Synthesis and Identification of [1,3,5]Triazine-pyridine Biheteroaryl as a Novel Series of Potent Cyclin-Dependent Kinase Inhibitors

Abstract

On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and compound B led to the discovery of [1,3,5]triazine-pyridine as a new series of potent CDK inhibitors. Palladium-catalyzed C-C bond formation reactions, particularly the Negishi coupling reaction, were used to assemble various triazine-heteroaryl analogues effectively. Among them, compound 20 displayed high inhibitory potency at CDK1 (IC(50) = 0.021 microM), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3beta. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 20 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase. Molecular docking studies were conducted in an attempt to enhance the understanding of the observed structure-activity relationship.

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

“…An illustration of the binding mode of compound 40 in the ATP-binding site of CDK1 is proposed by molecular docking (Figure 12). Compound 40 fits well into the ATPbinding site of CDK1 and makes extensively favorable van der Waals contacts with the binding site through its primary scaffold [7]. …”

“…It potently inhibited the proliferation of various tumor cell-lines including A375, U937, HCT-116 and HeLa. Compound 40 produced an effective survival increase to nude mice in human A375 xenografts models when administered at 150 and 125 mg/kg intraperitoneally [7]. An illustration of the binding mode of compound 40 in the ATP-binding site of CDK1 is proposed by molecular docking (Figure 12).…”

“…Additionally, many 1, 3, 5-triazine derivatives have proved to hold great promise for further development as new hits of antitumor agents [5][6][7][8][9]. The attractive reasons of 1, 3, 5-triazine scaffold were as follows: (1) 1, 3, 5-triazine has been utilized as a kinase inhibitor scaffold which is monocyclic and symmetrical [10].…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224]. Moreover, they are versatile synthetic intermediates [225], and many functionalized pyrazines possess pharmacological activities, such as antiviral [226,227] (242, 243), ATR kinase inhibitor [228] (244), antitumor [229], vascular endothelial growth factor inhibitory activity [230], or as epithelial sodium channel blockers [231] (Figure 15). Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224].…”

Metalated Heterocycles in Organic Synthesis: Recent Applications

“…389 This type of heteroaryl stannanes have been also obtained by halogen-lithium-tin exchange, and dedicated to Stille reactions in the synthesis of cyclin-dependant kinase inhibitors, 390 and also from 2-chloropyrazines by reaction with (tri-n-butylstannyl)lithium in the synthesis of polynuclear polyaza heterocycles. 391 In addition, 2-stannylpurines, generated by direct 2-lithiation followed by reaction with a trialkylstannyl chloride, have also been used in Stille reactions, for instance, in the synthesis of adenosine derivatives.…”