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Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research., Competing Interests: ◆ Conflict of Interest Disclosure: Guzmán, Pitts, Linley, Winder, Baker and Wright have no conflicts of interest to disclose. Xu, Tendyke, Oestreicher, Mitsuhashi and Suh are either current or former employees of Eisai, Inc., (© 2016 UICC.)

The design, synthesis, and biological evaluation of two diminutive forms of (+)-spongistatin 1, in conjunction with the development of a potentially general design strategy to simplify highly flexible macrocyclic molecules while maintaining biological activity, have been achieved. Examination of the solution conformations of (+)-spongistatin 1 revealed a common conformational preference along the western perimeter comprising the ABEF rings. Exploiting the hypothesis that the small-molecule recognition/binding domains are likely to comprise the conformationally less mobile portions of a ligand led to the design of analogues, incorporating tethers (blue) in place of the CD and the ABCD components of the (+)-spongistatin 1 macrolide, such that the conformation of the retained (+)-spongistatin 1 skeleton would mimic the assigned solution conformations of the natural product. The observed nanomolar cytotoxicity and microtubule destabilizing activity of the ABEF analogue provide support for both the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.

The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More importantly, (+)-spongistatin 1 exhibits significant in vivo antitumor activity in the LOX-IMVI human melanoma xenograft model. (+)-Spongistatin 1 is, thus, an important class of microtubule targeting anticancer agent that warrants further investigation.

The design, synthesis, and biological evaluation of two potential (+)-spongistatin 1 analogues have been achieved. The analogues, incorporating tethers (red) in place of the ABCD and the CD components of the (+)-spongistatin 1 macrolide, were designed such that the conformations of the retained skeleton (blue) would mimic the assigned major solution conformation of the natural product The nanomolar cytotoxicity observed for the ABEF analogue provides strong support for the assigned solution conformation.

We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.