Novel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated. Structure-activity relationships were deduced from biological results and will be used in further design of new active compounds. In particular, the acetoxymethyl substituent found at the 6-position of previously described active compounds can be replaced by an acetamidomethyl substituent without loss of potency; while the presence of an aryl ester function at the 3-position was preferred to a thioester or an amide function to induce marked biological activity.This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anticancer agents.

Multidrug resistance (MDR) against groups of therapeutic drugs emerged to a central problem in the treatment of various diseases, i.e. cancer and infectious diseases like HIV or malaria. ABC transporters namely P-glycoprotein (P-gp) and various multidrug resistance associated proteins (MRPs) mainly contribute to the MDR phenomenon in cancer treatment and HIV therapy. Their cellular expression in respective cells like cancer cells lowers the intracellular drug concentrations and thus reasons the cellular resistance. The induction of such efflux pumps occurs during the therapy with drugs which will be affected by the MDR phenomenon as a consequence of the induction. In this review studies which report such drugs-caused inductions will be viewed. The review will cover the literature of recent years and attract attention to this important question in drug resistance. Finally, the discussion will suggest possible strategies to overcome the problem, i. e. by using non-inducing drugs.

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Nonplanar 9,10-dihydroacridines were synthesized as promising C2 symmetric molecular scaffolds as inhibitors of the transmembrane efflux pump ABCB1. Within the series structure-activity relationships are discussed revealing the importance of hydrogen bond acceptor functions. A selectivity of ABCB1 inhibition is demonstrated for selected candidates and a bioanalytical study proved nontoxicity as well as missing ABCB1 substrate properties. The results encourage to further develop the promising class of ABCB1 inhibitors.

The development of blood vessels inside tumors is required to provide the nutrients and oxygen needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis. Angiogenesis is also implicated in ocular diseases like age-related macular degeneration. The present work describes the potential anti-angiogenic properties of a coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9), previously described as a potent inhibitor of HT 1080 fibrosarcoma cell invasion in vitro and tumor growth in vivo. In vivo, ex vivo, and in vitro models were used to delineate the anti-angiogenic properties of IK9. The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro. These findings suggest a complex mechanism of action of the compound via direct or indirect effects on endothelial cell properties. This study identifies IK9 as a new potent inhibitor of angiogenesis and suggests its potential use as a therapeutic agent. Drug Dev Res 71:209-218, 2010.