Circular dichroism and solution conformation of the tetracycline antibiotics.

Mitscher, Lester A.; Bonacci, Anthony C.; Sokoloski, Theodore D.

doi:10.1016/s0040-4039(00)75384-6

Cited by 37 publications

(39 citation statements)

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“…Figure 3 illustrates the various conformations that OTC can assume. In particular, it should be noted that the distance between the 12a-OH group and the 4-NMe2 group in conformation A is essentially the same as the distance between 5-OH and 4-NMe2 in conformation C and the same as the distance between 5-OH and 12a-OH in conformation D. Conformation A represents one extreme of the available conformations and is that regarded in our earlier work (10,11) as most satisfactory for rationalizing all the available data for TC species in neutral to slightly alkaline solutions. Conformation D represents the other extreme.…”

Section: Resultsmentioning

confidence: 74%

“…Thus, if conformation plays a role in the molecular biology of the antibiosis due to these antibiotics, OTC presents no exception under these "physiological" conditions. Beginning at pH 9, and particularly at pH 11, the spectrum of OTC is quite different from that of the non-5-hydroxyle x 10 ated antibiotics. Figure 2 shows a direct comparison of the CD spectra of OTC, TC, and DMDOTC at pH 8.98.…”

Section: Resultsmentioning

confidence: 95%

“…Earlier papers in this series (9)(10)(11) have presented evidence consistent with the concept that all of the common fermentation-derived tetracyclines (TC) possess the same solution conformation in dilute aqueous acidic media. These findings are in agreement with evidence gathered from nuclear magnetic resonance (NMR) (12,13)and X-ray (1, 2, 4-6, 14, 15) measurements.…”

mentioning

confidence: 72%

“…In the first papers in this series (9,10), it was shown by the virtual coincidence of CD spectra that OTC possesses the same conforma-66 on April 27, 2019 by guest http://aac.asm.org/ Downloaded from CIRCULAR DICHROISM MEASUREMENTS tion in dilute acid solutions as, for example, does 6-demethyl-6-deoxytetracycline (DMDOTC). Figure 1 shows the effect on the spectrum and, therefore, conformation, of raising the pH of dilute aqueous solutions of OTC.…”

Section: Resultsmentioning

confidence: 99%

“…In the 5-OH series, conformation A is slightly less favorable than when this group is absent, because of the peri-interaction between the 5-OH and the 6-Me groups. Conformation B represents a twisting of the A ring to relieve the steric crowding between 4-NMe2 and 12a-OH and represents the (9,10). Conformation C results from a continued twisting of the A ring until the 4-NMe2 group has become equatorial.…”

Section: Resultsmentioning

confidence: 99%

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Circular Dichroism Measurements of the Tetracyclines IV. 5-Hydroxylated Derivatives

Mitscher

Sokoloski

1972

Antimicrob Agents Chemother

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From extensive circular dichroism measurements of a variety of tetracycline (TC) derivatives in the presence and absence of a variety of chelating ions, it is concluded that 5-hydroxytetracycline possesses an identical solution conformation to that possessed by all fermentation-derived, bioactive TC species in dilute aqueous solutions at pH 7.5 or below. These conditions resemble those encountered under normal physiological circumstances. In alkaline solutions, the conformation of of 5-hydroxytetracycline diverges from the non-5-hydroxylated subclass of TC species. This divergence is rationalized as due to a buttressing effect of colinear perisubstituents at positions 4, 5, and 6 and is assisted by the possibility of hydrogen bonding between the 5 and 12a hydroxyl groups. Chelation, in alkaline solutions, with Mg ions "locks" the molecule into a conformation which has been detected by others in nuclear magnetic resonance studies in concentrated non-aqueous solvents and in X-ray studies with the 5,12a-diacetoxy analogue. Parallel studies with a variety of model TC species and Ca ions provide strong support for the hypothesis that both Ca and Mg ions bind at the BCD juncture and that, above pH 7.5, the Ca ion binds to the A ring between 4-NMe2 and 12a-OH, whereas Mg ion does not do this. If a 5-OH group is present, the Ca ion still binds as before, whereas the Mg ion will bind to the AB rings between 5-OH and 12a-OH. These factors are discussed in conjunction with the various conformations potentially available to the molecule.Earlier papers in this series (9-11) have presented evidence consistent with the concept that all of the common fermentation-derived tetracyclines (TC) possess the same solution conformation in dilute aqueous acidic media. These findings are in agreement with evidence gathered from nuclear magnetic resonance (NMR) (12, 13)and X-ray (1, 2, 4-6, 14, 15) measurements. We have proposed that under neutral conditions the TC species undergo a subtle, but potentially very meaningful, conformational alteration resulting from hydrogen bonding between the 1, 3-diaxially disposed 12a-OH and 4-NMe2 groups. This change results in considerable flattening of the A-ring chromophore.bThere is evidence in the literature, first from NMR work (12, 13) and, quite recently, from X-ray measurements (6, 15), that 5-hydroxytetracycline (OTC) and some of its derivatives may exist in another conformation under cer-I Present address: Parke-Davis and Co., Detroit, Mich. 48232. tain conditions. We have carried out extensive circular dichroism (CD) measurements and conclude that, indeed, under certain conditions, this TC subgroup does behave in a manner distinct from the TC species lacking this function. In this paper, we would like to present results which confirm this X-ray-and NMR-based hypothesis and define some of the conditions under which this conformation is preferred. MATERIALS AND METHODSThe TC derivatives used in this study are the purest samples available and were obtained through the generosity of J. M. Boo...

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Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 95%

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confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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