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. 2020 Feb 19;11(4):521-527.
doi: 10.1021/acsmedchemlett.9b00631. eCollection 2020 Apr 9.

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors

Phillip R Lazzara  1 , Atul D Jain  1 , Amanda C Maldonado  1 , Benjamin Richardson  1 , Kornelia J Skowron  1 , Brian P David  1 , Zamia Siddiqui  1 , Kiira M Ratia  1   2 , Terry W Moore  1   2   2
Affiliations

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors

Phillip R Lazzara et al. ACS Med Chem Lett. .

Abstract

The oxidative stress response, gated by the protein-protein interaction of KEAP1 and NRF2, has garnered significant interest in the past decade. Misregulation in this pathway has been implicated in disease states such as multiple sclerosis, rheumatoid arthritis, and diabetic chronic wounds. Many of the known activators of NRF2 are electrophilic in nature and may operate through several biological pathways rather than solely through the activation of the oxidative stress response. Recently, our lab has reported a nonelectrophilic, monoacidic, naphthalene-based NRF2 activator which exhibited good potency in vitro. Herein, we report a detailed structure-activity relationship of naphthalene-based NRF2 activators, an X-ray crystal structure of our monoacidic KEAP1 inhibitor, and identification of an underexplored area of the NRF2 binding pocket of KEAP1.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Top: KEAP1-NRF2 interaction under basal conditions. Bottom: Mechanism of NRF2 via electrophilic and nonelectrophilic pathways.
Chart 1
Chart 1. Representative Examples of Known KEAP1 Inhibitors−
Figure 2
Figure 2
Structure of KEAP1 Kelch domain bound to compound 1c. (A, B) Diagram of interactions between KEAP1 Kelch residues (depicted as violet circles) and compound 1c. Of the four KEAP1 Kelch:1c complexes crystallized in the asymmetric unit, two subunits contain a formate ion (FMT, shown in teal) within hydrogen bonding distance of 1c (A) and two subunits contain a water molecule (B). 2fo – fc electron density of 1c and formate (A) and 1c and bridging water (B) is shown in blue mesh contoured at 1σ. (C) Superposition of KEAP1 Kelch:1c complex with the structures of KEAP1 bound to two other naphthalene-based compounds (1d, orange; 1e, teal) previously reported in the literature. Associated PDB codes (6V6Z, 4XMB, 4ZY3) are shown at right. Amino acids in close proximity to bound ligands are labeled on the protein surface.
Scheme 1
Scheme 1. Synthesis of Monosulfonamide Analogs of 1b and 1c
(a) Pd(OAc)2, P(o-tolyl)3, K2CO3, ethyl acrylate, dioxane, 100 °C 16 h; (b) 4-methoxybenzenesulfonyl chloride, pyridine; (c) ethyl bromoacetate, K2CO3, MeCN, rt, 16 h; (d) 15% NaOH(aq), MeOH, rt, 4 h; (e) 10 wt % Pd/C, H2 (40 psi), EtOH, rt.
Scheme 2
Scheme 2. Synthesis of Phenethyl Analog 11
(a) Pd(PPh3)4, CuI, 4-ethynylanisole, NEt3, DMF, 80 °C, 20 h; (b) 4-methoxybenzenesulfonyl chloride, pyridine, rt, 18 h; (c) 5 wt % Pd/C, H2 (40 psi), EtOAc, rt, 18 h; (d) ethyl bromoacetate, K2CO3, MeCN, rt, 18 h; (e) 15% NaOH(aq), MeOH, rt, 5 h.
Scheme 3
Scheme 3. Synthesis of Sulfone Analog 12
(a) N-Bromosuccinimide, azabisisobutyronitrile, MeCN, rt, 6 h; (b) 4-methoxybenzenethiol, 1 M NaOH(aq), dioxane, rt, 18 h; (c) 30% H2O2, AcOH, Ac2O, rt, 5 h; (d) 10 wt % Pd/C, H2 (40 psi), EtOAc; (e) 4-methyoxybenzenesulfonamide, pyridine, rt, 18 h; (f) ethyl bromoacetate, K2CO3, MeCN, rt, 18 h; (g) 15% NaOH(aq), MeOH, rt, 5 h.
Chart 2
Chart 2. Sulfone Analogs of Compounds 1a and 1c
Chart 3
Chart 3. Structural Variations Explored by Lu et al. vs This Work
Chart 4
Chart 4. Propionate and Phenylacetic Acid Analogs of 1c and 12
Chart 5
Chart 5. Key Interactions and Sites for Optimization Identified
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