trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors

Abstract

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.

Fig. 1. Six possible configurations of 1^st row transition metal cyclam complexes.

Fig. 2. N-Functionalization patterns of the side-bridged and cross-bridged cyclam macrocycles and their corresponding configurations for 1^st row transition metal complexes. R = alkyl, R¹, R² ≠ H; M = Cu, Ni, Zn.

Scheme 1. General scheme for the formation of trans-IV cyclam complexes; (a) n-BuLi, DMSO, (b) MeI, (c) NaCN, MeCN/H₂O, (d) M(OAc)₂, MeOH (n = 0 or 1).

Fig. 3. Novel ligands synthesized following the described general synthetic pathway.

Fig. 4. Examples of N-functionalization of the side-bridged cyclam resulting in trans-IV configuration of the M²⁺ metal complex and associated crystal structures.