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Lipophilic balance

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Philip Gale
Philip Gale

The document describes experiments examining the chloride transport properties of different thiourea compounds (10a-g) incorporated into lipid vesicles. (a) Shows that compound 10e transports chloride most effectively without leaching from the vesicles, while 10a is lost to the aqueous phase. (b) Varies the alkyl chain length and finds transport peaks for 10e, where the phenylthiourea unit sits in the center of the lipid bilayer. (c) Proposes that 10e's position provides an optimal energy barrier for chloride transport, while compounds like 10g and 10a are less stable or have higher energy barriers.

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Lipophilic balance?
How many carbons? (a) Chloride transport by thioureas 10a (dotted, dark blue line), 10b (dashed, magenta line), and 10e (solid, dark green line) as followed by the lucigenin method. Transporters were preincorporated in vesicles formed from POPC/cholesterol (7:3) at loadings of thiourea:lipid = 1:250. F/F0 = lucigenin fluorescence output relative to starting value. (b) Chloride transport by 10e (transporter:lipid = 1:250) after dilution of vesicle suspensions to 0.4 mM (dashed, green), 0.2 mM (solid, blue) and 0.1 mM (dotted, red) total lipid. Traces are almost superimposable, implying that 10e does not leach from the membrane. (c) Chloride transport by 10a (transporter:lipid = 1:100) after dilution of vesicle suspensions to 0.4 mM (dashed, green), 0.2 mM (solid, blue) and 0.1 mM (dotted, red) total lipid. Activities decrease with vesicle concentration, implying that 10a is lost to the aqueous phase. R1 10a R 1 = H R 2 = hexyl S N H N H R2 10b R 1 = ethyl R 2 = hexyl 10e R 1 = pentyl R 2 = hexyl H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.
Moving the thiourea group (a) Chloride transport by thioureas 10c (solid red line), 10e (dashed blue line), and 10g (dotted green line) as followed by the lucigenin method. Transporters were preincorporated in vesicles formed from POPC/cholesterol (7:3) at loadings of thiourea:lipid = 1:250. (b) Plot of the half life (left axis, red squares) and initial rate values (right axis, blue dots) of chloride transport by thiourea compounds 10c-g as functions of the length of alkyl chain R1. Actvities peak for 10e in which the phenylthiourea unit sits close to the centre of the C11 chain. 10c R 1 = H R 2 = undecyl R1 10d R 1 = ethyl R 2 = nonyl S N H N H R2 10e R 1 = pentyl R 2 = hexyl 10f R 1 = octyl R 2 = propyl 10g R 1 = nonyl R 2 =ethyl H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.
Rationalisation AQUEOUS POLAR (ZWITTERIONIC) APOLAR (HYDROCARBON) APOLAR (HYDROCARBON) POLAR (ZWITTERIONIC) AQUEOUS POPC higher energy barrier S 10g N H N H Cl E slower transport - S more stable N H N H Cl less stable - lower energy barrier E faster transport 10e H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.

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Lipophilic balance

  • 2. How many carbons? (a) Chloride transport by thioureas 10a (dotted, dark blue line), 10b (dashed, magenta line), and 10e (solid, dark green line) as followed by the lucigenin method. Transporters were preincorporated in vesicles formed from POPC/cholesterol (7:3) at loadings of thiourea:lipid = 1:250. F/F0 = lucigenin fluorescence output relative to starting value. (b) Chloride transport by 10e (transporter:lipid = 1:250) after dilution of vesicle suspensions to 0.4 mM (dashed, green), 0.2 mM (solid, blue) and 0.1 mM (dotted, red) total lipid. Traces are almost superimposable, implying that 10e does not leach from the membrane. (c) Chloride transport by 10a (transporter:lipid = 1:100) after dilution of vesicle suspensions to 0.4 mM (dashed, green), 0.2 mM (solid, blue) and 0.1 mM (dotted, red) total lipid. Activities decrease with vesicle concentration, implying that 10a is lost to the aqueous phase. R1 10a R 1 = H R 2 = hexyl S N H N H R2 10b R 1 = ethyl R 2 = hexyl 10e R 1 = pentyl R 2 = hexyl H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.
  • 3. Moving the thiourea group (a) Chloride transport by thioureas 10c (solid red line), 10e (dashed blue line), and 10g (dotted green line) as followed by the lucigenin method. Transporters were preincorporated in vesicles formed from POPC/cholesterol (7:3) at loadings of thiourea:lipid = 1:250. (b) Plot of the half life (left axis, red squares) and initial rate values (right axis, blue dots) of chloride transport by thiourea compounds 10c-g as functions of the length of alkyl chain R1. Actvities peak for 10e in which the phenylthiourea unit sits close to the centre of the C11 chain. 10c R 1 = H R 2 = undecyl R1 10d R 1 = ethyl R 2 = nonyl S N H N H R2 10e R 1 = pentyl R 2 = hexyl 10f R 1 = octyl R 2 = propyl 10g R 1 = nonyl R 2 =ethyl H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.
  • 4. Rationalisation AQUEOUS POLAR (ZWITTERIONIC) APOLAR (HYDROCARBON) APOLAR (HYDROCARBON) POLAR (ZWITTERIONIC) AQUEOUS POPC higher energy barrier S 10g N H N H Cl E slower transport - S more stable N H N H Cl less stable - lower energy barrier E faster transport 10e H. Valkenier, C.J.E. Haynes, J. Herniman, P.A. Gale and A.P. Davis, Chem. Sci. 2014, DOI: 10.1039/c3sc52962b.