New Bicyclam−AZT Conjugates:  Design, Synthesis, Anti-HIV Evaluation, and Their Interaction with CXCR-4 Coreceptor

• Published in: Journal of medicinal chemistry 1999-01, Vol.42 (2), p.229-241
• Main Authors: Dessolin, Jean, Galea, Pascale, Vlieghe, Patrick, Chermann, Jean-Claude, Kraus, Jean-Louis
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; azidothymidine; bicyclam; Bicyclam-AZT Conjugates; Biological and medical sciences; Cell Line; CXCR4 protein; Drug Design; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; MT-4 cells; MT4 cells; Pharmacology. Drug treatments; Receptors, CXCR4 - drug effects; Spectrometry, Mass, Fast Atom Bombardment; Virus Replication - drug effects; Zidovudine - chemistry; Zidovudine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980358u

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 μg/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.