Gambierol is a marine polycyclic
ether toxin, produced along with
ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of
gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to
gambierol on
voltage-gated potassium channels (Kv) inhibition in neurons.
Gambierol and its truncated analogs share the main crucial elements for
biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of
gambierol on
potassium currents in resting T lymphocyte and their effects on
interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of
gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by
concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of
gambierol in human T cells are: (1) inhibition of
potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of
IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of
gambierol have additional potential for the development of therapeutic tools in
autoimmune diseases.