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Functionalized 3-benzylidene-indolin-2-ones: inducers of NAD(P)H-quinone oxidoreductase 1 (NQO1) with antiproliferative activity.

Abstract：

:Functionalized benzylidene-indolin-2-ones are widely associated with antiproliferative activity. The scaffold is not normally associated with chemoprevention in spite of the presence of a nitrogen-linked Michael acceptor moiety that may predispose members to induction of NQO1, a widely used biomarker of chemopreventive potential. To investigate this possibility, we have synthesized and evaluated a series of functionalized 3-benzylidene-indolin-2-ones for induction of NQO1 in murine Hepa1c1c7 cells as well as antiproliferative activity against two human cancer cell lines (MCF-7, HCT116). The benzylideneindolinones were found to be good inducers of NQO1 activity, with 85% of test compounds able to increase basal NQO1 activity by more than twofold at concentrations of 10 microM. By contrast, fewer compounds (11%) tested at the same concentration were able to reduce cell viability by more than 50%. Structure activity relationships showed that the nitrogen linked Michael acceptor moiety was an essential requirement for both activities. This common feature notwithstanding, substitution of the 3-benzylidene-indolin-2-one core structure affected NQO1 induction and antiproliferative activities in dissimilar ways, underscoring different structural requirements for these two activities. Nonetheless, promising compounds (10, 42, 45-48) were identified that combine selective induction of NQO1 with potent antiproliferative activity. A potential advantage of such agents would be the ability to provide added protection to normal cells by the up-regulation of NQO1 and other phase II enzymes while simultaneously targeting neoplastic cells.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Zhang W,Go ML

doi

10.1016/j.bmc.2008.12.052

subject

Has Abstract

pub_date

2009-03-01 00:00:00

pages

2077-90

issue

5

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)01230-3

journal_volume

17

pub_type

杂志文章

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