Abstract
A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC50 value of 12.5 μM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC50 value of 6.9 μM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.
Highlights
Chemotherapy is one of the most commonly used treatment options for malignant tumors, especially for unresectable patients [1]
In this article we describe a novel series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidine-6carbonitrile derivatives (Figure 1) and a cell-based phenotypic evaluation of their anti-tumor activities by the MTT method
We investigated if the methoxy group (R4) at C-5 position of the pyrido[2,3-d]pyrimidine scaffold was necessary by removing the methoxy group
Summary
Chemotherapy is one of the most commonly used treatment options for malignant tumors, especially for unresectable patients [1]. Disappointing results in recent clinical trials indicate that a major challenge of target-based drug discovery approaches is overcoming target mechanism heterogeneity among patients and inherent or acquired drug resistance [3]. Current cancer drug discovery approaches are not appropriately tailored to complex disease mechanism(s) [4]. Our research group focused our attention on the design, synthesis and cell-based phenotypic screening of novel tumor growth inhibitors and apoptosis inducer as potential anti-proliferative agents. In this article we describe a novel series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidine-6carbonitrile derivatives (Figure 1) and a cell-based phenotypic evaluation of their anti-tumor activities by the MTT method. The cell-cycle analysis of the most potent compound 4a is presented. Their preliminary structure–activity relationships (SARs) are discussed
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