Tetracycline structure-activity relationship

The tetracycline molecule (1) presents a special challenge widr regard to tlie study of structure-activity relationships. The difficulty has been to devise chemical pathways that preserve the BCD ring chromophore and its antibacterial properties. The lability of die 6-hydroxy group to acid and base degradation, plus the ease of epimerization at position 4. contribute to chemical instability under many reaction conditions. 

The first of these reported by Peradejordi et al. (6) concerned a quantum chemical approach to structure-activity relationships of tetracycline antibiotics. The correlation equation (2) contained seven independent variables each significant at the 1 level... 

Tetracyclines were the first broad-spectrum antibiotics and have been used successfully for decades to treat both gram-positive and gram negative bacterial infections (82). Chlortetra-cycline was the first tetracycline to be isolated, in 1948, from Streptomyces aureofaciens (83). Other common tetracyclines, such as oxytet-racycline and tetracycline, were isolated from Streptomyces sources in subsequent years. The abundance of natural, active tetracyclines, coupled with extensive synthetic alterations, provides a rich collection of compounds from which to build meaningful structure-activity relationships. As was found for the aminoglycosides, previous observations of tetracycline structure and activity can be rationalized from recent tetracycline/30S crystal structures (11,12). 

The unexpected biological activities of tetracyclines, such as 5a-epi-6-epitetracycline [19543-88-5], C22H24N208, and 7-chloro-5a,lla-dehydro-6-epitetracycline [22688-60-4], C22H21C1N208, make predicting structure-activity relationships difficult (64). Aside from the C-2 amide Mannich-base derivatives, variation at other centers in the molecule, ie, C-4, 4a, 5a, 12a, decreases the biological activity. 

The structure activity relationship amongst the various members of the tetracycline family has ben studied extensively. 

---