Talks
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Faculty
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School of Integrative Biological and Chemical Sciences
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Faculty
Academic Level (Author 2)
Staff
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Immunology and Microbiology
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Immunology and Microbiology
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Oral Presentation
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Medicinal Chemistry
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Research/Clinical
Abstract
Background: Four-membered cyclic amide, commonly known as β-lactam, has been playing a crucial role in drug discovery research since its discovery by Alexander Fleming in 1928 from Penicillium notatum. The β-lactam antibiotics are broadly effective against several bacterial infections through acylating the transpeptidase involved in cross-linking peptides to form peptidoglycan or periplasmic murein, which is a fundamental constituent of the bacterial cell wall for both the gram-positive (ten or more layers) and gram-negative (one or two layers) bacteria. Although for more than eight decades, β-lactams have been recognized as antibiotics, later, other medicinal activities of β-lactam derivatives have been reported, including lowering of high cholesterol levels, antidiabetic, anticancer, etc. On the other hand, synthesizing the spiro carbon center is highly challenging due to huge steric hindrances and interactions.
Methods: As a part of our ongoing research on synthesizing pharmacologically relevant spiro compounds, herein we report the multi-step synthesis of spiro-β-lactams wherein the Staudinger [2+2] ketene-imine cycloaddition has been identified as the key step. Before synthesis in silico validation against target protein was conducted. The reactions were monitored by thin-layer chromatography (TLC). The target products were purified by column and preparative chromatography. Structure elucidation was carried out by IR, NMR (1D- and 2D-), HRMS and X-ray crystallographic analyses.
Results: It is well-known that the stereochemistry of a drug molecule is greatly responsible for its pharmacological activity. Accordingly, the stereoisomer that produces better therapeutic activity is preferred. Due to enormous torsional, steric, and angular strains present in the molecule, the reactions took longer reaction time (48-96 hours, depending on substituents), and there is a high possibility of decomposition during separation. Accordingly, moderate yields were isolated.
Conclusions: Since β-lactam compounds have a wide range of pharmacological properties and some have shown promising potency against both drug-sensitive and drug-resistant cancer cell lines, and the spiro-β-lactam derivatives are flexible and appealing scaffolds for drug discovery. Therefore, the spiro-β-lactam moiety may serve as a valuable pharmacophore for developing new anticancer drugs.
Recommended Citation
Bandyopadhyay, Debasish; Mendes, Reinaldo; and Chauhan, Subhash C., "Synthesis of medicinally privileged spiro-β-lactams" (2025). Research Symposium. 7.
https://scholarworks.utrgv.edu/somrs/2025/talks/7
Included in
Heterocyclic Compounds Commons, Organic Chemicals Commons, Other Chemicals and Drugs Commons, Polycyclic Compounds Commons
Synthesis of medicinally privileged spiro-β-lactams
Background: Four-membered cyclic amide, commonly known as β-lactam, has been playing a crucial role in drug discovery research since its discovery by Alexander Fleming in 1928 from Penicillium notatum. The β-lactam antibiotics are broadly effective against several bacterial infections through acylating the transpeptidase involved in cross-linking peptides to form peptidoglycan or periplasmic murein, which is a fundamental constituent of the bacterial cell wall for both the gram-positive (ten or more layers) and gram-negative (one or two layers) bacteria. Although for more than eight decades, β-lactams have been recognized as antibiotics, later, other medicinal activities of β-lactam derivatives have been reported, including lowering of high cholesterol levels, antidiabetic, anticancer, etc. On the other hand, synthesizing the spiro carbon center is highly challenging due to huge steric hindrances and interactions.
Methods: As a part of our ongoing research on synthesizing pharmacologically relevant spiro compounds, herein we report the multi-step synthesis of spiro-β-lactams wherein the Staudinger [2+2] ketene-imine cycloaddition has been identified as the key step. Before synthesis in silico validation against target protein was conducted. The reactions were monitored by thin-layer chromatography (TLC). The target products were purified by column and preparative chromatography. Structure elucidation was carried out by IR, NMR (1D- and 2D-), HRMS and X-ray crystallographic analyses.
Results: It is well-known that the stereochemistry of a drug molecule is greatly responsible for its pharmacological activity. Accordingly, the stereoisomer that produces better therapeutic activity is preferred. Due to enormous torsional, steric, and angular strains present in the molecule, the reactions took longer reaction time (48-96 hours, depending on substituents), and there is a high possibility of decomposition during separation. Accordingly, moderate yields were isolated.
Conclusions: Since β-lactam compounds have a wide range of pharmacological properties and some have shown promising potency against both drug-sensitive and drug-resistant cancer cell lines, and the spiro-β-lactam derivatives are flexible and appealing scaffolds for drug discovery. Therefore, the spiro-β-lactam moiety may serve as a valuable pharmacophore for developing new anticancer drugs.
