Here, we describe the synthesis and biological characterization of 32 novel phenylalanine and leucine dipeptides modified on both the N and C termini by salicylic acid and aromatic or alicyclic amines, respectively. All compounds displayed antiproliferative activity in the tested cancer cell lines and eight of the compounds exhibited single digit micromolar GI50 values. Treated cells rapidly detached from surface of tissue culture dishes and we found that focal adhesion kinase (FAK), p130CAS and paxillin, which are important regulators of cell adhesion, were dephosphorylated at Y397, Y410 and Y118, respectively. The most potent compound reduced proliferation in the HCT-116 cell line in a dose-dependent manner, as shown by a decrease in 5-bromo-2'-deoxyuridine incorporation into DNA. Furthermore, this compound increased the levels of several apoptotic markers, including activated caspases, and increased site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- dipeptidy chemická syntéza chemie farmakologie MeSH
- fenylalanin chemická syntéza chemie farmakologie MeSH
- HCT116 buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- leucin chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- proliferace buněk účinky léků MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Polymer-supported N-(2-oxo-ethyl)-derivatized Ser/Thr/Cys-containing dipeptides were synthesized and subjected to acid-mediated tandem N-acylium ion cyclization-nucleophilic addition to yield tetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-ones. The reaction conditions and building-block combinations for stereoselective synthesis of the newly formed asymmetric carbon were developed. The synthesis was fully compatible with solid-phase peptide synthesis, and the products serve as conformationally constrained peptidomimetics. The traceless synthesis of bicycles is also reported as part of this work.
- MeSH
- acetaly chemie MeSH
- cyklizace MeSH
- dipeptidy chemická syntéza chemie MeSH
- molekulární struktura MeSH
- oxazoly chemická syntéza chemie MeSH
- polymery chemie MeSH
- pyrazolony chemická syntéza chemie MeSH
- stereoizomerie MeSH
- techniky kombinatorické chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.
- MeSH
- antigeny povrchové genetika MeSH
- dipeptidy chemická syntéza chemie farmakologie MeSH
- glutamátkarboxypeptidasa II antagonisté a inhibitory genetika MeSH
- kinetika MeSH
- konformace proteinů MeSH
- krystalografie rentgenová MeSH
- kvantová teorie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- mutageneze cílená MeSH
- substrátová specifita MeSH
- termodynamika MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
In the present study, we describe in detail the synthesis of a relatively rare class of phosphorus compounds, α-carboxyphosphinopeptides. We prepared several norleucine-derived α-carboxyphosphinic pseudopeptides of the general formula Nle-Ψ[PO(OH)]-Gly. These compounds could have important applications as transition state-mimicking inhibitors for methionine or leucine aminopeptidases or other enzymes. For the preparation of the key α-carboxyphosphinate protected precursors, we investigated, compared and improved two different synthetic methods described in literature: the Arbuzov reaction of a silylated N-protected phosphinic acid with a bromoacetate ester and the nucleophilic addition of a mixed O-methyl S-phenyl N-protected phosphonic acid or a methyl N-protected phosphonochloridate with tert-butyl lithioacetate. We also prepared two N-Fmoc protected synthons, Fmoc-Nle-Ψ[PO(OH)]-Gly-COOH and Fmoc-Nle-Ψ[PO(OAd)]-Gly-COOH, and demonstrated that these precursors are suitable building blocks for the solid-phase synthesis of α-carboxyphosphinopeptides.
- MeSH
- bakteriální léková rezistence MeSH
- bakteriální pouzdra chemie MeSH
- dipeptidy chemická syntéza MeSH
- glykopeptidy chemická syntéza MeSH
- glykosyltransferasy antagonisté a inhibitory MeSH
- peptidoglykan biosyntéza chemie MeSH
- sacharidy MeSH
- uridindifosfát chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Klíčová slova
- ALAPTID (VÚFB PRAHA),
- MeSH
- dipeptidy analogy a deriváty farmakologie chemická syntéza MeSH
- kuřecí embryo MeSH
- kyseliny cyklohexankarboxylové analogy a deriváty farmakologie chemická syntéza MeSH
- psychotropní léky farmakologie chemická syntéza MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- zvířata MeSH
