Research Interests
The objectives of our research are to execute the synthesis of potent antitumor agents isolated from natural sources such as marine sponges. These marine metabolites are typically available in very limited quantities from their natural sources. Development of synthetic approaches to these molecules can provide increased quantities for clinical evaluation and also provide structural analogs with different biological profiles. Current target molecules in our laboratory include such antitumor agents as callystatin A, spongistatin 1, laulimalide, apoptolidin and leucascandrolide A. Ultimately, perhaps less complex derivatives of these potent antitumor agents with similar or better biological activity can be prepared.

Spongistatin 1 has been found to be extraordinarily effective against a variety of highly chemoresistant tumor types that comprise the NCI panel of 60 human cancer cell lines. These include HL-60, SR leukemias; NCI-H226, NCI H23, NCI H460, NCI H522, non-small cell lung; DMS 114, DMS 273 small cell lung; HCT-116, HT29, KM12, KM20L2 and SW-620 colon; SF539, U-251 brain; SK-MEL-5 melanoma; OVCAR-3 ovarian; and RXF-393 renal cancers. Spongistatin 1 has an IC50 = 0.03 ng/mL for L1210 murine leukemia cells.

A highly potent polyketide, callystatin A, was recently isolated from the marine sponge, Callyspongia truncata, in the Nagasaki Prefecture. Callystatin A shows remarkable in vitro cytotoxicity (IC5o = 0.01 ng/mL) against KB cells and L1210 cells (IC5o = 0.02 ng/mL). One kilogram of the fresh sponge was extracted and bioassay-guided separation produced 1.0 mg (106 Io yield) of callystatin A.

Leucascandrolide A was isolated from the calcareous sponge Leucascandra caveolata. Leucascandrolide displayed significant cytotoxicity in vitro (IC5o = 0.05 and 0.25 Ng/ml with KB and P388 cells, respectively) as well as very strong inhibition of Candida albicans, a pathogenic yeast that attacks AIDS patients.

Apoptolidin is a structurally unique metabolite recently isolated from Norcardiopsis sp. Apoptolidin induced apoptotic cell death in rat glia cells transformed with the adenovirus EIA oncogene (IC5o=11 ng/mL) but not in normal glia cells or normal fibroblasts (IC5o >100 mg/mL). The selectivity of apoptolidin in the NCI-60 cell line panel was found to correlate well with that of several known anti-fungal natural products that inhibit the eukaryotic mitochondrial FOF1ATP synthase. Because of its interesting structural features and its unique biological properties, apoptolidin is an important target for total synthesis.

Laulimalide is a potent inhibitor of cell growth with low nanomolar IC5o values, which was isolated from an Okinawan sponge Fasciospongia rimosa. Laulimalide shows paclitaxellike microtubule stabilization, however, in contrast to paclitaxel, laulimalide inhibits proliferation of SKVLB-1 cells, a multidrug resistant cell line. Laulimalide stimulates tubulin polymerization more effectively than paclitaxel and is a representative of a new class of microtubule stabilizing agents with promise for therapeutic potential.

E-mail: crimmins@email.unc.edu
Telephone: 919-966-5177
FAX: 919-962-2388
Address: C644 Kenan Chapel Hill, NC

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