Novel anti-inflammatory agents targeting CXCR4: Design, synthesis, biological evaluation and preliminary pharmacokinetic study

Abstract

CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100. Furthermore, compound IIj blocked mice ear inflammation by 75% and attenuated ear edema and damage substantially in an in vivo model of inflammation. Western blot analyses revealed that CXCR4 modulator IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, compound IIj had no observable cytotoxicity and displayed a favourable plasma stability in our preliminary pharmacokinetic study. The preliminary structure-activity relationships were also summarized. In short, this novel amide-sulfamide scaffold exhibited potent CXCR4 inhibitory activity both in vitro and in vivo. These results also confirmed that developing modulators targeting CXCR4 provides an exciting avenue for treatment of inflammation.

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

“…This was observed in HCC [165]. Increasing evidence about the role of elevated CXCR4 levels in inflammation and cancer have been published [166][167][168][169] such that its use in identifying cancer therapy targets might be helpful [170] as CXRC4 also affects CXCR2, mitogen-activated protein kinase kinase (MEK, MAPK2, MAPKK), and PI3K signaling [171].…”

Fragmentation pathways of deprotonated amide‐sulfonamide CXCR4 inhibitors investigated by ESI‐IT‐MSn, ESI‐Q‐TOF‐MS/MS and DFT calculations

“…All the 15 compounds analyzed in this work were synthesized in our laboratory according to previously reported methods . The structures of 15 amide‐sulfonamides (shown in Scheme ) were confirmed by 1 H NMR, 13 C NMR and ESI‐MS after purification of the synthesized products.…”

“…The CXCL12/CXCR4 axis has been shown to be involved in cancer metastasis and inflammation . The amide‐sulfonamide scaffold is a novel class of CXCR4 inhibitors developed by our research group, which exhibited promising anti‐inflammatory effect both in vitro and in vivo . Taking RB‐108 (compound 9 ) as an example, this amide‐sulfonamide compound demonstrated potent binding affinity to CXCR4 at the concentration of only 1 nM and significantly inhibited the mice ear inflammation and damage …”

Modulators of CXCR4 and CXCR7/ACKR3 Function

“…4), is a prominent feature among CXCR4 small-molecule antagonists and serves as a starting point for ligand-based discovery of new analogs for improved potency against CXCR4. Likewise, several amidesulfonamide derivatives have CXCR4 binding properties and outperform AMD3100 in Matrigel invasion inhibition (Bai et al, 2017a(Bai et al, , 2017b.…”