The use of paclitaxel (PAC) for the treatment of certain types of cancers has been limited by its poor water solubility, toxicity to rapidly dividing normal cells, and weak activity against drug resistant tumors. Thus, there is a need to develop PAC conjugates that are selective toward cancer cells, while also having enhanced aqueous solubility and a reduced liability toward multidrug resistance (MDR). Previous studies in the Center for Drug Design and Development (CD3) have demonstrated that conjugating an acidic moiety on the Northern edge of PAC decreases the P-glycoprotein (Pgp) mediated MDR interactions. The acidic moiety not only reduces MDR liability, but also increases the aqueous solubility of these PAC conjugates. To further explore this structure-activity relationship (SAR) theme, several PAC analogues have been designed to examine the effect on MDR liability of different functional groups, such as amino acids, aliphatic acids, and alcohols.
Selective targeting of cancer cells can be achieved by attaching a tumor recognizing agent or ‘address’ molecule to the anticancer drug wherein the address can then selectively bind to receptors over-expressed on cancer cells. γ-Linked glutamic acid residues (dipeptides and tripeptides), recognized by PSMA enzyme over-expressed on prostate cancer cells, were conjugated to PAC’s Northern edge to selectively target prostate cancer and its malignancy sites. In addition, a novel peptidomimetic analogue, CD3-246, was synthesized to target prostate cancer at the late stages of the disease. The latter inhibits the secondary processing enzyme Peptidylglycine α-Amidating Monooxygenase (PAM) that is believed to be crucial in activating growth hormones essential for hormone-independent tumor growth. Alternatively, several PAC-RGD conjugates have been designed to selectively target breast cancer cells. The RGD peptide is recognized by many of the integrin receptors, especially αvβ3 which is over-expressed on blood vessels undergoing angiogenesis. In addition, the RGD address was utilized to develop a second generation contrast agent that may improve the accuracy of ultrasound imaging for breast cancer diagnosis. This was done by attaching a perfluorinated hydrocarbon chain as the ‘cargo’ for the RGD address system.
In another closely-related aspect of this overall ‘targeting’ program, several anthrapyrazole analogues were also designed in an attempt to overcome the side-effect toxicity of the anthracyclins when used to treat cancer. The proposed analogues were designed to have increased antitumor activity and reduced cardiotoxicity (being less prone to bioreduction).