Theoretical mechanistic insight into the gabapentin lactamization by an intramolecular attack: Degradation model and stabilization factors.

PURPOSE: Gabapentin is degraded directly into a high toxicity form known as gabapentin lactam (gaba-L) with a maximizing desire in mild pH and low humidity. This study reports the lactamization process of gabapentin, along with a detailed analysis of the energy landscape, geometry, and thermodynamic and kinetic preference of the process. To investigate the effect of the acidic/basic conditions on the energy landscape, the energy profiles were investigated for both protonation and deprotonation forms of gabapentin. METHODS: All the calculations were performed by using the density functional theory (DFT) and the G4MP2 levels of theory in the conductor-like polarizable continuum model, CPCM, and water as the solvent. RESULTS: The lactamization process is an intramolecular cyclization which results in formation of gabapentin-lactam. The chemically intact gabapentin exists in two forms of a stable, R, and a relatively disordered form, R*. The conversion of stable crystalline form R to the intact unstable isomer R* is considered as the primary step in the gabapentin degradation. The results exhibited that near the unstable geometry, R*, a transition state (TS), is 41.3 kcal/mol higher in energy than the optimized ground state, R* (4.1 kcal/mol). From the intrinsic reaction coordinates (IRC) computations, it can be concluded that this transition state led to the unstable R* in one direction and to gabapentin-lactam in the other. CONCLUSIONS: The thermodynamic stability of the lactam form (-13.63 kcal/mol) clarifies the more thermal stability of gaba-L than its related gabapentin form and the experimental preference for the lactamization. The corresponding energy profile on protonation/deprotonation forms of gabapentin indicates the pH-dependent of the process and the rate reduction in out of the mild pH.

Disquisition on the interaction of ibuprofen-Zn(II) complex with calf thymus DNA by spectroscopic techniques and the use of Hoechst 33258 and Methylene blue dyes as spectral probes.

The interaction between ibuprofen-Zn(II) complex and calf thymus DNA in physiological buffer (pH 7.4) was studied with the use of Hoechst 33258 and methylene blue dyes as spectral probes by multi-spectroscopic techniques, and viscosity measurements. It was found that ibuprofen-Zn(II) complex molecules could bind with DNA via groove binding mode as evidenced by: i- DNA binding constant (Kb = (1.00 ± 0.2) × 104 M-1) from Spectrophotometric studies of the interaction of ibuprofen-Zn(II) complex with DNA is comparable to groove binding drugs. ii- Absorption Spectra of Competitive interaction of ibuprofen-Zn(II) complex and Hoechst 33258 with DNA exhibited the reverse process, The results suggested that interaction of the ibuprofen-Zn(II) complex with calf thymus DNA, is similar to Hoechst 33258 interaction with calf thymus DNA (This was verified by the following fluorescence study). iii- Competitive fluorimetric studies with Hoechst 33258 have shown that ibuprofen-Zn(II) complex exhibit the ability of this complex to displace with DNA-bounded Hoechst 33258, indicating that it binds to DNA in strong competition with Hoechst 33258 for the groove binding. iv- There is no significantly change in the fluorescence intensity of the MB-DNA system upon adding the ibuprofen-Zn(II) complex, indicate that MB molecules are not released from the DNA helix after addition of the ibuprofen-Zn(II) complex and are indicative of a non-intercalative mode of binding. v- Small changes in DNA viscosity in the presence of ibuprofen-Zn(II) complex, indicating weak link to DNA, which is consistent with DNA groove binding. As well as, induced CD spectral changes, and the docking results revealed that groove mechanism is followed by ibuprofen-Zn(II) complex to bind with DNA.