Oxovanadium(IV) Cyclam and Bicyclam Complexes: Potential CXCR4 Receptor Antagonists

Abstract

Metal complexation can have a major influence on the antiviral and co-receptor binding properties of cyclam and bicyclam macrocycles. We report the synthesis of the vanadyl cyclam complexes [V (IV) O(cyclam)SO 4 ] (1) and [V (IV) O(cyclam)Cl]Cl -(2), and the analogous xylylbicyclam sulfato (3) and chlorido (4) complexes. The X-ray crystal structures of 1·1.33CH 3 OH and 2·CH 3 OH1.5H 2 O show short V=O bonds (1.6093(19) and 1.599(3) Å, respectively) with monodentate sulfate H-bonded to ring NH groups for 1, but a long V-Cl bond (2.650(12) Å) for 2. The solid-state structures of 3 and 4 were compared to those of 1 and 2 using vanadium K-edge EXAFS data. These suggested that complex 4 was oligomeric and contained bridging chlorido ligands. EPR studies suggested that the SO 4 2-(from 1) and Cl -(from 2) ligands are readily substituted by water in solution, whereas these remain partially bound for the V IV xylylbicyclam complexes 3 and 4. The vanadyl xylylbicyclam complexes were highly active against HIV-1 (III B ) and HIV-2 (ROD) strains with IC 50 values in the range 1-5 μM for 3 and 0.1-0.3 μM for 4; in contrast the vanadyl cyclam complexes 1 and 2 were inactive. The factors which contribute to the activity of these complexes are discussed. Studies of vanadyl cyclam docked into a model of the human CXCR4 coreceptor revealed that the coordination of vanadium to the carboxylate of Asp171 may be accompanied by H-bonding to the macrocycle and an attractive V=O··H interaction involving the backbone Trp195 α-carbon proton of CXCR4. In addition, hydrophobic interactions with Trp195 are present. Both ring configuration and the xylyl linker may play roles in determining the higher activity of the bicyclam complexes.

Vanadium compounds in medicine

“…22) were highly active against HIV-1 (IIIB) and HIV-2 (ROD) strains (IC 50 values in the range 1-5 M for 33 and 0.1-0.3 M for 34). However, the oligomeric V IV O-cyclam complexes showed to be inactive [129].…”

“…Computational stimulation of the interaction(s) between the V IV -porphyrin complexes and different molecular targets of HIV-1, revealed that 32 shows preferential binding to CD4 protein, with a binding energy suggesting that 32 may exhibit the anti-HIV-1 activity by blocking the entrance of the virus to its targeted host cells (e.g. However, the oligomeric V IV O-cyclam complexes showed to be inactive [129]. Oxidovanadium(IV) cyclam complexes were also developed as potential anti-HIV agents.…”

“…Examples of VCs that have been reported to have potential as antitumor agents are the inorganic complex Metvan [14,114], a V-cysteine complex [115] and a semicarbazone derivative [116] and VO(acac) 2 (see Section 4). Several VCs have also been reported to have prospective usefulness as anti-parasitic [117][118][119][120][121][122], spermicidal [123,124], anti-viral [125], anti-HIV [126][127][128][129][130], and anti-tuberculosis [131][132][133] agents (see below). Fig.…”

Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

“…Plerixafor TM is a highly selective metal‐chelating bicyclam antagonist of CXCR4 . The affinity of Plerixafor TM for CXCR4 is enhanced after chelating with copper, nickel, or zinc ions . Several additional phase I clinical trials are ongoing for treating AML, CLL, and WHIM syndrome administered via SC injection.…”

Photodynamic Applications of New Imidazo[4,5‐f][1,10]phenanthroline Oxidovanadium(IV) Complexes: Synthesis, Photochemical, and Cytotoxic Evaluation

“…These features make oxidovanadium complexes potential candidates for photochemotherapeutic applications. [43][44][45][46][47] Imidazo[4,5-f] [1,10]phenanthroline as an N,N-donor is a good π-acidic chelating ligand, and it provides a unique platform for the covalent attachment of a wide range of chromophores. [48][49][50] The 1,10-phenanthroline scaffold has been found to be medicinally active.…”