Amino-benzosuberone: A novel warhead for selective inhibition of human aminopeptidase-N/CD13

Albrecht, Sébastien; Al-Lakkis-Wehbe, Mira; Orsini, Alban; Defoin, Albert; Pale, Patrick; Salomon, Emmanuel; Tarnus, Céline; Weibel, Jean‐Marc

doi:10.1016/j.bmc.2011.01.008

Cited by 32 publications

(28 citation statements)

References 58 publications

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“…(B)] is conserved in all complexes whatever the substituent, the 7‐membered ring bearing the amino‐ketone functions being in a chair conformation. An important concern arises from the chirality of the liganded compound since all compounds were synthesized and evaluated as racemic mixtures, and have been co‐crystallized as such, since racemization is expected to occur . Interestingly, the structures reveal that a single isomer is present in the active site, with the asymmetric carbon bearing the primary amine in the S configuration, which corresponds to natural Cα amino acid chirality.…”

Section: Resultssupporting

confidence: 81%

“…Amino‐benzosuberone derivatives, shown in Figure , have proved to be highly selective and potent inhibitors of M1 mammalian APN/CD13 . The SAR determined on the human enzyme is very close to that determined on PepN (Table ).…”

Section: Resultsmentioning

confidence: 52%

“…The ketone function of the suberone is present in the active site in its hydrated form, which matches our previous model . Both oxygen atoms are close to the zinc ions (O 2 , 2.1 Å and O 1 , 2.8 Å) with O 2 being coordinated to the zinc ion in its tetrahedral geometry.…”

Section: Resultsmentioning

confidence: 96%

“…We have identified the aminobenzosuberone scaffold (Fig. ) as an interesting lead structure for competitive inhibition of this M1 family of “one‐zinc” aminopeptidases, due to its remarkable potency and selective profile toward the M17 and M18 isoforms that have a binuclear metal center, referred to as a co‐catalytic unit as well as all classes of proteolytic enzymes evaluated in the present work. Thus to elucidate the mode of binding of these previously proposed compounds we have determined the crystal structure of PepN in complex with three analogues that display various binding affinity constants (Ki µ M to n M ).…”

Section: Introductionmentioning

confidence: 99%

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Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis

et al. 2017

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Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc-binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN. We report the high-resolution X-ray structures of E. coli aminopeptidase N (PepN) in complex with three aminobenzosuberone scaffolds that display various Ki values (50, 0.33, and 0.034 µM) and provide a compelling view of the outstanding selectivity of these chemical entities for the M1 aminopeptidases. This series of inhibitors interacts as transition state mimics with highly conserved residues of the catalytic machinery and substrate recognition sites. Structural comparisons and model-building studies allowed a deep interpretation of the SAR observed for bacterial, as well as mammalian enzymes. Proteins 2017; 85:1413-1421. © 2017 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis

et al. 2017

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“…Similarly, the Asn-Gly-Arg (NGR) peptide is a specific recognition sequence of CD 13 (14). The NGR/CD 13 -based targeting delivery system is frequently reported in drug design for the treatment of cancer (15,16) and as an imaging system (17,18). However, to our knowledge, no study to date has investigated the potential of the combination of RGD with NGR as a targeted delivery system.…”

Section: Introductionmentioning

confidence: 99%

In vitro assessment of the dual-targeting behavior of a peptide-based magnetic resonance imaging contrast agent

Yang

Zhang

et al. 2013

International Journal of Molecular Medicine

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Abstract. In this study, a peptide-based dual-targeting magnetic resonance imaging (MRI) contrast agent (S8) was designed and synthesized. Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) were combined in the targeting vector so as to allow binding, on the surface of tumor cells, to integrin α v β 3 and aminopeptidase N (CD 13 ), respectively. The longitudinal relaxivity (r 1 ) value of S8 was 8.297 mM -1 sec -1 at a magnetic field of 11.7 T, which is approximately double the r 1 value (4.25 mM -1 sec -1 ) of Magnevist, a commercially available contrast agent. MDA-MB-231 human breast cancer cells (which overexpress α v β 3 ) and human prostate cancer cells PC-3 (which overexpress CD 13 ) were used to investigate the tumor-targeting behavior of S8. The results from the present study indicate that the designed contrast agent, S8, targets both MDA-MB-231 and PC-3 cells.

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Azides

Müller

Bräse

2012

Kirk-Othmer Encyclopedia of Chemical Technology

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Inorganic and organic azides (RN 3 ) likewise have fascinated scientists for over 150 years now. These versatile compounds have a very broad application spectrum due to their chemical reactivity, which is often orthogonal to a lot of chemical functionalities and thus is ideally suited to introduce chemical diversity in the presence of other reactive chemical functions without alternation of the latter. Besides, azides frequently allow for very mild reaction conditions tolerating a lot of other chemical functionalities as well as moisture and air. Thus, this has led to some general applications like the Staudinger ligation or the concept of Click chemistry which have found widespread use beyond the chemicals borders, eg, in biochemistry, polymer, and material sciences. Some azides are produced on industrial scale and are used, for example, in the automotive sector. Although azides are multipurpose compounds in chemistry and beyond, their laboratory and especially their industrial production have always been limited by their acute toxicity and their explosive nature. A lot of inorganic and organic azides are indeed highly toxic and their more or less pronounced tendency to liberate nitrogen gas (N 2 ) spontaneously upon shock, heating or electric discharge in an explosive fashion makes them relatively tricky to handle, especially on a large scale. Regardless of the health and safety issues, azides have never been completely abandoned by the scientific community and have known several revivals during their 150 years old history. Whenever dealing with azides, one should however always bear in mind their potential toxicity and explosive tendency and handle them accordingly.

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Amino-benzosuberone: A novel warhead for selective inhibition of human aminopeptidase-N/CD13

Cited by 32 publications

References 58 publications

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis

In vitro assessment of the dual-targeting behavior of a peptide-based magnetic resonance imaging contrast agent

Azides

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