Design, synthesis and anticancer activities of novel luotonin-inspired hybrid heterocycles


General Information

12MED2503-02

Design, synthesis and anticancer activities of novel luotonin-inspired hybrid heterocycles

Medical And Health

Non-Communicable Diseases

Cancer is a multifactorial disease that is characterized by the abnormal growth of cells and is a leading cause of death worldwide. In the past decade, the understanding of the biology of cancer has improved. Because cancer cells have a highly proliferative nature, the inhibition of proliferative pathways is considered an effective strategy to fight cancer, and much attention has recently been paid to the discovery and development of new, more selective anticancer agents. Many targets exist for anticancer therapy, including topoisomerase I (topo I), an enzyme that is crucial for DNA replication and transcription. Topo I is preferentially expressed during the S-phase of the cell cycle and has been found in high levels in several solid tumors in humans. A number of research studies have revealed that topo I is an attractive target for the design of cancer chemotherapeutics. Camptothecin and luotonin are naturally occurring pentacyclic alkaloids that selectively inhibit this nuclear enzyme, thus representing a very promising class of anticancer agents. Their semisynthetic analogs, such as topotecan and irinotecan, inhibit topo I by intercalating into the DNA-enzyme complex. Unfortunately, the clinical use of these compounds in cancer chemotherapy is often limited because of undesirable side effects, such as nausea, diarrhea, neutropenia and other types of toxicity. Hence, there is a clear need for new drug development in this area, and the ultimate objective is to identify an anticancer therapy that has minimal side effects and a low toxicity profile. One of the main problems in the clinical development of these topo I inhibitors and related drugs is their poor solubility, which prevents the preparation of a suitable pharmaceutical dosage and also hampers their absorption through the biological membrane. The main reason for this lack of solubility is the polycyclic structure of the compounds, which leads to strong intermolecular -stacking interactions that greatly stabilize their crystal lattices. Prompted by the above findings and with the aim of overcoming the limitations in the development of these inhibitors, we propose the synthesis of luotonin-mimicking pyrroloquinoline systems, i.e., (i) a library of novel de-carbonyl luotonin analogs in which the quinazolinone unit is replaced by benzimidazole, and (ii) libraries of pyrroloquinoline-fused isoquinoline, indole and pyrrolizinoquinoline derivatives that are prepared by employing intramolecular Povarov reactions. These compounds will be sufficiently analogous to luotonins to allow the formation of the DNA-topo I-drug ternary complex, but they are not completely planar, which will increase their solubility by hampering -stacking. The synthesized analogs will be screened for topo-I inhibition and anti-cancer activity. Topo I inhibition will be studied in vitro by analyzing the relaxation of supercoiled plasmid DNA in the presence of the enzyme. Anticancer activity will also be studied in vitro by determining the LD50 values from cell cultures of selected human tumors. For the most promising compounds, in vivo studies will be initiated on mouse xenograft models.

(a) Synthesize hitherto unreported novel camptothecin/luotonin analogs that are characterized by the presence of pyrroloquinoline fused heterocycles by employing intramolecular Povarov reactions. (b) Employ green eco-friendly synthetic protocols whenever possible. (c) Investigate the mechanism and stereochemistry of these reactions. (d) Establish the structure and stereochemistry of the products using NMR spectroscopy and/X-ray crystallographic studies. (e) Screen the aforementioned target molecules for topoisomerase inhibition and in vitro anticancer activity against various human cell lines.

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