CONFORMATIONAL-ANALYSIS OF THE ANHYDROTETRACYCLINE MOLECULE - A TOXICDECOMPOSITION PRODUCT OF TETRACYCLINE

Anhydrotetracycline (AHTC) is a toxic decomposition product of the wid ely used antibiotic tetracycline (TC). The side effects of AHTC have b een attributed to the conformational changes in the ring system. In th e present study a systematic conformational analysis has been carried out using the semiempirical quantum mechanical AM1 model. The conforma tional pH dependence has been analyzed through the study of all the io nized species. The results obtained showed two distinct families of co nformation, referred to as A and B, with the interconversion process i nvolving a rotation around the C-4a-C-12a 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 t he 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 equi librium for the LH3+ and LH2+/- species. However, for the LH- form, th e equilibrium is shifted to conformer A in water solution. The populat ion analysis in water solution for the L2- suggest the following relat ive 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 ob tained in the present study, the most abundant form of the LH2+/- zwii lerionic species for the AHTC molecule is the extended one (100% in bo th the gas phase and water solution). Therefore, from a pharmacodynami c point of view, this conformational difference should be taken into a ccount in order to explain the toxic effects of the anhydrous derivati ve, Another point related to the structure-activity relationship was a nalyzed through the investigation of the tautomerization process LH20 --> LH2+/-. The result obtained suggests that the LH20 tautomer should be dominant in the gas phase (nonpolar solvent) and adopt a conformat ion classified as B. In water solution, the tautomer LH2+/- is present as conformer A (96%). This result is in agreement with the conformati on changes involved in the tautomerization process for the OTC active derivative.