2. Academic Validation
  3. Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs

Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs

  • Bioorg Med Chem Lett. 2015 Apr 1;25(7):1556-60. doi: 10.1016/j.bmcl.2015.02.010.
Faqing Ye 1,  Liangfang Chen 2,  Lichuan Hu 3,  Tong Xiao 2,  Shufang Yu 2,  Di Chen 2,  Yu Wang 2,  Guang Liang 2,  Zhiguo Liu 2,  Sicen Wang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center Xi'an Jiaotong University, Xi'an 710061, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 3 Wenzhou Central Hospital, Wenzhou 325035, China.
  • 4 School of Pharmacy, Health Science Center Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: wangsc@mail.xjtu.edu.cn.
PMID: 25736993 DOI: 10.1016/j.bmcl.2015.02.010
Abstract

Two series of C-8 substituted guanine derivatives were synthesized, one bearing 2-amino substitutions and the Other bearing 2-acetamide substitutions. Biological activity tests showed that almost all of them possessed some extent of antitumor activities, and were with lower toxicity against normal human liver HL7702 cells than AZD4547 (the positive control). Among them, N-[8-(4-bromo-1H-indol-3-yl)-6-hydroxy-9H-purin-2-yl]-acetamide exhibited a relatively satisfied inhibition against FGFR1 kinase with IC50 of 1.56 μM and specifically against A549 cells with IC50 of 8.28 μM and B16-F10 cells with IC50 of 6.59 μM. Above all, the introduction of large substituents such as indolyl groups at 8-position of the guanine scaffold probably achieves higher selectivity for FGFR1 as compared with AZD4547.

Keywords

Antitumor activity; FGFR; Guanine; Kinase inhibitor.

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