Solid-phase synthesis of an arylsulfone hydroxamate library

Salvino, Joseph M.; Mathew, Rose; Kiesow, Terence; Narensingh, Ramesh; Mason, Helen J.; Dodd, Amy; Groneberg, Robert D.; Burns, Christopher J.; McGeehan, Gerald; Kline, Jane; Orton, Edward; Tang, Sheng-Yuh; Morrisette, Mathew; Labaudininiere, Richard

doi:10.1016/s0960-894x(00)00285-7

Cited by 17 publications

(9 citation statements)

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“…Compared to HTS, FBLD is purported to have several advantages, including a more efficient exploration of chemically diverse space and higher ligand efficiencies.Although the application of FBLD to metalloprotein targets of medicinal interest has been described, [3] the design, synthesis, and use of general fragment libraries based on metal chelators for FBLD applications has not been widely reported. [4][5][6][7] This is surprising in light of the fact that several small-molecule chelators have been shown to effectively inhibit metalloproteins. [8,9] Furthermore, FBLD using metal-chelating moieties should be particularly well suited for inhibitor discovery against metalloproteins because: a) chelators demonstrate binding affinities suitable for FBLD screening; b) chelators provide a diverse range of molecular platforms from which to develop lead compounds; and c) the propensity for chelators to bind metal ions allows for better prediction of their probable binding position within a protein active site in the absence of experimental structural data of the complex.…”

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confidence: 99%

Chelator Fragment Libraries for Targeting Metalloproteinases

et al. 2010

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A chelator fragment library based on a variety of metal binding groups was screened against a metalloproteinase. Lead hits were identified and an expanded library of select compounds was synthesized, resulting in numerous high-affinity hits against several metalloprotein targets. The findings clearly demonstrate that chelators can be used to generate libraries suitable for fragmentbased lead design (FBLD) directed at important metalloproteins. Keywordschelators; fragment-based lead design; libraries; metalloproteins; zinc Fragment-based lead design (FBLD), sometimes referred to as fragment-based drug discovery (FBDD), is an increasingly important strategy for the discovery of biologically active compounds.[1] FBLD generally uses libraries consisting of modest collections (100-1000 compounds) of small molecular fragments (MW <300 amu) that are screened against targets of interest.[2] Although such fragments do not bind as tightly (K d values in the micro-to millimolar range) as more complex molecules, including those used in high-throughput screening (HTS) approaches, they can provide 'hits' that serve as efficient starting structures for the development of potent inhibitors. Fragments that bind to a target are identified, after which one of two approaches is generally pursued: a) a single fragment can be elaborated in order to obtain a tight binder; or b) multiple fragments binding at adjacent and distinct sites can be connected by an appropriate linker to obtain a potent inhibitor. Compared to HTS, FBLD is purported to have several advantages, including a more efficient exploration of chemically diverse space and higher ligand efficiencies.Although the application of FBLD to metalloprotein targets of medicinal interest has been described, [3] Matrix metalloproteinases (MMPs) represent one of the most well-established targets in the realm of metalloproteins. These zinc(II)-dependent enzymes have been extensively studied, and the development of MMP inhibitors (MMPi) has played an important role in the discovery of inhibitors for other zinc(II)-dependent metalloproteins, such as anthrax lethal factor (LF), histone deacetylases (HDACs), and others.[10] Indeed, the earliest application of FBLD to a metalloprotein target was directed at MMP-3.[3] Therefore, we focused our preliminary library screening efforts on MMPs, as a representative system for identifying fragments that would bind zinc(II) metalloproteins. Based on widely-reported criteria for fragment libraries, [2] an initial chelator fragment library (CFL-1) was assembled. A modest library containing 96 structural cores was prepared from chelators with two to four donor atoms for binding metal ions and sufficient solubility for screening ( Figure 1). The chelating groups included picolinic acids, hydroxyquinolones, pyrimidines, hydroxypyrones, hydroxypyridinones and salicylic acids, in addition to other compounds that are well-established components of metalloprotein inhibitors, such as hydroxamic acids and sulfonamides ( Figure 1). The CFL-1 librar...

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confidence: 99%

Chelator Fragment Libraries for Targeting Metalloproteinases

et al. 2010

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“…Cleavage from the resin (47), with concomitant deprotection of the amino acid side-chains for peptides, yields lowmolecular-weight hydroxamic acids or C-terminally modified peptide hydroxamic acids. This final step is performed with cleavage cocktails containing 30-90% TFA in DCM and various scavengers [150][151][152]. Hydroxamic acids are generally obtained in high purity and good yields.…”

Section: Solid-phase Synthesis Of Hydroxamic Acidsmentioning

confidence: 99%

Hydroxamic Acids: Chemistry, Bioactivity, and Solutionand Solid‐Phase Synthesis

Griffith

Devocelle

Marmion

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…Solid-phase synthesis of β-(arylsulfonyl) hydroxamates was carried out to facilitate optimization of this series, resulting in sub-nanomolar MMPIs specific for MMP-2 (e.g. 14) [160]. 3,4-dialkoxylation at the arylsulfonyl moiety drastically curtailed the inhibitory activities for MMPs (the IC 50 values were all >10,000 nM), while retaining inhibitory activities for phosphodiesterase 4 (PDE4), as exemplified by 15.…”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases

Sang¹,

Jin²,

Newcomer³

et al. 2006

CTMC

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Acting on a broad spectrum of extracellular, intracellular, and membrane-associated substrates, the matrix metalloproteinases (MMPs) are critical to the biological processes of organisms; when aberrantly expressed, many pathological conditions may be born or exacerbated. The prospect of MMP inhibition for therapeutic benefit in cancer, cardiovascular disease, and stroke is reviewed here. MMP inhibitor (MMPI) development constitutes an important branch of research in both academic and industrial settings and advances our knowledge on the structure-function relationship of MMPs. Targeting MMPs in disease treatment is complicated by the fact that MMPs are indispensable for normal development and physiology and by their multi-functionality, possible functional redundancy or contradiction, and context-dependent expression and activity. This complexity was revealed by previous efforts to inhibit MMP activity in the treatment of cancer patients that yielded unsatisfactory results. This review focuses on MMPI development since the late 90s, in terms of natural products and their derivatives, and synthetic compounds of low molecular mass incorporating specific zinc-binding groups (ZBGs). A few polyphenols and flavonoids that exhibit MMPI activities may have chemopreventive and neuro- and cardiovascular-protective effects. A new generation of potent and selective MMPIs with novel ZBGs and inhibition mechanisms have been designed, synthesized, and tested. Although only one collagenase inhibitor (Periostat, doxycycline hyclate) has been approved by the Food and Drug Administration as a drug for the treatment of periodontal disease, new hope is emerging in the form of natural and synthetic MMPIs for the prevention and treatment of stroke, cardiovascular disease, cancer, and other medical conditions.

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Solid-phase synthesis of an arylsulfone hydroxamate library

Cited by 17 publications

References 4 publications

Chelator Fragment Libraries for Targeting Metalloproteinases

Chelator Fragment Libraries for Targeting Metalloproteinases

Hydroxamic Acids: Chemistry, Bioactivity, and Solutionand Solid‐Phase Synthesis

Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases

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