Development of New Cathepsin B Inhibitors: Combining Bioisosteric Replacements and Structure-Based Design To Explore the Structure–Activity Relationships of Nitroxoline Derivatives

Abstract

Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7, and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.

Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

“…Then the 2,3-dihydro-1H-indene derivatives were prepared following the literature procedure that reacts 1H-inden-2(3H)-one with secondary amine 4a or its derivative with a methoxyethyl chain 45 To prepare the nitroxoline part used in the subsequent coupling with the piperidine moiety, 8-hydroxyquinoline-7-carboxylic acid was nitrated with a HNO 3 /H 2 SO 4 mixture, to produce compound 7 in greater yield (98%) compared to almost the same reported procedure (52%). 50 Thionyl chloride was then added to carboxylic acid 7 suspended in toluene, and heated at 85 °C for 24 h, to provide the acyl chloride (8-hydroxy-5-nitroquinoline-7-carbonyl chloride). The crude acyl chloride from previous step was reacted with amines 6a-g (amine 6g…”

A new class of platinum(ii) complexes with the phosphine ligand pta which show potent anticancer activity

“…19,22 Also, it was discovered that nitroxoline is a potential selective and reversible inhibitor of cathepsin B which results in in vitro and in vivo tumor progression. [23][24][25] The activity of nitroxoline was explained by the inhibition of extracellular and intracellular degradation of the extracellular matrix (ECM), reducing tumor cell spreading. These facts suggest that nitroxoline has great potential as a drug candidate in the treatment of cancer and other diseases connected with increased cathepsin B activity.…”

“…These facts suggest that nitroxoline has great potential as a drug candidate in the treatment of cancer and other diseases connected with increased cathepsin B activity. [23][24][25] On the other hand, the chemistry of second-row transitionmetal complexes of 1,3,5-triaza-7-phosphaadamantane (pta) and related ligands has attracted much attention due to their potential as water-soluble catalysts. 26,27 These complexes show high stability due to the strong metal-phosphorus bond.…”

Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry

“…Cathepsin B also contributes to angiogenesis by degrading metalloprotease inhibitors and releasing growth factors that are bound to ECM components. 2,5,6 The crucial roles of cathepsin B at multiple points of the tumor development have been established in several in vitro and in vivo models and cathepsin B was proposed to be a prognostic marker in patients with various types of cancer. 1,2,7 Cathepsin B shows endopeptidase and exopeptidase activity, a unique feature for cysteine cathepsins, arousing from a flexible structural element, referred to as the occluding loop.…”

“…2,3 Further warheads for reversible inhibition of cysteine cathepsins are, for example, peptide aldehydes or ketones, while irreversible inhibition can be achieved with, for example, epoxide derivatives, vinyl sulfones or acyloxymethyl ketones. 2,3,13,14,16,17 Other cathepsin B inhibitor types include nitroxoline derivatives, 6,18 redox-reactive compounds, 19 1,2,4-thiadiazoles, 20 aziridinyl peptides, 21 and cystatin-derived azapeptides. 22 To enhance the selectivity of the broad spectrum cathepsin inhibitor E-64 (II, Figure S1), 23 further epoxysuccinyl derivatives, for example, the highly potent and cathepsin B-selective CA-074 and CA-030 (III and IV, Figure S1) have been developed, binding exclusively to the S1′ and S2′ pockets and exploiting interactions with the positively charged histidine residues of the occluding loop.…”