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1.
Chemistry ; : e202402151, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38924659

ABSTRACT

Reactive N-hydroxy-9-azabicyclo[3.3.1]nonane (ABNOH) linked 2'-deoxyuridine 5'-O-mono- and triphosphates were synthesized through a CuAAC click reaction of ABNO-H-PEG4-N3 with 5-ethynyl-dUMP or -dUTP. The modified triphosphate was used as substrate for enzymatic synthesis of modified DNA probes with KOD XL DNA polymerase. The keto-ABNO radical reacted with tryptophan (Trp) and Trp-containing peptides to form a stable 3-fused hexahydropyrrolo-indole conjugates. Similarly modified ABNO-H-linked nucleotides reacted with Trp-containing peptides to form a stable conjugate in the presence but surprisingly even in the absence of NaNO2 (presumably through activation by O2). The reactive ABNO-H-modified DNA probe was used for bioconjugations and crosslinking with Trp-containing peptides or proteins.

2.
Bioconjug Chem ; 2023 Mar 27.
Article in English | MEDLINE | ID: mdl-36972479

ABSTRACT

A series of 2'-deoxyribonucleoside triphosphates (dNTPs) bearing 2- or 4-linked trans-cyclooctene (TCO) or bicyclononyne (BCN) tethered through a shorter propargylcarbamate or longer triethyleneglycol-based spacer were designed and synthesized. They were found to be good substrates for KOD XL DNA polymerase for primer extension enzymatic synthesis of modified oligonucleotides. We systematically tested and compared the reactivity of TCO- and BCN-modified nucleotides and DNA with several fluorophore-containing tetrazines in inverse electron-demand Diels-Alder (IEDDA) click reactions to show that the longer linker is crucial for efficient labeling. The modified dNTPs were transported into live cells using the synthetic transporter SNTT1, incubated for 1 h, and then treated with tetrazine conjugates. The PEG3-linked 4TCO and BCN nucleotides showed efficient incorporation into genomic DNA and good reactivity in the IEDDA click reaction with tetrazines to allow staining of DNA and imaging of DNA synthesis in live cells within time periods as short as 15 min. The BCN-linked nucleotide in combination with TAMRA-linked (TAMRA = carboxytetramethylrhodamine) tetrazine was also efficiently used for staining of DNA for flow cytometry. This methodology is a new approach for in cellulo metabolic labeling and imaging of DNA synthesis which is shorter, operationally simple, and overcomes several problems of previously used methods.

3.
Data Brief ; 22: 471-483, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30619925

ABSTRACT

The data have been obtained from FABP4 inhibitor molecules previously published. The 120 compounds were used to build a 3D-QSAR model. The development of the QSAR model has been undertaken with the use of Forge software using the PM3 optimized structure and the experimental IC50 of each compound. The QSAR model was also employed to predict the activity of 3000 new isosteric derivatives of BMS309403. The isosteric replacement was also validated by the synthesis and the biological screening of three new compounds reported in the related research article "3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation" (Floresta et al., 2019).

4.
Bioorg Chem ; 84: 276-284, 2019 03.
Article in English | MEDLINE | ID: mdl-30529845

ABSTRACT

Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 µM, with a high level of agreement with the predicted values.


Subject(s)
Fatty Acid-Binding Proteins/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Fatty Acid-Binding Proteins/metabolism , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/metabolism , Models, Molecular , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/metabolism , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/metabolism
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