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A novel annulation approach for the synthesis of (4,5-b)quinolin-2-one is presented, representing the first synthesis of a ribonucleoside of imidazo(4,5-b)quinolines, and the regioselective ribosylation of this heterocycle investigated. Regioselective ribosylation methods are developed to afford both the N1 and the N3 ribonucleosides of 6,7-dichloroimidazo(4,5-b)quinolin-2-one in high yield. The photoassisted annulation method overcame a number of problems earlier encountered with the annulation procedure.

Demonstrates the synthesis of the polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB). Ribosylation of 6,7-dichloroimidazo[4,5-beta]quinolin-2-one; Structure of the analogues; Spatial limitation of the target enzymes.

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5β1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5β1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5β1 integrin inhibition as a promising therapy for pulmonary hypertension., One Sentence Summary: The α5β1 integrin plays a crucial role in pulmonary vascular remodeling.