Conformational analysis of the anhydrotetracycline molecule: a toxic decomposition product of tetracycline

Journal of Pharmaceutical Sciences
Hélio F Dos SantosM C Zerner

Abstract

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...Continue Reading

Citations

May 4, 2006·Journal of Molecular Modeling·Olaf G OthersenTimothy Clark
Mar 20, 2010·Journal of Computer-aided Molecular Design·Yvonne Connolly Martin
Aug 8, 2001·Journal of Pharmaceutical and Biomedical Analysis·J M Moreno-CerezoM Córdoba-Borrego
Jan 27, 1999·Journal of Pharmaceutical and Biomedical Analysis·A PenaB Castillo
Feb 24, 2001·Chemical & Pharmaceutical Bulletin·T MiyazakiS Okada
Sep 2, 1998·Journal of Pharmaceutical Sciences·W B De AlmeidaM C Zerner
Nov 6, 2012·The Journal of Physical Chemistry. B·Bruna L MarcialMaria J Ramos

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