TY - JOUR
T1 - N 4-(3-bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d] pyrimidines as potent multiple receptor tyrosine kinase inhibitors
T2 - Design, synthesis, and in vivo evaluation
AU - Gangjee, Aleem
AU - Zaware, Nilesh
AU - Raghavan, Sudhir
AU - Yang, Jie
AU - Thorpe, Jessica E.
AU - Ihnat, Michael A.
N1 - Funding Information:
This work was supported, in part, by the National Institutes of Health and National Cancer Institute Grant CA98850 (A.G.) and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (AG).
PY - 2012/4/1
Y1 - 2012/4/1
N2 - With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N 4-(3-bromophenyl)-7- (substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N 4-(3-bromophenyl)-7H-pyrrolo[2,3- d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).
AB - With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N 4-(3-bromophenyl)-7- (substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N 4-(3-bromophenyl)-7H-pyrrolo[2,3- d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).
KW - Antiangiogenic agents
KW - Multiple receptor
KW - Tyrosine kinase inhibitors
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U2 - 10.1016/j.bmc.2012.01.029
DO - 10.1016/j.bmc.2012.01.029
M3 - Article
C2 - 22370340
AN - SCOPUS:84862810926
SN - 0968-0896
VL - 20
SP - 2444
EP - 2454
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 7
ER -