New Bicyclam−AZT Conjugates: Design, Synthesis, Anti-HIV Evaluation, and Their Interaction with CXCR-4 Coreceptor
| Autor: | Patrick Vlieghe, Jean-Louis Kraus, Jean Dessolin, Jean-Claude Chermann, Pascale Galea |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Benzylamines
Receptors CXCR4 Magnetic Resonance Spectroscopy Anti-HIV Agents Spectrometry Mass Fast Atom Bombardment Cyclams Virus Replication Chemical synthesis Cell Line chemistry.chemical_compound Zidovudine Blood serum Heterocyclic Compounds Drug Discovery medicine Humans Molecular Structure Prodrug In vitro Mechanism of action chemistry Biochemistry Cell culture Drug Design HIV-1 Molecular Medicine medicine.symptom Lead compound medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 42:229-241 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We report the synthesis of mono- and bis-tetraazamacrocycle-AZT conjugates. All new compounds were screened for their ability to inhibit HIV-1 replication in MT4 cell line and were compared to AZT alone. It appears that N-protected covalent prodrugs are equipotent to AZT as inhibitor of HIV replication, while N-deprotected analogues exhibit both higher activity and selectivity against HIV-infected cells. The most active antiviral compounds 27, 28, 34, and 35 were then tested for their binding capability to CXCR-4 receptor. N-Boc analogues 27 and 34 were only weakly effective; in contrast, N-deprotected conjugates 28 and 35 were antagonists to 12G5 mAb binding until 0.05 and 5 microg/mL, respectively. The stability of compound 28 in human plasma was evaluated, and half-life was found to be approximately 8 h in the described conditions. All these results seem to demonstrate the confidence of our prodrug approach, with analogue 28 emerging as the best candidate as lead compound in HIV-1 polytherapy perspective. |
| Databáze: | OpenAIRE |
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