Abstract

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. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
9R01CA103314-13A2
Application #
6678958
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
1990-03-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
13
Fiscal Year
2003
Total Cost
$337,061
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Ojima, Iwao; Wang, Xin; Jing, Yunrong et al. (2018) Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery. J Nat Prod 81:703-721
Jelínek, Michael; Balušíková, Kamila; Daniel, Petr et al. (2018) Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel. Toxicol Appl Pharmacol 347:79-91
Ahmad, Gulzar; Gattacecca, Florence; El Sadda, Rana et al. (2018) Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Naïve and Tumor-Bearing Mice. Pharm Res 35:91
Yang, Chia-Ping Huang; Wang, Changwei; Ojima, Iwao et al. (2018) Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of ?-Tubulin and the Multidrug Resistance Associated P-Glycoprotein. J Nat Prod 81:600-606
Zheng, Xiaowei; Wang, Changwei; Xing, Yuanming et al. (2017) SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells. Int J Oncol 50:893-902
Ojima, Iwao (2017) Strategic Incorporation of Fluorine into Taxoid Anticancer Agents for Medicinal Chemistry and Chemical Biology Studies. J Fluor Chem 198:10-23
Zong, Yao; Shea, Christie; Maffucci, Katherine et al. (2017) Computational Design and Synthesis of Novel Fluoro-Analogs of Combretastatins A-4 and A-1. J Fluor Chem 203:193-199
Ahmad, Gulzar; El Sadda, Rana; Botchkina, Galina et al. (2017) Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth. Cancer Lett 406:71-80
Ojima, Iwao; Lichtenthal, Brendan; Lee, Siyeon et al. (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26:1-20
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

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