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GTP cyclohydrolase (GCYH-I) is an enzyme in the folate biosynthesis pathway that has not been previously exploited as an antibiotic target, although several pathogens including N. gonorrhoeae use a form of the enzyme GCYH-IB that is structurally distinct from the human homologue GCYH-IA. A comparison of the crystal structures of GCYH-IA and -IB with the nM inhibitor 8-oxo-GTP bound shows that the active site of GCYH-IB is larger and differently shaped. Based on this structural information, we designed and synthesized a small set of 8-oxo-G derivatives with ether linkages at O 6 and O 8 expected to displace water molecules from the expanded active site of GCYH-IB. The most potent of these compounds, G3, is selective for GCYH-IB, supporting the premise that potent and selective inhibitors of GCYH-IB could constitute a new class of small molecule antibiotics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off-target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure-based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hemangioma rarely presents as an isolated middle ear lesion. Because congenital hemangiomas usually regress spontaneously, surgical excision is not always necessary. However, a hemangioma in the middle ear can be complicated by infection and hearing impairment. We present 2 cases to show contrasting management strategies, both with successful outcomes. Two children who presented with unilateral otitis media were found to have concomitant mesotympanic hemangiomas on examination. The first child was asymptomatic and subsequently had an incisional biopsy, confirming the suspected diagnosis. The residual tumor then involuted over the following year. The second child, however, developed chronic otitis media refractory to medical therapy and required surgical removal of the entire hemangioma. Once a tissue diagnosis is made, middle ear hemangiomas can be managed expectantly (ie, wait for spontaneous resolution) or surgically. If growth of a middle ear hemangioma appears to be causing complications refractory to conservative therapy, then early surgical excision may be indicated.

Objective: To describe characteristic features of intralabyrinthine schwannomas (ISs) that may be used to distinguish them from other otologic disorders with similar symptoms so that appropriate evaluation and management can be instituted., Study Design: This study was a retrospective case review., Setting: This study was conducted at a university-affiliated urban tertiary care medical center and a university medical center in the same city., Patients: Seven patients with ISs were included in this study., Interventions: Tumor removal versus observation and monitoring with periodic magnetic resonance imaging (MRI) scans was investigated., Main Outcome Measures: Hearing, vertigo, and tumor growth were measured., Results: Four of seven patients with ISs underwent surgical excision with no evidence of tumor recurrence. The remaining three patients are being followed-up with repeat MRI that has demonstrated minimal or no tumor growth., Conclusions: ISs can be detected in early stages if MRI is performed in patients with unilateral sensorineural hearing loss without vertiginous symptoms typical of Meniere's disease. Although complete surgical excision can be achieved readily with labyrinthectomy, observation and monitoring with rep--MRI is an option for some patients.