The long-term objective of this research program is to discover and develop new and effective chemotherapeutic agents for fight against cancer, including cytotoxic agents, immunoconjugates, and multidrug resistance (MDR) reversal agents based on taxanes, taxoids and their congeners by combining new methodology in organic synthesis, medicinal chemistry, modern spectroscopic methods, chemical biology, and molecular pharmacology, connecting translational research to medical and clinical oncology. This research program is very interdisciplinary and has been and will be carried out in collaboration with world leading experts in each discipline. There are three specific aims: 1.1. Design and development of highly tumor specific taxoid-conjugates as new chemotherapeutic agents In general, widely used cytotoxic chemotherapeutic agents have serious drawbacks, i.e., these drugs cannot distinguish cancer cells from normal cells and this unfortunate feature constitutes major basis for a variety of undesirable side effects. In order to overcome these drawbacks, the PI will explore tumor activated prodrug strategy with the use of appropriate antibodies that recognize particular tumor surface antigens as well as special fatty acid that tumor cells seek for as vehicle for tumor-specific delivery of highly cytotoxic taxoid anticancer agents. 1.2. Development of taxane-based agents that can overcome drug-resistance in cancer The PI plans to undertake a systematic study on various drug-resistance in cancer and explore new approaches to overcoming this problem.
This specific aim i ncludes photoaffinity labeling of P-glycoprotein and development of new generation taxoid anticancer agents that are effective against drug-resistant tumors as well as highly effective taxane-MDR reversal agents (TRAs). 1.3. Design and development of de novo microtubule-stabilizing antitumor agents The PI will continue to investigate the microtubule-bound conformations of several microtubule-stabilizing anticancer agents and their common pharmacophore. Based on the tubulin-bound paclitaxel and taxoid structures, the PI will design and synthesize novel conformationally restricted taxoids as well as de novo antitumor agents that stabilize microtubules. ? ?
|Ojima, Iwao; Lichtenthal, Brendan; Lee, Siyeon et al. (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26:1-20|
|Vineberg, Jacob G; Wang, Tao; Zuniga, Edison S et al. (2015) Design, synthesis, and biological evaluation of theranostic vitamin-linker-taxoid conjugates. J Med Chem 58:2406-16|
|Seitz, Joshua D; Vineberg, Jacob G; Wei, Longfei et al. (2015) Design, Synthesis and Application of Fluorine-Labeled Taxoids as (19)F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems. J Fluor Chem 171:148-161|
|He, Zhijian; Schulz, Anita; Wan, Xiaomeng et al. (2015) Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation. J Control Release 208:67-75|
|Seitz, Joshua D; Vineberg, Jacob G; Herlihy, Evan et al. (2015) Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate-taxoid conjugate. Bioorg Med Chem 23:2187-94|
|Vineberg, Jacob G; Zuniga, Edison S; Kamath, Anushree et al. (2014) Design, synthesis, and biological evaluations of tumor-targeting dual-warhead conjugates for a taxoid-camptothecin combination chemotherapy. J Med Chem 57:5777-91|
|Matesanz, Ruth; Trigili, Chiara; RodrÃguez-Salarichs, Javier et al. (2014) Taxanes with high potency inducing tubulin assembly overcome tumoural cell resistances. Bioorg Med Chem 22:5078-90|
|Ojima, Iwao; Kumar, Kunal; Awasthi, Divya et al. (2014) Drug discovery targeting cell division proteins, microtubules and FtsZ. Bioorg Med Chem 22:5060-77|
|Seitz, Joshua; Vineberg, Jacob G; Zuniga, Edison S et al. (2013) Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery. J Fluor Chem 152:157-165|
|Ojima, Iwao (2013) Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology. J Org Chem 78:6358-83|
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