Vol. 296, Issue 2, 364-371, February 2001

Antimitotic Actions of a Novel Analog of the Fungal Metabolite Palmarumycin CP₁

John S. Lazo , Kenji Tamura , Andreas Vogt , Jae-Kyu Jung, Sonia Rodriguez, Raghavan Balachandran, Billy W. Day and Peter Wipf

Departments of Pharmacology (J.S.L., K.T., A.V.), Chemistry (J-K.J., S.R., P.W.), Environmental and Occupational Health (R.B., B.W.D.), and Pharmaceutical Sciences (B.W.D.), The Fiske Drug Discovery Laboratory (J.S.L., K.T., A.V.), and the Combinatorial Chemistry Center (J.-K..J., S.R., P.W.), University of Pittsburgh, Pittsburgh, Pennsylvania

The pentacyclic palmarumycins are structurally unique natural products with both antifungal and antibacterial activities but their antineoplastic effects are not well established. We have examined their antiproliferative actions against tumor cells using a temperature-sensitive tsFT210 mouse mammary carcinoma cell line and found that a novel palmarumycin analog, [8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1",8"-de][1',3'][dioxin] or SR-7, prominently blocked mammalian cell cycle transition in G₂/M but not in G₁ phase. We found no evidence for inhibition of the critical mitosis-controlling cyclin-dependent kinase Cdk1, or its regulator, the dual specificity phosphatase Cdc25. Moreover, Cdk1 was hypophosphorylated and not directly inhibited by SR-7. SR-7 also failed in vitro to hypernucleate bovine tubulin, did not compete with colchicine for tubulin binding, and only modestly blocked GTP-induced assembly. In addition, SR-7 caused almost equal inhibition of paclitaxel-sensitive and -resistant cell growth. Moreover, unlike benchmark tubulin-disrupting agents, SR-7 did not cause hyperphosphorylation of the antiapoptotic protein Bcl-2. Thus, SR-7 represents a novel chemical structure that can inhibit G₂/M transition by a mechanism that appears to be independent of marked tubulin disruption.