Purchase this article with an account.
David C. Paik, Marissa R. Solomon, Quan Wen, Nicholas J. Turro, Stephen L. Trokel; Aliphatic β-Nitroalcohols for Therapeutic Corneoscleral Cross-linking: Chemical Mechanisms and Higher Order Nitroalcohols. Invest. Ophthalmol. Vis. Sci. 2010;51(2):836-843. doi: 10.1167/iovs.09-3937.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The recent tissue cross-linking studies indicate that aliphatic β-nitroalcohols (BNAs) may be useful as pharmacologic corneoscleral cross-linking agents. The present study was performed to identify the specific chemistry involved under physiologic conditions, with the intent of identifying more effective agents.
The mechanism of chemical cross-linking at pH 7.4 and 37°C was studied using three techniques. The colorimetric Griess assay was used to follow the release of nitrite from three mono-nitroalcohols (2-nitroethanol [2ne], 2-nitro-1-propanol [2nprop]), and 3-nitro-2-pentanol [3n2pent]). Second, the evolution of 2nprop in 0.2 M NaH2PO4/Na2HPO4/D2O was studied using 1H-NMR. Third, thermal shrinkage temperature analysis (Ts), a measure of tissue cross-linking, was used to support information from 1the H-NMR studies.
A time-dependent release of nitrite was observed for all three mono-nitroalcohols studied. The maximum levels were comparable using either 2ne or 2nprop (∼30%). However, much less (∼10%) was observed from 3n2pent. Using 1H-NMR, 2nprop evolved into a unique splitting pattern. No match was observed with reference spectra from three possible products of denitration. In contrast, 2-methyl-2-nitro-1,3-propanediol (MNPD), a nitro-diol, was identified, implying the formation of formaldehyde from a retro-nitroaldol (i.e., reverse Henry) reaction. In support of this mechanism, Ts shifts induced by the nitro-triol 2-hydroxymethyl-2-nitro-1,3-propanediol (HNPD) were superior to the nitro-diol MNPD which were superior to the mono nitroalcohol 2nprop.
BNAs function as both formaldehyde and nitrite donors under physiologic conditions to cross-link collagenous tissue. Higher order BNAs are more effective than mono nitroalcohols, raising the possibility of using these agents for therapeutic corneoscleral cross-linking.
This PDF is available to Subscribers Only