representative clinical PI3K/mTOR dual inhibitors and target compounds.
Figure 2
Figure 2
The design concept based on the co-crystal structure of GDC-0941 with protein.
Scheme 1
Scheme 1
Synthetic routes of chalcones 3al. Reagents and conditions: a 10% NaOH, EtOH, r.t., 24 h.
Scheme 2
Scheme 2
Synthetic routes of target compounds 9al, 15al, and 21ah. Reagents and conditions: a 5 eq urea, 180 °C, 2h; b POCl3, DMF (cat.), reflux, 8 h; c 2.1 eq morpholine, MeOH, 0 °C, 30 min, r.t., 2h; d 80% hydrazine monohydrate, reflux, 8h; e Glacial acetic acid, H2SO4 (78%), 100 °C.
Figure 3
Figure 3
Docking modes of 9a and 15a. (A) Overview of the binding site of compound 9a with PI3Kα (3TL5) kinase. (B) Binding model of compound 9a with PI3Kα (3TL5) kinase. (C) Overview of the binding site of compound 15a with PI3Kα (3TL5) kinase. (D) Binding model of compound 15a with PI3Kα (3TL5) kinase.

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