Multidrug resistance (MDR) is a major impediment in the successful treatment of cancer. It is characterized by increased drug efflux mediated by ATP-binding cassette transporter P-glycoprotein (Pgp). Pgp inhibitors (e.g., verapamil) were found to abolish the drug transport across cellular membranes, and to reverse MDR in vincristine-resistant cancer cell lines. In the cancer cell lines overexpressing Pgp, these inhibitors modulate Pgp activity and re-sensitize the cancer cells to chemotherapeutic agents.Novel methods for chemical synthesis of derivatives of natural products as validated drug sources. The asymmetric synthesis of Strychnos alkaloids akuammicine, dihydroakuammicine, norfluorocurarine, dehydroleuconicine B, leuconicine A and leuconicine B was accomplished using methodology recently published by the Andrade group. Enabled by N-sulfinylamine chemistry, our novel sequential one-pot spirocyclization/aza-Baylis-Hillman method and Heck cyclization, we were able to make sufficient quantities of pure, synthetic natural products to begin biological evaluation.Alkaloids prepared as above were evaluated by an in vitro Pgp-Glo assay (Promega) to characterize inhibitory activity of test compounds on Pgp. Assessment of ATPase activity of human recombinant Pgp discriminated if a test compound was a substrate, had inhibitory, or had no effect on Pgp activity. These experiments showed that dihydroakuammicine was the most potent inhibitor followed by leuconicine B and norfluorocurarine. Akuammicine and dehydroleuconicine B had little effect, whereas leuconicine A stimulated ATPase activity suggesting it is a Pgp-substrate. . Our results indicate that the synthesized compounds could be effective reversal agents useful to improve anticancer activity of Pgp substrate.

New chemosensitizing strychnos alkaloids to improve clinical drug efficacy

244th National Meeting (2012)

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