Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition

Yingjun Li, Kalyan Kumar Pasunooti, Ruo Jing Li, Wukun Liu, Sarah A. Head, Wei Q. Shi, Jun O. Liu

Research output: Contribution to journalArticle

Abstract

Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC 50 of 73 nM without a significant effect on CYP3A4 (EC 50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.

Original languageEnglish (US)
Pages (from-to)11158-11168
Number of pages11
JournalJournal of medicinal chemistry
Volume61
Issue number24
DOIs
StatePublished - Dec 27 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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