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

Abstract

The poor uptake of fluorescent probesa nd therapeutics by mammalian cells is am ajor concern in biological applicationsr anging from fluorescencei maging 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 ande thanolc an cross the cell plasma membrane by simple passived iffusion, 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 as eries of fluorescent molecules remarkably enhances their cellular uptake, and that their trans-port can be increased to more than 95 %b yi ntroducing two iodine atoms at appropriate positions. The nature of the fluorophore does not play am ajor role in the cellular uptake when iodine atoms are presenti nt he molecules, as compoundsb earing naphthalimide, coumarin, BODIPY, and pyrene moieties shows imilar uptakes.I nterestingly,t he introduction of am aleimide-based fluorophore bearing two hydroxyethylthio moieties allows the molecules to cross the plasma and nuclear membranes, and the presence of iodine atoms furthere nhances the transport across both membranes. Overall, this study provides ag eneral strategy for enhancingt he uptake of organic molecules by mammalian cells.

Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity

“…Mugesh et al. reported that the introduction of either a 2,6‐diiodoanisole or 2,6‐diiodophenol group into various fluorophores dramatically promoted their cellular uptake with the assistance of a thyroid hormone cell membrane transporter (MCT‐8) . Interestingly, no significant difference in cellular uptake of PS Se‐H , PS Se‐Br , and PS Se‐I was observed (see Figure S16).…”

Directing Traffic: Halogen‐Bond‐Mediated Membrane Transport

“…For this purpose, the fluorescent properties of compounds 6 – 11 conatining a −CH 2 −CH 2 − moiety between the phenyl and naphthalimide groups have been investigated (Figure ). Although there was a decrease in the fluorescence upon introduction of bromine and iodine atoms due to heavy‐atom effect, the good fluorescence intensities observed for compounds 6 – 11 indicated that compounds 6 – 11 are suitable for the cellular uptake studies . As expected, a very weak fluorescence was observed for the cells treated with compounds 6 and 7 , and a remarkable enhancement of the fluorescence was observed for cells treated with the diiodo derivative 8 .…”

“…A similar increase in the cellular uptake was observed on moving from 9 (16 %) and 10 (38 %) to the diiodo derivative 11 (97 %), although the replacement of the −NH 2 group with an −NMe 2 group only marginally improved the cellular uptake. Further studies with other related naphthalimide‐based compounds 12 – 19 revealed that the uptake of iodine‐containing compounds 15 and 19 is significantly higher than that of their analogues 12 – 14 and 16 – 18 , respectively, although the position of the 2,6‐diiodoanisole in 15 and 19 is different from that of compound 5 (Figure D, E) . These observations indicate that the diiodoanisole and not the napthalimide moiety may act as a recognition unit for the membrane transport.…”

“…To this end, it was necessary to introduce 2,6‐diiodoanisole moiety to structurally different fluorescent molecules and study the cellular uptake. For this purpose, the two iodine‐containing derivatives 21 and 23 having a 2,3‐dithiomaleimide (DTM) and coumarin fluorophores, respectively, were synthesized (Figure ) . The ability of 21 and 23 to enter the cells was compared with that of the corresponding parent compounds 20 and 22 , respectively.…”

Halogen Bonding: An Underestimated Player in Membrane–drug Interactions

“…This is surprising since halogen atoms, present in c.a. 25% of marketed drugs and being even more prevalent in earlier stages of drug discovery and development processes, 39 have traditionally been employed in rational drug design to improve the pharmacokinetic profile of lead molecules, namely to enhance passive diffusion across membranes 40 or, as recently shown, to increase the receptor-mediated uptake of small fluorescent molecules 41,42 or proteins 43 by mammalian cells. 44 Also, iodination of polymers increases their cellular uptake by plant cells, an effect attributed to HaBs.…”