Emory University

Surya N Vangapandu

Ritu Aneja

Harish C Joshi

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are noscapine analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. While the antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans, structure-function analyzes pointed to a proton at position 9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Noscapine analogs with various functional moieties at position 9 on the isoquinoline ring kill human cancer cells resistant to other anti-microtubule agents, such as vincas and taxanes.

Noscapine analogs and their use in treating cancers

9-aminonoscapine, prodrugs thereof, and pharmaceutically acceptable salts thereof, are disclosed. Pharmaceutical compositions including 9-aminonoscapine, and methods of preparation and use thereof are disclosed. 9-aminonoscapine is a noscapine analog that can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, by binding tubulin and inducing apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. 9-aminonoscapine can perturb the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of TUNEL-positive cells. Thus, 9-aminonoscapine is a novel therapeutic agents for a variety of cancers, including ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

9-aminonoscapine and its use in treating cancers, including drug-resistant cancers

The present invention is directed to compounds which are conjugates of two non-toxic natural products, noscapine (and various noscapine analogs) and folic acid (and various folic acid analogs), where the folic acid is conjugated to noscapine or the noscapine analog at the 9-position on the isoquinoline ring on the noscapine framework. Pharmaceutical compositions including the compounds, and methods of treating various tumors using the compounds and compositions, are also disclosed. The conjugates are particularly useful for treating cancers which overexpress the Folate Receptor &#x3b1; (FRa) receptor.

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Alpharetta, GA, United States of America

Surya N Vangapandu