benzofurans and Leukemia-L5178

This chapter deals with the discovery of sorbicillactone A, as an illustrative example of the fruitful cooperation within BIOTECmarin--its isolation and chemical characterization, and its biological activities. Sorbicillactone A was isolated from a strain of Penicillium chrysogenum cultured from a sample of the Mediterranean sponge Ircinia fasciculata; it possesses a unique bicyclic lactone structure, seemingly derived from sorbicillin. Among the numerous known sorbicillin-derived structures, it is the first found to contain nitrogen and thus the first representative of a novel type of 'sorbicillin alkaloids', apparently originating from a likewise remarkable biosynthesis. Furthermore, the compound exhibits promising activities in several mammalian and viral test systems, in particular a highly selective cytostatic activity against murine leukemic lymphoblasts (L5178y) and the ability to protect human T cells against the cytopathic effects of HIV-1. These properties qualify sorbicillactone A or one of its derivatives for animal and (hopefully) also future therapeutic human trials.

Topics: Alkaloids; Animals; Anti-HIV Agents; Antifungal Agents; Apoptosis; Benzofurans; Chromatography, High Pressure Liquid; Chromatography, Liquid; Circular Dichroism; Dose-Response Relationship, Drug; Fungi; Humans; Lactones; Leukemia L5178; Mass Spectrometry; Mice; Models, Chemical; Penicillium; Porifera; T-Lymphocytes; Time Factors

The MDRI protein is an energy-dependent transport protein responsible for the multi-drug resistance seen in many tumors. A variety of drugs have been shown to inhibit the function of this pump, including compounds known to block various ion channels. The mouse lymphoma cell line L5178Y has been transduced with the human mdrI gene. Using this cell line, we have tested a number of compounds to determine whether there is a correlation between the ability to block a specific type of ion channel, or shift membrane potential, and the ability to act as an MDR-reversing agent using the fluorescent substrates Rhodamine 123 and daunorubicin as test compounds. Our results show no apparent correlation between the ability to block a specific ion channel and reversal of MDR transport ability. We have found active MDR inhibitors in compounds that affect K+, Na+, Ca++, H+, but not Cl- channels. Our data suggest that Cl- channel activity may be distinct from MDR activity. Several immunosuppressive compounds and analogs were also tested and found to be active reversing agents. Measurements suggest a significant difference in resting membrane potential between the L5178YvMDR line and the L5178Y parental cell line used in these experiments. No correlation was found between the ability of drugs to alter membrane potential and to inhibit MDR transport activity. Our results suggest that MDR transport function may be independent of the physiological movement of ions and show that a wide variety of compounds can inhibit MDR transport.

Topics: Amino Acid Sequence; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzofurans; Biological Transport, Active; Carrier Proteins; Cell Membrane; Daunorubicin; Drug Resistance; Ethers, Cyclic; Flow Cytometry; Fluorescent Dyes; Hydrogen-Ion Concentration; Immunosuppressive Agents; Intracellular Fluid; Ion Channels; Leukemia L5178; Lymphoma, T-Cell; Membrane Glycoproteins; Membrane Potentials; Mice; Molecular Sequence Data; Potassium; Potassium Channels; Rhodamine 123; Rhodamines; Tumor Cells, Cultured