Synthesis and evaluation of 2,5-furan, 2,5-thiophene and 3,4-thiophene-based derivatives as CXCR4 inhibitors.

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.

Synthesis and evaluation of 2,5 and 2,6 pyridine-based CXCR4 inhibitors.

Targeting the interaction between G-Protein Coupled Receptor, CXCR4, and its natural ligand CXCL12 is a leading strategy to mitigate cancer metastasis and reduce inflammation. Several pyridine-based compounds modeled after known small molecule CXCR4 antagonists, AMD3100 and WZ811, were synthesized. Nine hit compounds were identified. These compounds showed lower binding concentrations than AMD3100 (1000nM) and six of the nine compounds had an effective concentration (EC) less than or equal to WZ811 (10nM). Two of the hit compounds (2g and 2w) inhibited invasion of metastatic cells at a higher rate than AMD3100 (62%). Compounds 2g and 2w also inhibit inflammation in the same range as WZ811 in the paw edema test at 40% reduction in inflammation. These preliminary results are the promising foundation of a new class of pyridine-based CXCR4 antagonists.

Symmetrical bis-tertiary amines as novel CXCR4 inhibitors.

CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.

Synthesis of pyridine derivatives as potential antagonists of chemokine receptor type 4.

A series of pyridine derivatives were synthesized as potential inhibitors of chemokine receptor type 4. This chemokine receptor has been linked to various disease pathways including HIV-1 proliferation, autoimmune disorders, inflammatory diseases, and cancer metastasis. The compounds were tested for activity using an affinity binding assay and an assay that tests the ability to inhibit cell invasion. Two hit compounds (2b and 2j) have been identified for further evaluation that inhibit cell invasion by at least 50% and have an effective concentration of less than 100 nM in the binding affinity assay. The structures of the synthesized compounds were confirmed by spectral data.

Innovation in bladder assessment: use of technology in extended care.

Nursing homes are required to conduct a comprehensive assessment and screening of residents with urinary incontinence (UI) and indwelling catheter upon admission, and if there is a change in cognition, physical ability, or urinary tract function (Centers for Medicare and Medicaid Services [CMS], 2005). The desired goal is to improve the quality of care through the maintenance and the restoration of bladder function. CMS regulations and revised Tag F315 mandate that long-term care facilities appropriately assess and treat the specific bladder disorder of UI and decrease the inappropriate use of indwelling urinary catheters. Assessment includes evaluation for reversible factors that may cause UI, such as urinary retention and urinary tract infection. The scope of this article is to demonstrate the relationship between these bladder disorders and assessments that can be performed by nursing staff. Because invasive instrumentation of the bladder can increase the likelihood of urinary tract infections, the use of non-invasive technology that ensures quality and evidence-based clinical practice, while preventing associated medical problems in vulnerable residents, is necessary for bladder assessment in the extended care setting. With this technology, assessment of bladder function is easy for staff and provides information that can be vital to successful nursing care outcomes. The staff of CRISTA Senior Community changed clinical practice through incorporation of technology to determine the presence of bladder dysfunction. Staff accurately and effectively applied ultrasonography to determine the bladder volume and abnormalities with bladder emptying, with ultimate improvement in resident care. Adoption of technology can preserve the resident's dignity and respect, while ensuring the highest level of bladder function.