Synthesis of noscapine analogs and their use as cancer treatments, including drug resistant cancers.
- Efficient, high yielding synthesis of noscapine derivatives.
- Selective for cancer cells over normal human cells.
The effectiveness of microtubule-targeting drugs as treatments for cancer has been validated through the extensive clinical use of vinca alkaloids and taxanes. Though useful, the success of the currently used microtubule drugs is limited due to their insolubility in water, emergence of drug resistance, and associated toxicities. Noscapine, which has been primarily used as an antitussive agent, has also been shown by Emory researchers to be a microtubule-interfering agent that binds stoichiometrically to tubulin resulting in an alteration of tubulin conformation. Similar to other antimicrotubule agents, noscapine suppresses the dynamics of microtubule assembly and blocks cell cycle progression at mitosis, followed by apoptotic cell death in a variety of cancer cells. The water solubility and feasibility for oral administration of noscapine also represent valuable advantages over other antimicrotubule drugs. Analogs of noscapine with increased anti-cancer properties have been synthesized and evaluated for activity. The inventors have shown that these analogs bind tubulin, effectively inhibiting cell proliferation of ovarian cancer cells and human lymphoblastoid cells. Most importantly, these compounds are more potent against cancer cells that have become resistant to currently used drugs i.e., vinblastine, teniposide, and paclitaxel, as compared to their respective parent lines.
Several analogs have been synthesized and evaluated in vitro for anti-cancer activity.