Modulation of taxane binding to tubulin curved and straight conformations by systematic 3'N modification provides for improved microtubule binding, persistent cytotoxicity and in vivo potency.

The taxane class of microtubule stabilizers are some of the most effective and widely used chemotherapeutics. The anticancer activity of taxanes arises from their ability to induce tubulin assembly by selectively recognizing the curved (c-) conformation in unassembled tubulin as compared to the straight (s-) conformation in assembled tubulin. We first designed and synthesized a series of 3'N-modified taxanes bearing covalent groups. Instead of discovering covalent taxanes, we found a series of non-covalent taxanes 2, in which the 3'N side chain was found to be essential for cytotoxicity due to its role in locking tubulin in the s-conformation. A representative compound bearing an acrylamide moiety (2h) exhibited increased binding affinity to the unassembled tubulin c-conformation and less cytotoxicity than paclitaxel. Further exploration of chemical space around 2h afforded a new series 3, in which derivatives such as 3l bind more tightly to both the s- and c-conformations of tubulin compared to paclitaxel, leading to more efficient promotion of tubulin polymerization and a greater persistence of in vitro efficacy against breast cancer cells after drug washout. Although 3l also had improved in vivo potency as compared to paclitaxel, it was also associated with increased systemic toxicity that required localized, intratumoral injection to observe potent and prolonged antitumor efficacy.

Continuous Passive Elongation Through an External Fixator: A Versatile and Beneficial Adjunct Technique to Treat Severe and Recurrent Cases of Dupuytren Contracture.

Dupuytren disease and its associated digit contracture often negatively impact the quality of life for patients. Severe cases of Dupuytren contracture and symptom recurrence are both difficult for hand surgeons to treat. Improved treatment options are therefore needed. One method is continuous passive elongation (CPE). In CPE, a device is affixed to the digit, which applies a continuous extending force to pull the affected finger out of flexion. Multiple external fixators used to induce CPE have been reported. However, a low-profile, hand-specific external fixator, the DigiFix, provides benefits over previously reported devices. We present the technique of CPE using DigiFix as a beneficial and versatile adjunct treatment for severe and recurrent cases of Dupuytren contracture.