Structure of N-(2-dimethylaminoethyl)phenothiazine-1-carboxamide hydrochloride

Christiansen, J.; Clark, George R.; Denny, W. A.; Palmer, Brian D.

doi:10.1107/s0108270192003330

Cited by 3 publications

(4 citation statements)

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“…The average dissociation rate for the acridonecarboxamide is at least 3-fold faster than that of DACA, whereas for the other compounds in the “peri NH” group, this factor rises to between at least 12- to- 25-fold. In the case of the phenothiazinecarboxamide, 16 , the extraordinarily rapid kinetics may be attributable, at least in part, to the fact that the ring is not flat but butterfly-shaped . Nevertheless, this buckling of the chromophore does not inhibit intercalative binding …”

Section: Resultsmentioning

confidence: 99%

“…Indeed, the crystal structure of the free phenothiazinecarboxamide, 16, reveals the carboxamide group to be doing just this, although in this case the tricyclic ring is buckled. 22 However, notwithstanding this hydrogen-bonding potential, the side chains of none of these compounds appear to interact with guanine. One possible explanation is that the internal hydrogen bond is intrinsically weak, since the NH group is uncharged, and made yet weaker in the DNA intercalation complex where π-orbital stacking with the base pairs and interaction with the electrostatic field derived from the phosphate charges can modify chromophore orbital energies and electron distributions.…”

Section: Discussionmentioning

confidence: 99%

“…The phenoxazine-, acridone-, pyridoindole-, and phenothiazinecarboxamides, compounds 11 − 13 and 16 , share an NH structural motif which, in principle, would not necessarily prevent the peri carboxamide from being coplanar with the chromophore since the carbonyl oxygen could form an internal hydrogen bond in the cis configuration. Indeed, the crystal structure of the free phenothiazinecarboxamide, 16 , reveals the carboxamide group to be doing just this, although in this case the tricyclic ring is buckled . However, notwithstanding this hydrogen-bonding potential, the side chains of none of these compounds appear to interact with guanine.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of the phenothiazinecarboxamide, 16, the extraordinarily rapid kinetics may be attributable, at least in part, to the fact that the ring is not flat but butterfly-shaped. 22 Nevertheless, this buckling of the chromophore does not inhibit intercalative binding. 13 The xanthenone and thioacridonecarboxamides, compounds 14 and 15, possess oxygen and sulfur atoms peri to the side chain, and their DNA complexes dissociate very fast with only 38% and 18%, respectively, of the reaction occurring in the stopped-flow time range (Table 2).…”

Section: Spectrophotometric Measurementsmentioning

confidence: 99%

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Kinetic Studies of the Binding of Acridinecarboxamide Topoisomerase Poisons to DNA: Implications for Mode of Binding of Ligands with Uncharged Chromophores

2002

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We have used stopped-flow spectrophotometry and the sodium dodecyl sulfate sequestration technique to study the kinetics of dissociation of DNA complexes of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (termed DACA) and a range of related linear tricyclic carboxamides with neutral chromophores. Complexes of DACA and related acridine and phenazinecarboxamides bearing an N,N-dimethylaminoethyl side chain dissociate from calf thymus DNA by a kinetic pathway involving four discernible steps in a manner similar to complexes of N-[(2-dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (termed 9-amino-DACA). We infer from these findings that the side chains of DACA, its phenazine homologue, and 9-amino-DACA make comparable interactions with the DNA base pairs. In the case of 9-amino-DACA, a selective topoisomerase II poison, these are known, by crystallographic analysis, to involve hydrogen-bonding interactions between the protonated dimethylammonium group of the side chain and the O6/N7 atoms of guanine and to include a bridging water molecule hydrogen bonded to the carboxamide group and a phosphate oxygen. By contrast, we find that other linear tricyclic carboxamides with neutral chromophores which lack a peri nitrogen atom and are biologically inactive dissociate from DNA by a different mechanism in which it appears their side chains fail to interact with guanine. We conclude that the ability of the carboxamide group to lie preferentially in the plane of the chromophore, so facilitating the dimethylammonium-guanine hydrogen bond and ensuring maintenance of the water-bridged carboxamide-phosphate interaction, is a critical requirement for antitumor activity among ligands of the linear tricyclic carboxamide class. However, unlike the situation for 9-amino-DACA, for ligands with uncharged chromophores containing peri nitrogen atoms such as DACA, this outcome is possible with the 4-carboxamide group rotated cis or trans with respect to the ring nitrogen. This difference may have relevance to the ability of DACA to be a dual poison of both topoisomerases I and II.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Spectrophotometric Measurementsmentioning

confidence: 99%

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Kinetic Studies of the Binding of Acridinecarboxamide Topoisomerase Poisons to DNA: Implications for Mode of Binding of Ligands with Uncharged Chromophores

2002

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1,4-Thiazines and their Benzo Derivatives

Aitken

2008

Comprehensive Heterocyclic Chemistry III

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Systematic Study on the Structures and Reactivity of Hydrazobenzenes and Azobenzenes Bearing a Chalcogenophosphoryl Group

2006

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Hydrazobenzenes 3-5 bearing a chalcogenophosphoryl group were synthesized by palladium-catalyzed cross-coupling reactions. Their X-ray crystallographic analyses and NMR and IR spectra showed the presence of intramolecular hydrogen bonds between the N-H protons and the chalcogenophosphoryl groups. The intermolecular hydrogen bonds in phosphine oxide 3 and selenide 5 were observed in the solid state. Phosphine oxide 3, sulfide 4, and selenide 5 constructed a dimeric structure, a discrete monomeric structure, and a chain structure, respectively. As the chalcogen atom changed, the crystalline structures of the 2-chalcogenophosphorylhydrazobenzenes also changed. The hydrogen bonds affected the oxidation reactions of the hydrazobenzenes, and oxidation of hydrazobenzenes bearing a lighter chalcogen atom was more difficult. For azobenzenes bearing a chalcogenophosphoryl group, X-ray crystallographic analyses and NMR spectra showed little interaction between the azo group and the chalcogenophosphoryl groups. However, in the UV-vis spectra, the red shifts of the absorption maxima due to the n --> pi transitions indicated intramolecular interactions in the excited state, in contrast to the corresponding 4-substituted azobenzenes. In addition, photoirradiation of phosphine oxide (E)-7 gave (Z)-7, whereas that of phosphine sulfide (E)-8 and phosphine selenide (E)-9 did not give (Z)-8 and (Z)-9, suggesting that heavy chalcogen atoms quench excited states by through-space interactions. Introduction of a chalcogenophosphoryl group at the 2-position had a significant effect on the structure, spectral properties, and reactivity of hydrazobenzenes and azobenzenes. Although azobenzene (E)-10 bearing a hydroxyphosphoryl group at the 2-position did not show hydrogen bonding in the crystalline state, its optical properties and photoisomerization ratio were different from those of (E)-7.

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Structure of N-(2-dimethylaminoethyl)phenothiazine-1-carboxamide hydrochloride

Cited by 3 publications

References 1 publication

Kinetic Studies of the Binding of Acridinecarboxamide Topoisomerase Poisons to DNA: Implications for Mode of Binding of Ligands with Uncharged Chromophores

Kinetic Studies of the Binding of Acridinecarboxamide Topoisomerase Poisons to DNA: Implications for Mode of Binding of Ligands with Uncharged Chromophores

1,4-Thiazines and their Benzo Derivatives

Systematic Study on the Structures and Reactivity of Hydrazobenzenes and Azobenzenes Bearing a Chalcogenophosphoryl Group

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