Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents

doi:10.3390/molecules17032351

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Molecules 2012, 17(3), 2351-2366; doi:10.3390/molecules17032351

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Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents

Tao Yang¹, Hong He¹, Wei Ang², Ying-Hong Yang³, Jian-Zhong Yang¹, Yan-Ni Lin¹, Hua-Cheng Yang³, Wei-Yi Pi¹, Zi-Cheng Li³, Ying-Lan Zhao^1,* , You-Fu Luo^1,* and Yuquan Wei¹

¹ State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China ² Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China ³ Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China

* Authors to whom correspondence should be addressed.

Received: 12 January 2012; in revised form: 17 February 2012 / Accepted: 20 February 2012 / Published: 24 February 2012

(This article belongs to the Section Medicinal Chemistry)

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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 mM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC₅₀ value of 6.9 mM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.

Keywords: 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives; cell-based phenotypic screening; anti-tumor activity; structure-activity relationship (SAR); apoptosis

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MDPI and ACS Style

Yang, T.; He, H.; Ang, W.; Yang, Y.-H.; Yang, J.-Z.; Lin, Y.-N.; Yang, H.-C.; Pi, W.-Y.; Li, Z.-C.; Zhao, Y.-L.; Luo, Y.-F.; Wei, Y. Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents. Molecules 2012, 17, 2351-2366.

AMA Style

Yang T, He H, Ang W, Yang Y-H, Yang J-Z, Lin Y-N, Yang H-C, Pi W-Y, Li Z-C, Zhao Y-L, Luo Y-F, Wei Y. Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents. Molecules. 2012; 17(3):2351-2366.

Chicago/Turabian Style

Yang, Tao; He, Hong; Ang, Wei; Yang, Ying-Hong; Yang, Jian-Zhong; Lin, Yan-Ni; Yang, Hua-Cheng; Pi, Wei-Yi; Li, Zi-Cheng; Zhao, Ying-Lan; Luo, You-Fu; Wei, Yuquan. 2012. "Syntheses and Cell-Based Phenotypic Screen of Novel 7-Amino pyrido[2,3-d]pyrimidine-6-carbonitrile Derivatives as Potential Antiproliferative Agents." Molecules 17, no. 3: 2351-2366.

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