Synthesis and multidrug-resistance modulating activity of a series of thienothiazines.
A series of thienothiazines was synthesized and tested for their ability to inhibit P-glycoprotein, which is responsible for multidrug resistance in tumor cells. Highest activity was found for compounds with a homoveratryl side chain, which is also present in other modulators of multidrug resistance, such as verapamil. Although for several classes of MDR-modulators lipophilicity was shown to be a major determinant for high activity, no satisfactory correlation was obtained for the set of thienothiazines (r = 0.35). However, the use of molar refractivity as descriptor yields a good correlation with biological activity. This gives renewed evidence for the importance of molar refractivity and indicates that, in addition to lipophilicity, polar interactions also play an important role in ligand/receptor interaction.
Chiba
Peter
P
Institute of Medical Chemistry, University of Vienna, Wien, Austria.
Erker
Thomas
T
Galanski
Maria
M
Hitzler
Manuela
M
Ecker
Gerhard F
GF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D013843:Thiazines