Synthesis and biological evaluation of a small molecule library of 3rd generation multidrug resistance modulators.
The development of new modulators possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcoming P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in tumour cells. In this study 39 compounds are presented which have been synthesized and pharmacologically investigated in our laboratory. Similarly to the potent 3rd generation MDR modulator tariquidar (XR9576) the compounds contain a tetrahydroisoquinoline-ethyl-phenylamine substructure that, in contrast to XR9576, is connected to a smaller hydrophobic part, thus leading to molecules of lower molecular weight. The connection between the tetrahydroisoquinoline-ethyl-phenylamine substructure and the hydrophobic part was achieved through four different types of linkers: amide, urea, amide-ether and amide-styryl. A number of structural modifications in the hydrophobic part were created. The calcein AM assay served as test system to determine the P-gp transport inhibitory potencies of the compounds. For the amide linker derivatives a structure-activity relationship analysis was performed outlining which structural modifications contributed to the inhibitory potency. The compounds containing a bicyclic hydrophobic part with a particular substituent in a specific orientation were identified as the most potent amide derivatives. Among the urea derivatives the compounds with highest inhibitory potency possessed an ortho-nitro substituent. The conformational analysis revealed that this position enables the formation of a hydrogen bond to the urea linker thus stabilizing the conformation. Regarding the amide-styryl derivatives the elongation of the amide linker seemed to be most decisive for the observed increase in activity. The most promising candidate in the whole library possess an amide-ether linker and an ortho-nitro substituent in the hydrophobic part. This compound inhibites P-gp slightly less than tariquidar and can serve as a lead structure for new potent P-gp modulators.
Klinkhammer
Werner
W
Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Müller
Henrik
H
Globisch
Christoph
C
Pajeva
Ilza K
IK
Wiese
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1