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 IC50 of 61 nM to IC50 4.1 nM.

Precursor-directed generation of amidine containing ammosamide analogs: ammosamides E–P

“…9b These results demonstrated methylation of the C-6 amine of 4 can greatly enhance the inhibition of quinone reductase (from 61 nM to 4.1 nM), whereas conversion of the pyrroloquinoline ring to a bicyclic quinoline ring greatly reduces activity. Due to the route to synthetic analogs, variation of the functionality at C-2 was not examined.…”

“…In the work by Cushman and Mesecar 9b , X-ray crystal structures of QR2 in complex with 3 and the C-6 N -methyl analog of 3 demonstrate that there is a strong role for formation of a hydrogen bond network between the primary amide and Asn161 and between the C-8 NH 2 and Thr71. The surprising aspect of the binding of 3 to QR2 is a H 2 O-mediated hydrogen bond from the primary amide NH 2 , the C-6 NH 2 and the ring-nitrogen to the backbone carbonyl oxygen of Gly174.…”

“…Although it is important to point out that Cushman, as described previously, was able to efficiently exploit total synthesis to access ammosamide analogs that would not have been possible through precursor-directed synthesis. 9b …”

“…8 Further studies on 4 and synthetic analogs by Cushman and co-workers showed potent nM inhibition of quinone reductase-2 (QR2, NQO2), a cytosolic protein that has been implicated as a target for cancer chemoprevention, via inhibition of the conversion of quinone substrates into highly reactive and toxic species. 9,10 Lymphostin and related analogs exhibit inhibition of mTOR and lymphocyte kinase. 5,11 Based on the range of biological activity for pyrroloquinoline natural products, we were drawn to a marine-derived strain of Streptomyces variabilis that produced a variety of ammosamide analogs, including the oxidatively ring opened analog ammosamide D ( 6 ), previously reported from our lab.…”

New Developments in the Mechanism of Drug Action and Toxicity of Conjugated Imines and Iminiums, including Related Alkaloids

“…Pyrroloquinolines (53) isolated from gliding bacterium Ohtaekwangia kribbensis showed antibacterial, antifungal and moderate cytotoxicity against growing mammalian cell lines [33]. Ammosamide alkaloids (54), isolated from the marine Strepmyces strain CNR-698, were found to inhibit quinone reductase 2 [34]. Pyrrolocarbazoles (55) and synthetic analogues were found to inhibit topoisomerase I and diverse kinases [35].…”