Both undergraduate and graduate students learn various aspects of scientific research, including designing and executing experiments, utilizing various scientific equipment for research (Biotage® flash chromatography, HPLC, LC-MS, GC-MS, NMR, spectrophotometry) and laboratory management skills. Overall, students gain expertise in the following scientific areas: drug design, chemical synthesis, molecular modeling, natural products chemistry, microbiology, antibacterial drug discovery and anticancer drug discovery. We collaborate with several faculty members within the Department of Pharmaceutical Sciences in the areas of cancer biology, multi-drug resistance to cancer drugs, inflammation associated diseases and tissue-regeneration to successfully develop promising new drug leads.
Research Areas
- The Yoganathan laboratory has a long-standing interest in studying secondary metabolites from microorganisms as therapeutic leads. Siderophores, a unique class of natural metal ion chelators are of particular interest to us. The first siderophore-antibiotic, Cefiderocol (Fetroja) was approved by US FDA in 2019. In addition to being promising lead compounds for antibiotic discovery, siderophores and their derivatives show promise as anticancer agents due to their high affinity towards iron and copper. Since iron and copper ions are in high demand during cancer cell proliferation and metastasis, metal ion chelators provide a new and unique approach to target various types of cancer.
One of our projects related to this topic focuses on the design and synthesis of structural analogs azotochelin. This catechol-based siderophore provides the needed metal ion binding property through the two catechol motifs. The carboxylic acid group provides a suitable handle for structure diversification. We have shown that the carboxylic acid motif is amenable to synthetic derivatization to transform the natural product into a very potent anticancer agent (IC50 of 0.7M against NCI-H460 cell line). Our current research focuses on improving the potency and investigating the mechanism of anticancer activity in colon and lung cancer cell lines.
- Benzimidazole is a privileged heterocyclic scaffold and is found in numerous clinically used therapeutic agents. The Yoganathan laboratory has recently established simple and scalable synthetic methodologies to synthesize structurally diverse benzimidazoles (Barasa and Yoganathan, 2018) and chemoselective derivatization of a drug-like ‘indolyl-benzimidazole’ core (Barasa, Yong and Yoganathan, 2020). These synthetic methodology projects enabled us to establish an extensive small molecule library for medicinal chemistry. Among these analogs, we have found several compounds that show promising anticancer activities (Barasa et al.2020). Additionally, another series of benzimidazoles have been identified as novel small molecule agonists of Bone Morphogenetic Proteins (BMPs). BMPs play a significant role in human health, including would healing, bone fracture healing, neuron development, and pulmonary arterial hypertension.
- Polyphenols are another class of natural products our lab investigates due to their structural diversity and biological interest (Yoganathan et al.2021). We have several projects that focus on the synthesis of structural analogs of polyphenols, including alpha-mangostin, resveratrol and ellagic acid. Despite the remarkable biological properties of these polyphenols, their clinical potential is limited due to poor physiochemical properties and PK properties. Moreover, access to large amount of structurally complex polyphenols through isolation from natural sources or via chemical synthesis is a major hurdle for medicinal chemistry efforts. Our aim is to design structurally simpler polyphenol derivatives and develop simple and scalable synthetic routes to access these analogs for medicinal chemistry studies and structure activity relationship evaluation.
Narayanan, S.; Wu, Z.-X.; Wang, J.-Q; Ma, H.; Acharekar, N.; Koya, J.; Yoganathan, S.; Fang, S.; Chen, Z.-S.; Pan, Y. The spleen tyrosine kinase inhibitor, entospletinib (GS-9973) restores chemosensitivity in lung cancer cells by modulating ABCG2-mediated multidrug resistance. Int. J. Biol. Sci. 2021, 17, 2652.
Yoganathan, S.*; Alagaratnam, A.; Acharekar, N.; Kong, J. Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer. Cells, 2021, 10, 458.
Kong, J.; Wu, X. -Z.; Wei, L.; Chen, Z. -S.*; Yoganathan, S.* Exploration of antibiotic activity of aminoglycosides, ribostamycin alone and in combination with EDTA against pathogenic bacteria. Front. Microbiol., 2020, 11, 1718.
Barasa, L.; Yong, A.; Yoganathan, S.* An efficient chemo-selective N-alkylation methodology for the structure diversification of indolylbenzimidazoles. ChemistrySelect 2020, 5, 3173-3178.
Barasa, L.; Vemana, H.; Surubhotla, N.; Ha, S. S.; Kong, J.; Yong, A.; Croft, J. L.; Dukhande, V.*; Yoganathan, S.* Synthesis and biological evaluation of structurally diverse benzimidazole scaffolds as potential anticancer agents. Anti-Cancer Agents Med. Chem. 2020, 20, 301-314.
Shao, X.; AbdelKhalek, A.; Abutaleb, N. S.; Velagapudi, U. K.; Yoganathan, S.; Seleem, M. N.; Talele, T. T. Chemical space exploration around thieno[3,2-d]pyrimidin-4(3H)-one scaffold led to a novel class of highly active Clostridium difficile inhibitors. J. Med. Chem. 2019, 62, 9772-9791.
Barasa, L.; Yoganathan, S.* An efficient one-pot conversion of carboxylic acids into benzimidazoles via an HBTU-promoted methodology. RSC Adv. 2018, 8, 35824-35830.
Yoganathan, S.; Miller, S. J.* Structure diversification of vancomycin through peptide-catalyzed, site-selective lipidation: A catalysis-based approach to combat glycopeptide-resistant pathogens. J. Med. Chem. 2015, 58, 2367–2377.
Contact
For questions or general information about the laboratory, please e-mail Dr. Yoganathan at [email protected].
