Synthesis of 5,7-disubstituted-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amines as microtubule inhibitors
Bioorganic and Medicinal Chemistry
Microtubule inhibitors, Microwave assisted organic synthesis, Pyrrolo[2, 3-d]pyrimidines
Compounds 1-4 were previously reported as potent antimitotic and antitumor agents with Pgp modulatory effects. Compounds 5-18 have been synthesized in an attempt to optimize the various activities of 1-4. Compounds 5-10 explored the influence of methoxy substitutions on the 7-benzyl moiety in 1, while 11-18 investigated the influence of incorporation of a sulfur linker at C5 compared to 1-3. Compounds 5-10 demonstrated potent single-digit micromolar tumor cell cytotoxicity, Pgp modulation and microtubule inhibition. Compound 7 of this series was the most potent and showed GI50 values in the nanomolar range against several human tumor cell lines in the standard NCI preclinical in vitro screen. Antitumor activity and Pgp modulatory effects were found to decrease for the 5-phenylthio compounds 11-14 compared to their 5-phenylethyl analogs 2-4 and the standard compound Taxol. Incorporation of methoxy substitutions on the 7-benzyl moiety improved antitumor activity for the 5-phenylthio compounds 16 and 17. Compounds 16 and 17 demonstrated single to two-digit micromolar inhibition of tumor cells. © 2012 Elsevier Ltd. All rights reserved.
Gangjee, A., Kurup, S., & Smith, C. (2013). Synthesis of 5,7-disubstituted-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amines as microtubule inhibitors. Bioorganic and Medicinal Chemistry, 21 (5), 1180-1189. https://doi.org/10.1016/j.bmc.2012.12.029