Design and synthesis of CXCR4 antagonists with anti-proliferative activity

CXC-chemokine receptor 4 (CXCR4) is involved in a number of physiological and pathological pathways thus representing one of the most promising target for the development of innovative therapeutic agents with a broad-spectrum of activity. In particular, a crucial role for this receptor has been hypothesized during cancer growth and progression. At data, numerous non-peptides compounds, belonging to various N-containing heterocyclic classes, have been shown to significantly inhibit CXCR4.[1,2] Among the chemical scaffolds identified, a very interesting class of active compounds is represented by indole derivatives, since molecular modeling experiments showed that this nucleus meets the spatial requirements for interaction with the three key residues identified in the pharmacophoric model. Herein we report the design and the synthesis of new series of indole based compounds, such as N-indolbenzohydrazides and 5H-indole[1,2-a][3,1]benzoxazin-5-one hydrazine derivatives, showing affinity toward the receptor. The new molecules will be subjected to various in vitro tests, in order to assess their capability to antagonize the effects of the CXCR4 ligand SDF-1 on anchorage-dependent breast cancer cell proliferation. [1] F. Grande, A. Garofalo, N. Neamati Curr Pharm Des, 2008, 14, 385-404. [2] B. Debnath, S. Xu, F. Grande, A. Garofalo, N. Neamati Theranostics, 2013, 3, 47-75.