Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: Design, synthesis, and evaluation as topically applied, dermal anti-scarring agents

Bailey, Simon; Fish, Paul V.; Billotte, Stephane; Bordner, Jon; Greiling, Doris; James, K.; McElroy, Andrew B.; Mills, James E.; Reed, Charlotte; Webster, Robert O.

doi:10.1016/j.bmcl.2008.10.036

Cited by 24 publications

(11 citation statements)

References 18 publications

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“…2J), confirming that it is an inhibitor of BMP1. Because of the high serum binding and turnover rate of UK383367 24,25 , we employed a subcutaneous (subQ) cancer cell injection model followed by peritumoral dosing (Fig. 2o).…”

Section: Resultsmentioning

confidence: 99%

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

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Section: Resultsmentioning

confidence: 99%

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

et al. 2021

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“…These inhibitors are hydroxamete derivatives of diamino acid (10), glutamic acid (58), and succinic acid (2) that bind specifically to the Zn atom in the active site of PCP and thereby inhibit enzyme activity. Interestingly, some succinyl hydroxamates have shown antifibrotic properties in either a cell-based model of collagen deposition (fibroplasia model) or in a rabbit model of cutaneous scarring (2).…”

Section: Therapeutic Modulation Of Lox In Cardiac Diseasesmentioning

confidence: 99%

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

López

González

Hermida

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

221

198

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Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOXmediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function. collagen; diastolic dysfunction; hypertensive heart disease; myocardial remodeling THE ELEVATION IN myocardial stress that results from cardiac injury and/or persistent elevations in ventricular pressure or volume triggers a response of the myocardium in an attempt to return the tissue stress to its normal value. This response leads to progressive structural remodeling of the cardiomyocyte, vascular and extracellular matrix (ECM) components of the myocardium that manifest as changes in ventricular wall and chamber dimensions, as well as in diastolic and systolic function (5).Alterations in the myocardial collagen network are a hallmark of the ECM response to stress, either hemodynamic or nonhemodynamic in origin. A collagen network, composed largely of collagen types I and III fibers, is found in the interstitial space of the myocardium. Because collagen is a relatively stiff material with a high-tensile strength, small changes in its concentration have been shown to exert marked effects on the passive mechanical properties of the human heart (7). In addition to the concentration of collagen, experimental data suggest that the passive behavior of the myocardium may also be dependent on the relative proportion of the types of collagen, the diameter of the collagen fibers and their spatial alignment, and the degree of cross-linking. Accordingly, tissue containing predominantly type I collagen, large-diameter collagen fibers, and/or a high degree of cross-lin...

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“…Reductive debenzylation of O-benzyl hydroxamates has been reported before in the literature, though yields are sometimes low and over-reduction to amides is a known problem [21, [26][27][28][29][30]; however, an appropriate catalyst system (e.g., Pd-BaSO 4 ) can solve this problem in a number of cases [31][32][33]. Our debenzylation studies commenced with 1-benzyloxypyrazin-2(1H)-one (3a) using batch chemistry (Table 1) with hydrogen gas and different palladium catalysts (e.g., Pd-C and Pd-BaSO 4 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of N-Hydroxypyrazin-2(1H)-ones via Selective O-Debenzylation of 1-Benzyloxypyrazin-2(1H)-ones Using Flow Methodology

Hung¹,

Borggraeve²

2015

J Flow Chem

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Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: Design, synthesis, and evaluation as topically applied, dermal anti-scarring agents

Cited by 24 publications

References 18 publications

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

Synthesis of N-Hydroxypyrazin-2(1H)-ones via Selective O-Debenzylation of 1-Benzyloxypyrazin-2(1H)-ones Using Flow Methodology

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