Abstract
New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / therapeutic use
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Antineoplastic Agents / toxicity
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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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Drug Evaluation, Preclinical
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Drug Resistance, Neoplasm / drug effects
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Drug Screening Assays, Antitumor
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G1 Phase Cell Cycle Checkpoints / drug effects
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HCT116 Cells
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HEK293 Cells
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Humans
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Indoles / chemistry*
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Indoles / therapeutic use
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Indoles / toxicity
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Phenanthrolines / chemistry*
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Phenanthrolines / therapeutic use
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Phenanthrolines / toxicity
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Signal Transduction / drug effects
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Stereoisomerism
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
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Transplantation, Heterologous
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Water / chemistry
Substances
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Antineoplastic Agents
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Indoles
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Phenanthrolines
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antofine
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Water
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TOR Serine-Threonine Kinases