Design, synthesis, and biological evaluation of potent quinoline and pyrroloquinoline ammosamide analogues as inhibitors of quinone reductase 2

Abstract

A variety of ammosamide B analogues have been synthesized and evaluated as inhibitors of quinone reductase 2 (QR2). The potencies of the resulting series of QR2 inhibitors range from 4.1 to 25,200 nM. The data provide insight into the structural parameters necessary for QR2 inhibitory activity. The natural product ammosamide B proved to be a potent QR2 inhibitor, and the potencies of the analogues generally decreased as their structures became more distinct from that of ammosamide B. Methylation of the 8-amino group of ammosamide B was an exception, resulting in an increase in quinone reductase 2 inhibitory activity from an IC(50) of 61 nM to IC(50) 4.1 nM.

Figure 1

X-ray crystal structures of ammosamide B (2) and compound 38 in complex with QR2. Ligands are shown in ball and stick and colored according to atom type. Water molecules are shown as solid spheres and hydrogen bonds are shown in grey dashes (2.8-3.4 Å). Electron density maps (2Fo-Fc) are contoured to 1.0 σ and shown in grey mesh. Electron density difference maps (Fo-Fc) are contoured to 3.0 σ and are shown in red mesh. The binding orientation of the ligands are the same in both active sites of the dimer and therefore for simplicity, only the inhibitors in the A-chain active site are shown. (A) X-ray structure of QR2 in complex with compound 2. (B) X-ray structure of QR2 in complex with compound 38. (C) Superposition of the X-ray structures shown in A and B with the colors of inhibitors conserved. Active site water molecules correspond to compound coloring. Fo-Fc Electron density omit maps for ammosamide B and compound 38 are provided in Supporting Information, Figure S3.

Scheme 1

Approach to the Synthesis of the Ammosamides

Scheme 2

Synthesis of Ammosamide Analogues 9-16^a

Scheme 3

Synthesis of Ammosamide Analogues 18-20^a

Scheme 4

Synthesis of Ammosamide Analogue 23^a

Scheme 5

Synthesis of Ammosamide Analogues 27-34^a

Scheme 6

Synthesis of Ammosamides Anaglogue 38^a