Aliphatic β-Nitroalcohols for Therapeutic Corneoscleral Cross-Linking: Chemical Stability Studies Using 1H-NMR Spectroscopy

• Published in: Photochemistry and photobiology 2014-03, Vol.90 (2), p.338-343
• Main Authors: Li, Xia, Li, Yongjun, Kim, MiJung, Trokel, Stephen L., Turro, Nicholas J., Paik, David C.
• Format: Article
• Language: English
• Subjects: Alcohols - chemistry; Alcohols - pharmacology; Alcohols - therapeutic use; Cornea - drug effects; Humans; Keratoconus - therapy; Nitro Compounds - chemistry; Proton Magnetic Resonance Spectroscopy; Sclera - drug effects
• ISSN: 0031-8655; 1751-1097
• DOI: 10.1111/php.12165

Recent studies suggest that aliphatic β‐nitro alcohols may represent a useful class of compounds for use as in vivo therapeutic corneoscleral cross‐linking agents with higher order nitroalcohols (HONAs) showing enhanced efficacy over the mono‐nitroalcohols. The current study was undertaken in order to evaluate the chemical stability of these compounds during storage conditions. Two mono‐nitroalcohols (2‐nitroethanol=2ne and 2‐nitro‐1‐propanol=2nprop) and two HONAs, a nitrodiol (2‐methyl‐2‐nitro‐1,3‐propanediol=MNPD), and a nitrotriol (2‐hydroxymethyl‐2‐nitro‐1,3‐propanediol=HNPD) were monitored for chemical stability by 1H‐NMR for up to 7 months. Each compound was studied at two concentrations (1% and 10%) either in unbuffered H2O or 0.2 m NaH2PO4/Na2HPO4 (pH=5), and at 0°C and room temperature (RT) for a total of eight conditions for each compound. The 1H‐NMR spectra for the starting material were compared to subsequent spectra. Under all four of the conditions studied, both the nitrodiol (MNPD) and nitrotriol (HNPD) were stable for the duration of 7 months. 2nprop became unstable under all conditions at 3 months. 2ne was the most unstable of all the compounds tested. HONAs exhibit excellent chemical stability under long‐term storage conditions. In contrast, the nitromonols tested are significantly less stable. These findings are relevant to the translation of this technology into clinical use. Certain β‐nitroalcohols undergo a base‐catalyzed thermally driven retronitroalcohol reaction to give formaldehyde under physiologic conditions. Because they also exhibit a favorable safety profile (unlike free formaldehyde), they represent a potentially useful class of agents for clinical therapeutic corneoscleral tissue cross‐linking. In this brief report, compound stability under long‐term storage conditions was studied in anticipation of clinical translation of this potential treatment modality. Higher order nitroalcohols (a nitrodiol and nitrotriol) were found to be significantly more stable than their mononitroalcohol counterparts.