Synthesis and biological evaluation of novel coumarin-based inhibitors of Cdc25 phosphatases

The cell division cycle 25 (Cdc25) family of proteins are dual specificity phosphatases that activate cyclin-dependent kinase (CDK) complexes, which in turn regulate progression through the cell division cycle. Overexpression of Cdc25 proteins has been reported in a wide variety of cancers; their inhibition may thus represent a novel approach for the development of anticancer therapeutics. Herein we report new coumarin-based scaffolds endowed with a selective inhibition against Cdc25A and Cdc25C, being 6a and 6d the most efficient inhibitors and worthy of further investigation as anticancer agents. (C) 2010 Elsevier Ltd. All rights reserved

Synthesis and Molecular modeling of some new chalcones derived from coumarine as CDC25 phosphatases inhibitors

International audienceNew chalcones derived from coumarines were synthesized and tested as CDC25 phosphataseinhibitors. Molecular modeling of these new compounds was also presented in aim to study the mode ofcompounds orientation within CDC25 A and B. The reversibility of compounds 3, 4 and 5 was confirmed byapplication of MALDI–TOFMS technique

Coumarin polysulfides inhibit cell growth and induce apoptosis in HCT116 colon cancer cells

Coumarins and coumarin derivatives as well as diallyl polysulfides are well known as anticancer drugs. In order to find new drugs with anticancer activities, we combined coumarins with polysulfides in the form of di-coumarin polysulfides. These novel compounds were tested in the HCT116 colorectal cancer cell line. It turned out that they reduced cell viability of cancer cells in a time and concentration dependent manner. Cells tested with these coumarin polysulfides accumulate in the G(2)/M phase of the cell cycle and finally they go into apoptosis. A decrease in bcl-2 level, and increase in the level of bax, cytochrome c release into the cytosol, cleavage of caspase 3/7and PARP suggested that coumarin polysulfides induced the intrinsic pathway of apoptosis. Comparison of these new coumarin compounds with the well known diallyl polysulfides revealed that the coumarin disulfides were more active than the corresponding diallyl disulfides. The activities of the coumarin tetrasulfides and the corresponding diallyl tetrasulfides are similar. The novel coumarin compounds regulated the phosphatase activity of the cell cycle regulating cdc25 family members, indicating that these phosphatases are implicated in the induction of cell cycle arrest and possibly in apoptosis induction as well. In addition, coumarin polysulfides also down-regulated the level of cdc25C, which also contributed to the arrest in the G(2)-phase of the cell cycle. (C) 2011 Elsevier Ltd. All rights reserved

A novel coumarin-quinone derivative SV37 inhibits CDC25 phosphatases, impairs proliferation, and induces cell death.

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 µM) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc

A Novel Coumarin-Quinone Derivative SV37 Inhibits CDC25 Phosphatases, Impairs Proliferation, and Induces Cell Death

International audienceCell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 mu M) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure

Reactivity of 4-Vinyl-2H-1-benzopyran-2-ones in Diels-Alder Cycloaddition Reactions: Access to Coumarin-Based Polycycles with Cdc25 Phosphatase-Inhibiting Activity

International audienceThe reactivity of 4-(1-butoxyvinyl)-2H-chromen-2-one (1) and (E)-4-(2-butoxyvinyl)-2H-chromen-2-one (2) as diene in thermal DielsAlder cycloaddition reactions with several electron-poor dienophiles is reported. Among several dienophiles used in this study 1,4-benzoquinone afforded cycloadducts 11-butoxy-1H-naphtho[1,2-c]chromene-1,4,5-trione (3e) and 1H-naphtho[1,2-c]chromene-1,4,5-trione (4g) that showed Cdc25 phosphatase-inhibition activity at low micromolar values, with both compounds more effective against Cdc25 A and Cdc25 C isoforms

Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases

<p>The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization.</p> <p></p