Small Molecule Probes for Studies of Signal Transduction Pathways and Development of Theraputic and Diagnostic Agents.
My research is interdisciplinary in nature and deals with:
- Chemistry (diversity-oriented small organic molecule synthesis)
- Chemical Biology (elucidating signal transduction pathways using small molecule probes)
- Molecular Imaging (developing new diagnostic agents using nuclear probes)
- Biomolecular Nanotechnology (synthesizing non-natural foldamers based nanoparticles for biological application)
- Molecular modeling.
(a) Discovery and development of new reactions (using organo catalysts and Boron catalysts).
(b) Application of new reactions to the synthesis of chemical libraries of diversity oriented small molecules.
We are developing new catalytic asymmetric reactions using organo catalysts. By using these reactions, we are synthesizing diversity oriented five membered and six membered biologically significant molecules.
Discovery of small molecule probes for signal transduction pathways :
The systematic identification of small molecules that interact in a specific molecular recognition mode with the products of the genome and modulate their biological function is a key scientific challenge for the 21st century. Chemical biology is the new technology that aims to address these scientific challenges. To address this important need, diversity oriented synthesis (DOS) has emerged as a valuable approach to generating libraries that explore untapped or underrepresented regions of chemical structure space. Efforts in DOS have produced powerful new biological probes and also spurred continuing advances in synthetic organic chemistry.
1) Developing new imaging agents for known target.
2) Developing new targeting agents to discover new biomarker.
A. Development of RGD Peptidomimetic libraries for Glioblastoma Multiforme.
Malignant gliomas, the most common primary brain tumors, remain largely incurable despite intensive multimodality treatment including surgical resection, irradiations, and chemotherapy. Several investigators have shown a correlation between the expression of αvβ3 and the metastatic potential of Glioblastomas. It has also shown that the αvβ3 integrin is also important during tumor-induced angiogenesis (proliferation of blood vessels). The involved endothelial cells (inner lining of the new blood vessels) express αvβ3 to adhere on the extra cellular matrix during migration towards the tumor. The development of radiolabeld αvβ3 antagonists, in the combination with PET, should allow targeting of αvβ3 positive tumors (tumor cells or involved cells) and an in vivo quantification of the receptor density and thus provide a helpful tool for treatment planning. We are synthesizing small organic Azabicyclo [x.3.0] alkane aminoacids as Pseudopeptide attaching with RGD peptidomimetics (peptidemimic bond is more stable to proteolysis). We will also radiolabel these compounds with a PET (Positron Emission Tomography) isotope (F-18 and I-124) to find out the bio-distribution of these molecules in vivo using an animal PET scanner (micro PET). The radiolabeled new compound could potentially be useful as an imaging agent for early diagnosis of GBMs (which is not currently available) non-invasively. We also plan to label one of these compounds with I-131 for potential use as radio-molecular therapeutic agent. We hope that these studies will lead to development of effective therapeutics and diagnostics for glioma tumors and other αvβ3 integrins.
B. Nanoparticle libraries for rhabdoid tumor imaging and therapeutics.
Using micro-PET approach to diagnose the diseases at early stage: Our basic objective is to use nanoscience and nanotechnology in chemical biology, for drug discovery and development. Nanotechnology has potential application in brain tumor research. The main hurdle to develop and discover new therapeutic agents and diagnostic agents for brain tumor is the Blood Brain Barrier (BBB). Often a therapeutic agent or diagnostic small molecule that is effective in vitro is not efficacious in vivo partly because of its inability to cross BBB. It is possible to overcome this difficulty by use of nanoparticle based molecular agents. By combining the medicinal chemistry and nanotechnology to synthesize small molecular weight therapeutic agents conjugated to nanoparticles can greatly facilitate the study the biology, diagnostic and therapeutic intervention of brain tumors.
1. Synthesizing non-natural foldamers based nanoparticles for biological application:
Nanotechnology is the development and study of devices on the atomic to macromolecular scale, approximately one to one-hundred nanometer size ranges. Nanoscale structures are important because new properties emerge when molecules are constructed that are large enough to encapsulate other molecules and control their reactivity. Biological molecules, in the forms of enzymes, receptors and motor proteins are proven examples of the feasibility and the utility of nanotechnology towards goal of biomolecular nanotechnology (Nanotechnology existing in living systems and resulting from our ability to use biomolecules as components for molecular nanotechnology).
The goal of my research is to develop a new technology and that will allow the rational design and rapid synthesis of biological functional molecules with molecular weight in the kilo-Dalton range and dimension on the order of tens of nanometer. With this approaches my group will synthesize biological protein (catalytic activity, modulators and information processing capabilities and other). It will allow us to systematically alter their structures and explore structure and functions relationship. By using this technology we will construct new catalysts, biosensors, biomarkers and complex macromolecules that self assembles in to functional biomaterials and further more in long run basis for synthetic vaccine. We are synthesizing non-natural foldamers based nanoparticles starting from diversity oriented monomers.
2. Application of the foldamers
This universal scaffolds should allow the construction of molecules with new catalytic and binding function that could approach the functionality of natural proteins, and allow the systematic exploration of structure/function relationships in the newly developed molecules and could applied for synthesis of asymmetric catalyst (enzyme mimics), inhibitors of therapeutically relevant protein-protein interactions, biological sensors and biomarkers.
1. A Forward Chemical Screen Using Zebrafish Embryos with Novel 2-Substituted 2H- Chromene Derivatives. Todd Evans.; Bhaskar C.Das*. Accepted Chemical Biology & Drug Design (CBDD-RL-07-08-0065) 2008, October.
2. Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR: NR1I2; also termed as SXR, PAR). Bhaskar C. Das*.; Ankanahlli V. Madhukumar.; Jaime Anguiano.; Sean Kim.; Michael Sinz.; Tatyana A. Zvyaga.; Eoin C Power.; C. Robin Ganellin.; Sridhar Mani. Bioorganic & Medicinal Chemistry Letters. 2008, 18, 3974-3977.
3. Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl) benzoic acid. Bhaskar C. Das*.; George W. Kabalka. Tetrahedron Letters. 2008, 49, 4695-4696.
4. Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors. Bhaskar C. Das*.; Melissa E. Smith.; Ganjam V. Kalpana. Bioorganic & Medicinal Chemistry Letters. 2008, 18, 4177-4180.
5. Inhibition of the TGF- receptor I kinase promotes hematopoiesis in MDS. Li Zhou, Aaron N Nguyen, Davendra Sohal, Jing Ying Ma, Perry Pahanish, Krishna Gundabolu, Josh Hayman, Adam Chubak, Yongkai Mo, Tushar Bhagat, Bhaskar Das*, Ann M Kapoun, Tony A Navas, Simrit Parmar, Suman Kambhampati, Andrea Pellagatti, Ira Braunschweig, Ying Zhang, Amittha Wickrema, Satyanarayana Medicherla, Jacqueline Boultwood, Leonidas C Platanias, Linda S Higgins, Alan F List, Markus Bitzer, and Amit Verma. Blood, May 2008; doi: 10.1182/blood-2008-02-139824.
6. Design and synthesis of 4-HPR derivatives for rhabdoid tumors. Bhaskar C. Das*.; Melissa E.Smith.; Ganjam V. Kalpana. Bioorganic & Medicinal Chemistry Letters. 2008, 18, 3805-3808.
7. Synthesis of 2-Substituted 2H-Chromenes Using Potassium Vinyltrifluoroborates Fei Liu.; Todd Evans.; Bhaskar C. Das* Tetrahedron Letter. 2008, 49, 1578-1581