An enantioselective addition reaction of various alkyl groups to unactivated internal alkenes under Cu catalysis has been developed. The reaction uses amide-linked aminoquinoline as the directing group, 4-alkyl Hantzsch esters as the donor of alkyl radicals, and rarely used biaryl diphosphine oxide as a chiral ligand. β-lactams featuring two contiguous stereocenters at Cβ and the β substituent can be obtained in good yield with excellent enantioselectivity. Mechanistic studies indicate that a nucleophilic addition of the alkyl radical to CuII-coordinated alkene is the enantio-determining step.

A new protocol for amide-directed Cu-catalyzed aminoalkylation of unactivated alkenes using cyclobutanone oxime esters as alkyl radical donors is developed. Both primary and secondary alkyl groups can be selectively installed at the C4 position of terminal or cis-internal 3-alkenamides in moderate to good yield. This reaction offers a useful method for the diastereoselective synthesis of β-lactams bearing 4-cyanoalkyl β-substituents. The use of a weakly coordinating counteranion as the Cu catalyst is critical for the formation of β-lactam products.

JOURNAL/nrgr/04.03/01300535-202403000-00045/inline-graphic1/v/2023-08-11T153926Z/r/image-tiff Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer’s test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.

Background:PRDM12 is a newly discovered gene responsible for congenital insensitivity to pain (CIP). Its clinical manifestations are various and not widely known.Methods: The clinical data of two infants diagnosed with CIP associated with PRDM12 mutation were collected. A literature review was performed, and the clinical characteristics of 20 cases diagnosed with a mutation of PRDM12 were summarized and analyzed.Results: Two patients had pain insensitivity, tongue and lip defects, and corneal ulcers. The genomic analysis results showed that variants of PRDM12 were detected in the two families. The case 1 patient carried heterozygous variations of c.682+1G &gt; A and c.502C &gt; T (p.R168C), which were inherited from her father and mother, respectively. We enrolled 22 patients diagnosed with CIP through a literature review together with our cases. There were 16 male (72.7%) and 6 female (27.3%) patients. The age of onset ranged from 6 months to 57 years. The prevalence of clinic manifestation was 14 cases with insensitivity to pain (63.6%), 19 cases with self-mutilation behaviors (86.4%), 11 cases with tongue and lip defects (50%), 5 cases with mid-facial lesions (22.7%), 6 cases with distal phalanx injury (27.3%), 11 cases of recurrent infection (50%), 3 cases (13.6%) with anhidrosis, and 5 cases (22.7%) with global developmental delay. The prevalence of ocular symptoms was 11 cases (50%) with reduced tear secretion, 6 cases (27.3%) with decreased corneal sensitivity, 7 cases (31.8%) with disappeared corneal reflexes, 5.5 cases (25%, 0.5 indicated a single eye) with corneal opacity, 5 cases (22.7%) with corneal ulceration, and 1 case (4.5%) with a corneal scar.Conclusion: The syndrome caused by PRDM12 mutation is a clinically distinct and diagnosable disease that requires joint multidisciplinary management to control the development of the disease and minimize the occurrence of complications.