Abstract
8,9-Dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28nM in the PARP-1 and 7.7nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively.
Keywords:
Anticancer; Inhibitors; PARP-1/2; Tricyclic.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Azulenes / chemistry*
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Azulenes / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Humans
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Models, Molecular
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Neoplasms / pathology
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Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
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Poly (ADP-Ribose) Polymerase-1 / metabolism
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Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
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Poly(ADP-ribose) Polymerases / metabolism
Substances
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Antineoplastic Agents
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Azulenes
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Poly(ADP-ribose) Polymerase Inhibitors
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PARP2 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases