Amino acids are called the building blocks of life and aminoboronic acids mimic natural amino acids in many biochemical reactions. There have been numerous reports in the literature about the utility of aminoboronic acids as pharmaceutical agents e.g. Velcade (approved in 2003 for multiple myeloma) and Talabostat (Phase III trials for metastatic NSCLC and Phase II trials for advanced CLL, metastatic melanoma and pancreatic cancer). But the current procedures available to prepare aminoboronic acids are very limited and tedious, adding to the extremely high cost of treatment. Part A: We have developed several inexpensive and practical procedures for the enantioselective synthesis of five different classes of aminoboronic acids namely ?-boronoglutamic acid, ?-boronoglutamic acid, ?-boronoaspartic acid, ?-borono-?-amino acids, and boronophenylalanine (BPA). We have proposed three new methodologies for the synthesis of ?- and ?-aminoboronic acids. The preliminary results in this regard are very encouraging and these procedures when fully optimized, would provide facile access to a plethora of aminoboronic acids in optically pure form. Part B: These aminoboronic acids would be utilized in the synthesis of several folic acid conjugates as targeted antifolates for folate receptor (FR) overexpressing cancer cells. Antifolates are molecules that inhibit folate metabolic pathway at one or more stages. There are several antifolates that are in clinical usage as anticancer and antibiotic agents. Typically they are transported via ubiquitously expressed reduced folate carriers (RFC). FR is a tumor marker that is overexpressed on a variety of neoplastic tissues and folic acid is a very high affinity ligand of the FR. It exhibits high tumor specificity because of high receptor affinity and lack of normal tissue receptor expression. Part C: The presence of aminoboronic acid unit in the proposed folate-aminoboronates should make them very good substrates for proteasome inhibition. We envision that the presence of pterin or aminopterin unit should facilitate the intracellular delivery of the proposed molecules and make them tight binding inhibitors of folate metabolic enzymes like DHFR, TS, FPGS, etc. The multiple mechanisms of action should make these molecules ideal candidates for investigation as potential anticancer agents. The preliminary biological data on the truncated folate aminoboronate substrates showed very encouraging results (IC50 ~2.5-15 ?M on MDA231 breast cancer cells). The detailed biological studies have been planned to identify potent inhibitors for further development. This project will provide an excellent opportunity for training the undergraduate and MS students to develop skills in organic and biological chemistry.
We propose to synthesize novel folate aminoboronic acid analogs as potential anti-cancer agents. These molecules could act as targeted molecules for folate receptor overexpressing cancer lines and may be useful for especially for the treatment of metastasized and relapsed cancers. ? ? ?
| Kumar, J Sravan; Jonnalagadda, Subash C; Mereddy, Venkatram R (2010) An Efficient Boric Acid Mediated Preparation of ?-Hydroxyamides. Tetrahedron Lett 51:779-782 |
| Kumar, J Sravan; Bashian, Christopher M; Corsello, Michael A et al. (2010) Development of Practical Methodologies for the Synthesis of Functionalized Benzoboroxoles. Tetrahedron Lett 51:4482-4485 |
| Jonnalagadda, Subash C; Cruz, Jonathan S; Connell, Ryan J et al. (2009) Synthesis of ?-carboranyl-?-acyloxy-amides as potential BNCT agents. Tetrahedron Lett 50:4314-4317 |
