Bicyclic Compounds having Antitumor Activity and Methods of Use

Microtubule polymerizations play an important role in cell replication (Mitosis) which makes it a target for antitumor agents. Antimitotic agents such as vinca alkaloids, colchicine, and combretastastins block mitosis by keeping the mitotic spindle from being formed while, paclitaxel binds to the tubulin protein of microtubules, locking microtubules in place and inhibiting their depolymerization.

The development of multiple drug resistance (MDR) to antimitotic agents has been a leading cause of chemotherapy failure. MDR is either inherently expressed in cancer cells or is acquired after exposure to chemotherapy. P-glycoprotein (Pgp, an ATP-binding cassette transporter) is a primary cause of MDR in tumors and is found in the gut, gonads, kidneys, biliary system, brain and other organs. Over expression of Pgp is often associated numerous tumor types .This therefore makes Pgp a viable target to reverse MDR.

This invention describes bicyclic compounds that have antimitotic activity and antitumor activity in a single molecule. Importantly these compounds inhibit Pgp and may overcome multiple drug resistance (MDR) to other chemotherapies. Compounds may be used alone as a single agent in the treatment of cancer, or in combination with additional chemotherapeutic agents. By using a single compound, the drawback of transporting two or more drugs to their target, the additive toxicity and the cost associated with multiple chemotherapies can be circumvented.

Several of the described compounds have delivery advantages over existing antimitotic agents such as Taxol and Combretastatin in that they are water soluble and do not require any solubilizing agents. These compounds can be co-administered with existing anti-mitotic chemotherapies and may enhance the effectiveness of the combined therapy.

General formula of Bicyclic heteroaromatic compound with anti-mitotic and anti tumor activity.

Duquesne University has filed for patent protection on the compounds having the general structure shown above and the therapeutic use of these compounds including various pharmaceutical carriers and other excipients that are compatible. Efficacy has been demonstrated by flow cytometric analysis and microtubule depolymerization immunofluroscence assays using various human cell lines.

File Number: 12/170571 

Web site: http://www.research.duq.edu

Disease: Cancer