Structure-activity relationships in cholapod anion carriers: enhanced transmembrane chloride transport through substituent tuning.
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.
McNally
Beth A
BA
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame IN 46556 (USA).
Koulov
Atanas V
AV
Lambert
Timothy N
TN
Smith
Bradley D
BD
Joos
Jean-Baptiste
JB
Sisson
Adam L
AL
Clare
John P
JP
Sgarlata
Valentina
V
Judd
Luke W
LW
Magro
Germinal
G
Davis
Anthony P
AP
D000838:Anions / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000838:Anions; D002712:Chlorides; D013256:Steroids
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