Design, synthesis and structure-activity relationship studies of novel survivin inhibitors with potent anti-proliferative properties

Min Xiao, Jin Wang, Zongtao Lin, Yan Lu, Zhenmei Li, Stephen W. White, Duane Miller, Wei Li

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.

Original languageEnglish (US)
Article numbere0129807
JournalPLoS ONE
Volume10
Issue number6
DOIs
StatePublished - Jun 12 2015

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structure-activity relationships
Structure-Activity Relationship
Cells
synthesis
cell lines
Neoplasms
Scaffolds
neoplasms
Tumors
apoptosis
Apoptosis
Oxyquinoline
Apoptosis Regulatory Proteins
Cell Line
antineoplastic agents
melanoma
Heterografts
Antineoplastic Agents
inhibitory concentration 50
Assays

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Design, synthesis and structure-activity relationship studies of novel survivin inhibitors with potent anti-proliferative properties. / Xiao, Min; Wang, Jin; Lin, Zongtao; Lu, Yan; Li, Zhenmei; White, Stephen W.; Miller, Duane; Li, Wei.

In: PLoS ONE, Vol. 10, No. 6, e0129807, 12.06.2015.

Research output: Contribution to journalArticle

Xiao, Min ; Wang, Jin ; Lin, Zongtao ; Lu, Yan ; Li, Zhenmei ; White, Stephen W. ; Miller, Duane ; Li, Wei. / Design, synthesis and structure-activity relationship studies of novel survivin inhibitors with potent anti-proliferative properties. In: PLoS ONE. 2015 ; Vol. 10, No. 6.
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