Design, Synthesis and Stability of N-Acyloxymethyl- and N-Aminocarbonyloxymethyl-2-azetidinones as Human Leukocyte Elastase Inhibitors

Clemente, A.; Domingos, Ana; Grancho, A. P.; Iley, Jim; Moreira, Rui; Neres, João; Palma, P. Nuno; Santana, Ana Bela; Valente, Emília

doi:10.1016/s0960-894x(01)00131-7

Cited by 47 publications

(25 citation statements)

References 22 publications

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“…leucine). 25,31,35,36 Finally, sulfones 5h and 5i present k inact /K i values superior to that of the Merck Company's compound M618614 used as standard in our assays.…”

Section: Enzyme Inhibition Studiesmentioning

confidence: 74%

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

et al. 2007

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“…leucine). 25,31,35,36 Finally, sulfones 5h and 5i present k inact /K i values superior to that of the Merck Company's compound M618614 used as standard in our assays.…”

Section: Enzyme Inhibition Studiesmentioning

confidence: 74%

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

et al. 2007

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“…In contrast, the inhibition of MMP-2 and MMP-9, two gelatinases instrumental in cell invasion, is markedly lower (IC 50 Ͼ 100 M versus 10 -30 M) (Garbisa et al, 1999), widening the span between the efficacy on gelatinases and LE, and thus rendering the ␤-lactam even more specific for this potent proteolytic weapon. In addition, and in line with the effects obtained with other LE inhibitors (Clemente et al, 2001), the new ␤-lactam hinders the LE-triggered activation of the zymogen form of MMP-9, the major protease involved in PMN leukocyte migration across basement membrane (BM) during extravasation (see below).…”

mentioning

confidence: 56%

Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden-β-lactam with a Galloyl Moiety

Dell’Aica

Sartor

Galletti

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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␤-Lactams, a well known class of antibiotics, have been investigated as inhibitors of the disruptive protease released by inflammatory cells, leukocyte elastase (LE). We have synthesized a new ␤-lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative ␤-lactam inhibits the LE activity with a K i of 0.7 M, whereas it exerts weak activity against cathepsin G and protease-3 (IC 50 Ͼ 100 M), and matrix metalloproteinase (MMP)-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC 50 of 1-2 M) blocking the LE-triggered activation of pro-MMP-9, instrumental to extravasation. Daily i.p. injection of compound enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results indicate that the new ␤-lactam is a potent anti-inflammatory compound with therapeutic potential.

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“…β-lactams are effective antibiotics [30] but also show inhibitory activities against serine- [31], elastase- [32–35], and HIV-1 protease [36] and papain [37]. For the design of β-lactams, the Staudinger reaction involving a [2 + 2] cycloaddition of ketenes and imines is the most common method used [38].…”

Section: Reviewmentioning

confidence: 99%

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Koopmanschap¹,

Ruijter²,

Orru³

2014

Beilstein J. Org. Chem.

233

117

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SummaryIn the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR-components that bear an additional alkene, alkyne or azide moiety and can be cyclized via either a deprotection–cyclization strategy, a ring-closing metathesis, a 1,3-dipolar cycloaddition or even via a sequence of multiple multicomponent reactions. The sequential IMCR-cyclization reactions can afford small cyclic peptide mimics (ranging from four- to seven-membered rings), medium-sized cyclic constructs or peptidic macrocycles (>12 membered rings). This review describes the developments since 2002 of IMCRs-cyclization strategies towards a wide variety of small cyclic mimics, medium sized cyclic constructs and macrocyclic peptidomimetics.

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Design, Synthesis and Stability of N-Acyloxymethyl- and N-Aminocarbonyloxymethyl-2-azetidinones as Human Leukocyte Elastase Inhibitors

Cited by 47 publications

References 22 publications

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

Inhibition of Leukocyte Elastase, Polymorphonuclear Chemoinvasion, and Inflammation-Triggered Pulmonary Fibrosis by a 4-Alkyliden-β-lactam with a Galloyl Moiety

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

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