Harbor Branch Oceanographic Institution, Inc.

Richard A Isbrucker

Ross E Longley

Amy E Wright

Shirley A Pomponi

Sarath P Gunasekera

Jennifer L Cummins

Gopal K Paul

Dictyostatin-1 has been found to stabilize microtubules and prohibit their depolymerization to free tubulin. Because of these activities, the dictyostatin compounds can be used in the treatment of a number of diseases in which aberrant cellular proliferation occurs such as drug-sensitive and drug-resistant cancers, autoimmune disorders, and inflammatory diseases.

Compositions and uses of dictyostatin compounds

The subject invention provides novel compositions of biologically active discodermolide compounds which can advantageously be used for immunomodulation and/or treating cancer. The compounds of the subject invention have utility for use in the treatment of cancer, as tubulin polymerizers and as microtubule stabilization agents. The present invention also pertains to the identification of regions of the discodermolide molecule which are responsible for certain aspects of the bioactivity of discodermolide compounds.

Biologically active analogs of discodermolide

The subject invention provides novel biologically active compounds which are useful for inhibiting cellular proliferation. Because of the biological activity of these compounds, they can be used for immunomodulation and/or treating cancer. In a preferred embodiment, the novel compounds, compositions and methods of use of the subject invention can advantageously be used to inhibit the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cells of breast, colon, CNS, ovarian, renal, prostate, bone, gastrointestinal, stomach, testicular, or lung tumors, as well as human leukemia or melanoma cells. Specifically exemplified are discalamides A and B.

Discalamide compounds and their use as anti-proliferative agents

The subject invention pertains to a series of cyclic peptides known as the microsclerodermins, which possess unusual amino acids, and which have been observed to inhibit the proliferation of tumor cell lines. The subject invention also pertains to methods useful in inhibiting pathological cellular proliferation in animals, including humans and other mammals. In accordance with the teachings of the subject invention, microsclerodermin compounds can be used to inhibit cellular proliferation including that which is responsible for tumors and other cancers. In a specific embodiment, the novel compositions and methods of use of the subject invention can advantageously be useful in the treatment of a patient hosting cancer cells, for example, inhibiting the growth of tumor cells in a mammalian host.

Antiproliferative activity of microsclerodermins

Imidazole and indole compounds were found to inhibit neural nitric oxide synthase (bNOS) activity. Nortopsentin-C inhibited bNOS as well as calcineurin activities suggesting that its actions are directed against calmodulin, a co-factor common to these two enzymes. Two indole compounds, as well as dragmacidin-D, inhibited bNOS, but not calcineurin, activity. Murine macrophage viability and induced NOS (iNOS) activity in cultured cells was also unaffected by these compounds.

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Toronto, Canada

Richard A Isbrucker