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Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies

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Abstract

Carbon monoxide (CO) is an endogenously produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a bimolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal reaction without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.

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Acknowledgements

The authors thank the financial support from the National Institutes of Health for our CO-related work (R01DK119202 for CO and colitis; R01DK128823 for CO and acute kidney injury). We also acknowledge financial support from the Georgia Research Alliance in the form of an Eminent Scholar endowment (BW), the Dr. Frank Hannah Chair endowment (BW), and other GSU internal resources. Mass spectrometric analyses were conducted by the Georgia State University Mass Spectrometry Facilities, which are partially supported by an NIH grant for the purchase of a Waters Xevo G2-XS Mass Spectrometer (1S10OD026764-01). Figure 2 is generated with Biorender.com.

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  1. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia, 30303, USA

    Shameer M. Kondengadan, Shubham Bansal, Xiaoxiao Yang & Binghe Wang

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  1. Shameer M. Kondengadan
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Kondengadan, S.M., Bansal, S., Yang, X. et al. Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies. Med Chem Res (2024). https://doi.org/10.1007/s00044-024-03232-0

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