Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Heterocyclic Iminoquinones and Quinones from National Cancer Institute (NCI, USA) COMPARE Analysis

Version 1 : Received: 5 June 2023 / Approved: 6 June 2023 / Online: 6 June 2023 (07:59:36 CEST)

A peer-reviewed article of this Preprint also exists.

Haji, N.; Faizi, M.; Koutentis, P.A.; Carty, M.P.; Aldabbagh, F. Heterocyclic Iminoquinones and Quinones from the National Cancer Institute (NCI, USA) COMPARE Analysis. Molecules 2023, 28, 5202. Haji, N.; Faizi, M.; Koutentis, P.A.; Carty, M.P.; Aldabbagh, F. Heterocyclic Iminoquinones and Quinones from the National Cancer Institute (NCI, USA) COMPARE Analysis. Molecules 2023, 28, 5202.

Abstract

This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition across the 60-cell line panel of the NCI Developmental Therapeutic Program (DTP). Many natural products and synthetic analogues are revealed, as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates through correlations to dipyridoimidazo[5,4-f]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of active compound with benzo[e]perimidines, phenoxazinones, benz[f]pyrido[1,2-a]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-b]naphthoquinones, hypothesized as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-b][1,4]oxazepane-6,11-diones, benzo[a]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidizing moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.

Keywords

bioreduction; heterocycles; natural products; NQO1; reductases; synthesis; thioredoxin

Subject

Chemistry and Materials Science, Medicinal Chemistry

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