Structure–Activity Relationships in Cholapod Anion Carriers: Enhanced Transmembrane Chloride Transport through Substituent Tuning
Beth A. McNally
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorAtanas V. Koulov
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorTimothy N. Lambert
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorBradley D. Smith Prof. Dr.
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorJean-Baptiste Joos Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorAdam L. Sisson
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorJohn P. Clare
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorValentina Sgarlata Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorLuke W. Judd
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorGerminal Magro Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorAnthony P. Davis Prof. Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorBeth A. McNally
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorAtanas V. Koulov
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorTimothy N. Lambert
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorBradley D. Smith Prof. Dr.
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA), Fax: (+1) 574 631 6652
Search for more papers by this authorJean-Baptiste Joos Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorAdam L. Sisson
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorJohn P. Clare
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorValentina Sgarlata Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorLuke W. Judd
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorGerminal Magro Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorAnthony P. Davis Prof. Dr.
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS (UK), Fax: (+44) 117-9298611
Search for more papers by this authorGraphical Abstract
Optimised anion carriers: A study of 16 steroid-based anion transporters shows that changing substituents can have dramatic effects on transport rates. The current champion (see diagram) is effective in vesicle membranes with a transporter/lipid ratio of 1:250 000 (<2 transporter molecules per vesicle in the system studied).
Abstract
Chloride transport by a series of steroid-based “cholapod” receptors/carriers was studied in vesicles. The principal method involved preincorporation of the cholapods in the vesicle membranes, and the use of lucigenin fluorescence quenching to detect inward-transported Cl−. The results showed a partial correlation between anion affinity and transport activity, in that changes at the steroidal 7 and 12 positions affected both properties in concert. However, changes at the steroidal 3-position yielded irregular effects. Among the new steroids investigated the bis-p-nitrophenylthiourea 3 showed unprecedented activity, giving measurable transport through membranes with a transporter/lipid ratio of 1:250 000 (an average of <2 transporter molecules per vesicle). Increasing transporter lipophilicity had no effect, and positively charged steroids had low activity. The p-nitrophenyl monourea 25 showed modest but significant activity. Measurements using a second method, requiring the addition of transporters to preformed vesicle suspensions, implied that transporter delivery was problematic in some cases. A series of measurements employing membranes of different thicknesses provided further evidence that the cholapods act as mobile anion carriers.
Supporting Information
Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors.
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