Research Projects

Natural products, are playing important role in cancer treatment with their diverse and targeted properties, offering hope for overcoming the limitations of conventional therapies and improving cancer treatment. Currently used medications for cancer treatments, includes paclitaxel and vincristine, are derived from natural sources, demonstrating their potential in oncology. In present proposal we propose total synthesis of recently isolated natural product leptochelins (A−C), showing very potent cytotoxic activity and effective against a diverse range of cancer cell lines. Among leptochelins natural product leptochelin A shown a remarkable inhibition of cell viability, with IC₅₀ values 390 nM against D283-med medulloblastoma cells, 400 nM against HCT116 colon carcinoma cells and sub-micromolar IC₅₀ against various other cancer cell lines. Establishing a successful synthetic pathway will provide access to leptochelins through total synthesis (originally isolated compounds less than 1.5 mg) in substantial quantities, facilitating further research into their biological properties. Additionally, these studies could contribute to a structure-activity relationship (SAR) analysis, to simplify the natural product leptochelins structure. We propose a synthetic route, which is notable for its flexibility, allowing for the rapid generation of multiple analoges. Following the synthesis of leptochelins and their analogs, these compounds will be evaluated for their anti-cancer properties. By investigating a variety of analogs with different structural modifications, this research seeks to identify the key components of the pharmacophore, particularly functional groups, stereochemical arrangements, or conformational characteristics that are crucial for sustaining or enhancing biological activity. The observed potency across multiple cancer cell lines also underscores the broad-spectrum anti-proliferative activity of these scaffolds, making them promising candidates for further preclinical and clinical investigation. In addition, to anti-proliferative activity leptochelins A and B revealed promiscuous binding to metals such as copper, iron, zinc and cobalt, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. Unique structural features, along with potent cytotoxic effect of leptochelin A in inducing cell death in cancerous tissues, potentially offer a more potent alternative or adjunct to marketed anti-proliferative agents. The ultimate objective is to develop total synthesis of leptochelins and analogues to discover a lead compound or a class of compounds with improved pharmacological profiles, potentially leading to the development of more effective and viable anti-proliferative drug candidate. Our collaborative research team brings expertise in complex natural product synthesis, cancer signaling pathways, protein-protein interaction biology, and translational oncology. In conclusion, this proposal originates from the need to identify new anti-proliferative agent with unique structural features capable of overcoming the limitations of existing treatment. It also expands the horizon of natural product synthesis and its applications to discovery of new drug candidates.