Hydrophobic tail length, degree of fluorination and headgroup stereochemistry are determinants of the biocompatibility of (fluorinated) carbohydrate surfactants

Abstract

A series of hydrocarbon and fluorocarbon carbohydrate surfactants with different headgroups (i.e., gluco-, galacto-and maltopyranoside) and (fluorinated) alkyl tails (i.e., C 7 and C 14 to C 19 ) was synthesized to investigate trends in their cytotoxicity and haemolytic activity, and how surfactantlipid interactions of selected surfactants contribute to these two measures of biocompatibility. All surfactants displayed low cytotoxicity (EC 50 = 25 to > 250 μM) and low haemolytic activity (EC 50 = 0.2 to > 3.3 mM), with headgroup structure, tail length and degree of fluorination being important structural determinants for both endpoints. The EC 50 values of hydrocarbon and fluorocarbon glucopyranoside surfactants displayed a "cut-off" effect (i.e., a maximum with respect to the chain length). According to steady-state fluorescence anisotropy studies, short chain (C 7 ) surfactants partitioned less readily into model membranes, which explains their low cytotoxicity and haemolytic activity. Interestingly, galactopyranosides were less toxic compared to glucopyranosides with the same hydrophobic tail. Although both surfactant types only differ in the stereochemistry of the 4-OH group, hexadecyl gluco-and galactopyranoside surfactants had similar apparent membrane partition coefficients, but differed in their overall effect on the phase behaviour of DPPC model membranes, as assessed using steady-state fluorescence anisotropy studies. These observations suggest that highly selective surfactant-lipid interactions may be responsible for the differential cytotoxicity and, possible, haemolytic activity of hydrocarbon and fluorocarbon carbohydrate surfactants intended for a variety of pharmaceutical and biomedical applications.

Synthesis, thermal properties, and cytotoxicity evaluation of hydrocarbon and fluorocarbon alkyl β-d-xylopyranoside surfactants

“…9c Briefly, boron trifluoride ethyl etherate was used to glycosylate 2 and 6 , yielding 8g and 10 , respectively (Scheme 3). 2k, 12 The yield was higher for the reaction with the perbenzoate 6 (56 %) than with the peracetylated derivative 2 (33 %), as with the Koenigs-Knorr reaction described above. Both products were readily deprotected with sodium methoxide/Dowex 50W×8–100 ion exchange resin to provide 9g in 62 % yield.…”

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1‐gangliosidosis and Morquio B disease

“…Such interactions are characteristic for fluorous substituents and cannot be readily achieved with unsubstituted alkyl and aryl groups which mainly act by lipophilic van der Waals contacts and/or π-stacking. In addition, due to the strong aliphatic carbon-fluorine single bonds, fluorous compounds are usually biologically inert, non-toxic and thus potentially well tolerated (Li et al 2008, Li et al 2009) . Both, the tertiary amine as well as the ether bond are also biochemically very stable moieties.…”

Water-soluble lipophilic MR contrast agents for cell membrane labeling

“…This is consistent with other studies that have found a correlation between aliphatic tail length and cytotoxicity. [27, 28] It is likely that the high labeling of 2 perturbs the cell membrane, and results in a lower IC 50 value compared to the other agents.…”