Halogen‐Mediated Membrane Transport: An Efficient Strategy for the Enhancement of Cellular Uptake of Synthetic Molecules

• Published in: Chemistry : a European journal 2019-03, Vol.25 (13), p.3391-3399
• Main Authors: Ungati, Harinarayana, Govindaraj, Vijayakumar, Nair, Chithra R., Mugesh, Govindasamy
• Format: Article
• Language: English
• Subjects: Bearing; Benzene; Carbon dioxide; cellular uptake; Chemistry; Coumarin; Drug delivery; Drug delivery systems; Ethanol; Fluorescence; Fluorescent indicators; fluorescent probes; halogen-bonding; Hydrophobicity; Iodine; Mammalian cells; Mammals; MCT8 transporter; Membranes; Nuclear membranes; Organic chemistry; Proteins; Pyrene; thyroid hormones; Traffic control
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201806122

The poor uptake of fluorescent probes and therapeutics by mammalian cells is a major concern in biological applications ranging from fluorescence imaging to drug delivery in living cells. Although gaseous molecules such as oxygen and carbon dioxide, hydrophobic substances such as benzene, and small polar but uncharged molecules such as water and ethanol can cross the cell plasma membrane by simple passive diffusion, many synthetic as well as biological molecules require specific membrane transporters and channel proteins that control the traffic of these molecules into and out of the cell. This work reports that the introduction of halogen atoms into a series of fluorescent molecules remarkably enhances their cellular uptake, and that their transport can be increased to more than 95 % by introducing two iodine atoms at appropriate positions. The nature of the fluorophore does not play a major role in the cellular uptake when iodine atoms are present in the molecules, as compounds bearing naphthalimide, coumarin, BODIPY, and pyrene moieties show similar uptakes. Interestingly, the introduction of a maleimide‐based fluorophore bearing two hydroxyethylthio moieties allows the molecules to cross the plasma and nuclear membranes, and the presence of iodine atoms further enhances the transport across both membranes. Overall, this study provides a general strategy for enhancing the uptake of organic molecules by mammalian cells. Iodo substituents ease passage: The introduction of iodine atoms into a series of fluorescent molecules remarkably enhances their uptake by mammalian cells (see graphic). The iodine atom can also facilitate the transport of organic compounds through the nuclear membrane, indicating that the introduction of heavier halogen atoms can be used as a general strategy to increase the cellular uptake of organic molecules.