Conformational Analysis of the Anhydrotetracycline Molecule: A Toxic Decomposition Product of Tetracycline

• Published in: Journal of pharmaceutical sciences 1998-02, Vol.87 (2), p.190-195
• Main Authors: Dos Santos, Helio F., De Almeida, Wagner B., Zerner, Michael C.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; General aspects; Hydrogen-Ion Concentration; Ions; Medical sciences; Models, Chemical; Molecular Conformation; Molecular Structure; Pharmacology. Drug treatments; Tetracycline - chemistry; Tetracyclines - chemistry
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js970275l

□ Anhydrotetracycline (AHTC) is a toxic decomposition product of the widely used antibiotic tetracycline (TC). The side effects of AHTC have been attributed to the conformational changes in the ring system. In the present study a systematic conformational analysis has been carried out using the semiempirical quantum mechanical AM1 model. The conformational pH dependence has been analyzed through the study of all the ionized species. The results obtained showed two distinct families of conformation, referred to as A and B, with the interconversion process involving a rotation around the C4a–C12a bond. The solvent effect has been considered using the continuum model COSMO. From the population analysis in the gas phase, we conclude that form A should be dominant for the LH3+ and LH2± species and B is the preferred conformer for the L2− ionized form (97.54%). For the LH− derivative, we predict that both conformations should be present in the equilibrium mixture in the gas phase, with the relative concentration found to be 68.47% (A) and 31.53% (B). The inclusion of the solvent does not change the A/B equilibrium for the LH3+ and LH2± species. However, for the LH− form, the equilibrium is shifted to conformer A in water solution. The population analysis in water solution for the L2− suggest the following relative concentrations: A (34.46%) and B (65.54%). The biological activity of the TC parent compound is attributed to the zwitterionic species, which should adopt a twisted conformation. According to the results obtained in the present study, the most abundant form of the LH2± zwitterionic species for the AHTC molecule is the extended one (100% in both the gas phase and water solution). Therefore, from a pharmacodynamic point of view, this conformational difference should be taken into account in order to explain the toxic effects of the anhydrous derivative. Another point related to the structure–activity relationship was analyzed through the investigation of the tautomerization process LH20→f LH2±. The result obtained suggests that the LH20 tautomer should be dominant in the gas phase (nonpolar solvent) and adopt a conformation classified as B. In water solution, the tautomer LH2± is present as conformer A (96%). This result is in agreement with the conformation changes involved in the tautomer- ization process for the OTC active derivative.