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The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds Ilb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.

Amide-sulfonamides provide a potent anti-inflammatory scaffold targeting the CXCR4 receptor. A series of novel amide-sulfonamide derivatives were investigated for their gas-phase fragmentation behaviors using electrospray ionization ion trap mass spectrometry and quadrupole time-of-flight mass spectrometry in negative ion mode. Upon collision-induced dissociation (CID), deprotonated amidesulfonamides mainly underwent either an elimination of the amine to form the sulfonyl anion and amide anion or a benzoylamide derivative to provide sulfonamide anion bearing respective substituent groups. Based on the characteristic fragment ions and the deuterium-hydrogen exchange experiments, three possible fragmentation mechanisms corresponding to ion-neutral complexes including [sulfonyl anion/amine] complex (INC-1), [sulfonamide anion/benzoylamide derivative] complex (INC-2) and [amide anion/sulfonamide] complex (INC-3), respectively, wereproposed. These three ion-neutral complexes might be produced by the cleavages of S-N and C-N bond from the amide-sulfonamides, which generated the sulfonyl anion (Route 1), sulfonamide anion (Route 2) and the amide anion (Route 3). DFT calculations suggested that Route 1, which generated the sulfonyl anion (ion c) is more favorable. In addition, the elimination of SO 2 through a three-membered-ring transition state followed by the formation of C-N was observed for all the amidesulfonamides.