Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Abstract

Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.

SAR study on N2,N4-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents

“…In addition, as a privileged scaffold for kinase inhibitors, the pyrimidine scaffold were also found in inhibitors against other kinases, such as aurora, ALK, PI3K. 20 – 22 Taking together, these inhibitors were likely to exert inhibitory effects against tumor cells via non-selective inhibition against multiple CDKs and even members of other kinase families.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Similarly, further optimization at position(s) within existing scaffolds ( 39 and 41 ) that orient toward the solvent without specific hydrogen bond formation resulted in the discovery of selective PI3K inhibitors ( 40 and 42 ) …”

“…These additional binding contacts improved the potency of R221239 against a panel of HIV-1-resistant strains bearing the V106A, Y188L, and F227C mutations ( Figure 2). 18 In an effort to more fully explore the structure-activity relationships (SARs) of the diarylpyrimidine (DAPY)-based NNRTIs (exemplified by 6, etravirine, ETV) and potentially attenuate the resistance of the existing mutants, a further investigation of the interactions of the DAPYs with the solvent-exposed region of RT resulted in the identification of piperidine-linked aminopyrimidine and thiophene [3,2-d]pyrimidine derivatives, which exhibited broad-spectrum activity with low (single-digit) nanomolar EC 50 values toward a panel of WT, single-mutant, and double-mutant HIV-1 strains. [19][20][21][22][23][24][25] Compared with 6, piperidine-linked aminopyrimidine derivatives 7 and 8 possess broad potency against…”

“…47,48 Similarly, further optimization at position(s) within existing scaffolds (39 and 41) that orient toward the solvent without specific hydrogen bond formation resulted in the discovery of selective PI3K inhibitors (40 and 42). 49,50 (A) (B) F I G U R E 9 Optimization of peripheral substituents for the solvent-exposed regions of kinases, affording advanced inhibitors. The regions colored blue can be considered as flexible sites that can tolerate a range of substituents, allowing us to generate new ligands having druggable properties, without loss of potency.…”

Synthesis of Multifunctional Long-Wavelength-Emitting Fluorescent Probe Based on Hydrazine Dihydrazone and Its Copper Complex for Detection of H2S

“…在对接结果中选取能量最低(CDOCKER energy -122.80 kJ/mol; CDOCKER interaction energy -243.37 kJ/mol)的分子构象进行 2D 谱图分析 [38] , 从图 …”