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Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2004 Nov; Vol. 3 (11), pp. 1365-74. - Publication Year :
- 2004
-
Abstract
- A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.
- Subjects :
- Antineoplastic Agents chemistry
Benzopyrans chemistry
Benzopyrans pharmacology
Caspases metabolism
Cell Cycle drug effects
Cell Line
Cell Proliferation drug effects
Endothelial Cells cytology
Endothelial Cells drug effects
Endothelial Cells metabolism
Enzyme Activation drug effects
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Humans
Microtubules drug effects
Microtubules metabolism
Molecular Structure
Neoplasms drug therapy
Neoplasms metabolism
Phosphorylation drug effects
Proto-Oncogene Proteins c-bcl-2 metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Drug Screening Assays, Antitumor
Neoplasms blood supply
Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-7163
- Volume :
- 3
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 15542775