Amphipathic and other double-sided alpha-helix mimetics based on a 1,2-diphenylacetylene scaffold

摘要

Small-molecule scaffolds based on 1,2-diphenylacetylene that accurately replicate the spatial and angular projections of several side chains on both faces of an α-helix, specifically the i and i+7 side chains on one face, and the i and i+2 side chains on the other. The amphipathic α-helix mimetic can be used to disrupt disease-promoting protein-protein interactions that are mediated by α-helices.

主权项

1. A compound of formulas 1a-1c:wherein:
R1, R4 and R5 can be alkyl, cycloalkyl, alkenyl, alkynyl, aryl, CH2-aryl, heteroaryl, CH2-heteroaryl, CH2CO2H, CH2CH2CO2H, CH2OH, (CH2)4NH2, (CH2)3N═C(NH2)2, O-alkyl, O-cycloalkyl, O-alkenyl, O-alkynyl, O-aryl, O—CH2-aryl, O-heteroaryl, O—CH2-heteroaryl, O—CH2CO2H, O—CH2CH2CO2H, O—(CH2)2OH, O—(CH2)4NH2, or O—(CH2)3N═C(NH2)2; R2 can be alkyl, cycloalkyl, alkenyl, alkynyl, aryl, CH2-aryl, heteroaryl, CH2-heteroaryl, O-alkyl, O-cycloalkyl, O-alkenyl, O-alkynyl, O-aryl, O—CH2-aryl, O-heteroaryl, O—CH2-heteroaryl, NH-alkyl, NH-cycloalkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH—CH2-aryl, NH-heteroaryl, NH—CH2-heteroaryl, CO-alkyl, CO-cycloalkyl, CO-alkenyl, CO-alkynyl, CO-aryl, CO—CH2-aryl, CO-heteroaryl, CO—CH2-heteroaryl, CO2-alkyl, CO2-cycloalkyl, CO2-alkenyl, CO2-alkynyl, CO2-aryl, CO2—CH2-aryl, CO2-heteroaryl, or CO2—CH2-heteroaryl; R3 can be alkyl, cycloalkyl, alkenyl, alkynyl, aryl, CH2-aryl, heteroaryl, CH2-heteroaryl, CO-alkyl, CO-cycloalkyl, CO-alkenyl, CO-alkynyl, CO-aryl, CO—CH2-aryl, CO-heteroaryl, CO—CH2-heteroaryl, CO2-alkyl, CO2-cycloalkyl, CO2-alkenyl, CO2-alkynyl, CO2-aryl, CO2—CH2-aryl, CO2-heteroaryl, CO2—CH2-heteroaryl, COCO2H, COCO2-alkyl, COCO2-cycloalkyl, COCO2-alkenyl, COCO2-alkynyl, COCO2-aryl, COCO2—CH2-aryl, COCO2-heteroaryl, COCO2—CH2-heteroaryl, SO2-alkyl, SO2-cycloalkyl, SO2-alkenyl, SO2-alkynyl, SO2-aryl, SO2—CH2-aryl, SO2-heteroaryl, or SO2—CH2-heteroayl; and X═H or OCH2CO2H, wherein the latter functionality serves as a solubilizing group.