Tetracycline Extension Of Chromophore Elimination

Loss of H (together with C6-OH) Remove OH, CH3 or both CI, Br, N02, (CH,)2N-Little information available ClandCHj

"Inviolate zone" including C-l Epimerizing a-OH or deoxy

Inactive degradation product Active, more stable drugs Activity retained

Decreased activity (compared to 7 substitution) Any change lowers or eliminates all activity Decreased activity

3 Also refer to structure in Fig. 6-23. 6 Relative to tetracycline.

Dimethylammonium ion

Figure 6-19. Tetracycline "activity" regions.

Phenoldiketone system pKa 2 = 7.2 to 7.8

Figure 6-19. Tetracycline "activity" regions.

enhance, reduce, or eliminate activity.27 The chemistry around C-4 is particularly interesting. The most "naked" tetracycline exhibiting antimicrobial activity is 6-demethyl-6-deoxy-4-dedimethylamino-tetracycline. This compound, which has no nitrogen moiety at C-4, has some in vitro activity against several Gm+ organisms. In vivo activity is absent. Addition of a dimethylamino group at C-4 (6-demethyl-6-deoxytetracycline) is the simplest tetracycline having in vivo activity. Also of particular interest from an SAR standpoint is the structural integrity of the "inviolate zone" encompassing CIO, CI 1, CI2, and CI. The oxygen functions in this region generate two distinct ultraviolet absorbing chro-mophoric groups. One group of the Tt-electron region is the tricarbonylmethane moiety comprising CI, C2, and C3 (Fig. 6-19); the other is the phenoldiketone system consisting of CIO, CI 1, and CI2. The interposition of the 12a-hydroxyl function ensures the electron separation of these two areas. Modification of these chromophores by aromatization of ring C, cleavage of a ring, extension, or blocking of the chromophore all lead to essentially inactive compounds.

Aromatization of ring C is actually a chemical instability occurring as a dehydration reaction under acidic conditions and, of course, accelerated by elevated temperatures (Fig. 6-20). The elements of H20 derive from the 6-OH and 5a-H atom affording a 5a-6 DB. The 1 la—12 DB spontaneously isomerizes to the 11-1 la position yielding anhy-drotetracycline (ATC). This inactive degradation product is therefore formed in aging TC-containing products, and its rate of formation is increased if improperly stored (e.g.,



27 An extensive discussion will be found in Blackwood and English (1977).








Figure 6-20. Chemical instabilities of tetracycline.

elevated temperatures, increased acidity). ATC28 has been shown to be nephrotoxic. Another degradation reaction is ring cleavage resulting in isotetracycline (ITC). Following tautomerization of TC to the 12-keto form, base catalyzes (i-ketone cleavage of the 11-1 la bond followed by lactonization of the 6-OH with the 11-keto function (Fig. 6-20). It will be noted that both these degradation reactions involve the 6-OH group. The semisynthetic tetracyclines, MNC, MC, and DC (Table 6-9), are therefore not subject to these instabilities.

Elimination of the 12a-OH function would extend the chromophore (by producing an additional DB at 12a-l) and eliminate activity. Substituting a halogen into position 11a would constitute a chromophoric block. Both of the preceding actions would predictably result in considerably decreased activity.

Another instability leading to a dramatic decrease of antibacterial action, to which all clinically used tetracyclines are subject, is epimerization of the "natural" 4-a-dimethy-lamino group A to the p-epimer B (Eq. 6.11). Under acidic conditions a 1:2 equilibrium is established in solution within a day. This occurs in a variety of solvents, especially acetic acid. Anions also tend to support this process. Divalent ions that chelate tetracyclines, particularly Ca2+, facilitate the reversal of the epimerization from the epi to the natural isomer.

Even though any modification of C-2 leads to inferior activity, or none at all, the pyrro-lidinomethyl derivative of the 2-carboxamide (rolitetracycline) appears to be an exception. However, on closer scrutiny this Mannich reaction product (Eq. 6.12) will be seen as a prodrug of TC. The compound is 2,500 times more water soluble than the parent TC compound (comparing free bases), to which it hydrolyzes in vivo. Thus its activity is essentially that of the parent compound.

28 Actually anhydro-4-epitetracycline.


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