Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors

Qinghui Wang, Kinsie E. Arnst, Yi Xue, Zi Ning Lei, Dejian Ma, Zhe Sheng Chen, Duane Miller, Wei Li

Research output: Contribution to journalArticle

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Abstract

The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC-112 with an indole moiety was preferred to other moieties. Among these UC-112 analogs, 10f, 10h, 10k, 10n showed the most potent antiproliferative activities. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold.

Original languageEnglish (US)
Pages (from-to)211-224
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume149
DOIs
StatePublished - Apr 10 2018

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Cells
Neoplasms
Melanoma
Apoptosis Regulatory Proteins
Chemotherapy
Radiotherapy
P-Glycoprotein
Cell Line
Heterografts
Scaffolds
Toxicity
Structure-Activity Relationship
Tumors
5-((benzyloxy)methyl)-7-(pyrrolidin-1-ylmethyl)quinolin-8-ol
indole
Neoplasm Metastasis
Drug Therapy
Growth
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors. / Wang, Qinghui; Arnst, Kinsie E.; Xue, Yi; Lei, Zi Ning; Ma, Dejian; Chen, Zhe Sheng; Miller, Duane; Li, Wei.

In: European Journal of Medicinal Chemistry, Vol. 149, 10.04.2018, p. 211-224.

Research output: Contribution to journalArticle

Wang, Qinghui ; Arnst, Kinsie E. ; Xue, Yi ; Lei, Zi Ning ; Ma, Dejian ; Chen, Zhe Sheng ; Miller, Duane ; Li, Wei. / Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 149. pp. 211-224.
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