A team of researchers from London Metropolitan University’s School of Human Sciences has developed an innovative method to create novel mono- and bismethylated pyrroloquinoxaline derivatives. The team, led by Dr Bhaven Patel, also includes Margarita Damai, Dr Norman Guzzardi, Dr Viliyana Lewis, Dr Zenobia Rao and Dr Daniel Sykes. Their innovative method uses a shared precursor and has been successfully applied to the total synthesis of marinoquinoline A. The research results were published in the peer-reviewed journal RSC Advances.
Nitrogen-containing heterocycles are crucial in natural products and medicinal chemistry, as they offer significant biological activity. Traditionally, the synthesis of pyrroloquinoxalines has faced challenges due to toxic and hazardous methods. The new strategy described by Dr. Patel and his team involves adding unstable methyl radicals to aryl isocyanides under specific reaction conditions, producing mono- and bismethylated derivatives. “This novel approach not only simplifies the synthetic process but also improves the safety and efficiency of the production of these biologically active compounds,” explained Dr. Patel.
The researchers focused on optimizing the conditions for selective methylation. They found that using dicumyl peroxide (DCP) as a source of methyl radicals provided the highest yield for monomethylated products. However, when Fenton reaction conditions were applied, predominantly bismethylated pyrroloquinoxalines were formed. This selective control over the methylation process is a significant advancement in the field.
Key to this research is the successful application of the methodology to the total synthesis of marinoquinoline A, a natural product known for its acetylcholinesterase-inhibiting properties. “Our method allowed us to efficiently synthesize marinoquinoline A in just five steps from commercially available starting materials,” noted Dr. Patel. This achievement highlights the practical utility of their approach in the production of complex natural products.
The team's findings demonstrate the potential of these new derivatives in medicinal chemistry, given their diverse biological activities, including anticancer, antimalarial and antiproliferative effects. “The magic-methyl effect, in which the addition of methyl groups can significantly increase the affinity and binding potency of a drug, underscores the importance of our work,” Dr. Patel said.
In their study, Dr. Patel and his colleagues detailed the synthesis process, beginning with the preparation of the cyclization precursor. They employed several methods to generate methyl radicals and finally found that DCP gave the best results. The team also explored the electronic effects of different cyclization precursors and achieved successful cyclization for most isocyanides, except for the electron-rich variants.
This research not only advances the synthesis of pyrroloquinoxaline derivatives, but also opens new avenues for the development of nitrogen-based heterocycles with important pharmaceutical applications. “Our approach offers a versatile and efficient route to synthesize biologically active compounds, paving the way for future discoveries in drug development,” Dr. Patel emphasized.
Magazine reference
Margarita Damai, Norman Guzzardi, Viliyana Lewis, Zenobia X. Rao, Daniel Sykes and Bhaven Patel. “Elaboration of mono- and new bis-methylated pyrroloquinoxaline derivatives from a shared precursor and their application in the total synthesis of marinoquinoline A.” CSR Advances (2023). DOI: https://doi.org/10.1039/d3ra05952a
About the authors
Bhaven Patel He is Professor of Organic Chemistry at London Metropolitan University. He obtained his MSc in Chemistry from King's College London and his PhD in Organic Chemistry from the University of Birmingham. He then obtained a prestigious EPSRC PhD Plus scholarship working at the University of Birmingham and the Queensland University of Technology. He also worked as a postdoctoral fellow at the University of Nottingham and the UCL School of Pharmacy. He currently co-chairs the Applied Chemistry and Pharmaceutical Technology research theme and is a Fellow of the Royal Society of Chemistry. His current scientific interests incorporate reaction discovery and the development of innovative synthetic methods, including the application of synthesis of natural products and bioactive molecules. His expertise also extends to medicinal chemistry and the application of 3D printing in science. Recently, his research has focused on the development of new chemosensors.
Daniel Sykes He obtained an MSc in Chemistry (Honours) with a year in industry at the University of Manchester. He remained in Manchester to study for a PhD under the supervision of Professor Stephen Faulkner. After postdoctoral work at the University of Manchester, the University of Oxford and the University of Sheffield, he moved to London Metropolitan University and is now the Head of Chemical and Pharmaceutical Sciences. He is a Fellow of the Royal Society of Chemistry and his research work has been cited over 1000 times. His research interests include photophysical measurements of metal complexes, particularly iridium and f-block metals, with a focus on the energy transfer processes between them. This work has recently been extended to cellular imaging and the use of complexes as emitting probes for diagnostic applications.
Margarita Damai is a second-year student at London Metropolitan University pursuing a degree in Biomedical Sciences. Her research work mainly revolves around the synthesis of complex molecular structures and their applications in medicinal chemistry. She is an active person and has participated in several research conferences to represent her work. In addition to research, Margarita is very involved in democracy, particularly within the LondonMet student union, where she worked for a year as a sabbatical officer.
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