Structures of two DNA minor-groove binders, based on pyrrolo[2,1-c][1,4]benzodiazepines

Neidle, Stephen; Webster, Gordon; Jones, Geraint; Thurston, DE

doi:10.1107/s0108270191005966

Cited by 8 publications

(4 citation statements)

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“…This structure is similar to that previously described by Neidle et al [23] and is a lead compound of a family of molecules able to bind to the minor groove of DNA. In addition, we point out that our independent findings, showing that pyrrolobenzodiazepine-5,11dione is formed very rapidly and spontaneously by acid treatment of Boc-Abz-Pro-NH2 or Boc-Abz-Pro-OH, are in agreement with the results published by other groups during the preparation of this work and suggesting this synthetic procedure to be a very convenient alternative route for the synthesis of this class of compounds, which have potential applications in cancer therapy [11,12].…”

Section: Discussionsupporting

confidence: 81%

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

et al. 1998

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The ortho-aminobenzoic acid (Abz) group is widely employed as a fluorescent marker for peptides used as substrates for the study of proteolytic enzyme activity. In fact, a direct correlation has been observed between fluorescence intensity and enzyme activity. An unusual behavior of the fluorescence properties of this group, which would lead to erroneous evaluation of the enzyme activity, was observed when it is bound directly to proline. Here we report a systematic NMR, fluorescence and X-ray diffraction study of the compounds obtained from Boc-Abz-Pro-NH2, Boc-Abz-Pro-OH, as well as from various other Boc-Abz-Pro-X derivatives, after treatment with HC1 or TFA under anhydrous conditions. We verified that, as recently reported, even under these synthetic conditions, deprotection of Boc-Abz-Pro-NH2 or Boc-Abz-Pro-OH leads to the formation of the same product: pyrrolobenzodiazepine-5,11-dione. However, the formation of this compound was not detected with Abz-Pro-N(CH3)2, Abz-Pro-Leu-Gly-NH2 or Abz-pyrrolidine. For all these compounds we observed an unusual behavior for the fluorescence quantum yield of Abz that can be explained as the consequence of a non-radiative deactivation process produced, specifically, by the amidation of the Abz carboxyl group with proline or a similar secondary amine such as pyrrolidine. In conclusion, these results indicate that Abz cannot be used as an internal fluorescence marker for proteolytic enzyme activity when bound directly to proline.

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Section: Discussionsupporting

confidence: 81%

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

et al. 1998

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“…The core structures of the ligands were taken from available X-ray crystallographic coordinates or generated using the SYBYL fragment library. ,,,,− The structures which resulted were energy-minimized using MM2 (molecular mechanics program 2) or MMFF (Merck molecular force field) force fields, − and the subsequent Monte Carlo conformational searches were carried out on MacroModel 4.5 or MacroModel 6.0 on a Silicon Graphics Personal Iris 4D/35 workstation or a Silicon Graphics Octane SI 2P 175 R10000 workstation, respectively. The low-energy conformations were then fully optimized via molecular orbital calculations at the 3-21G basis set with torsional angles fixed.…”

Section: Computer Modeling Methodsmentioning

confidence: 99%

Pharmacophore/Receptor Models for GABA_A/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

et al. 1999

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Pharmacophore/receptor models for three recombinant GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (alpha1-3,5,6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the alpha1-, alpha5-, and alpha6-containing subtypes indicated that region L(2) for the alpha5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other two subtypes. Moreover, region L(3) in the alpha6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the alpha5beta3gamma2 receptor subtype. alpha5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.

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“…Four basic anchor points, H 1 , H 2 , A 2 , and L 1 , were assigned, and 4 additional lipophilic regions were defined as L 2 , L 3 , L Di , and the new L 4 (see captions in Figure 31 for details); regions S 1 , S 2 , and S 3 represent negative areas of steric repulsion. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model [ 99 , 100 , 104 , 105 , 119 , 124 – 127 ].…”

Section: Bzr Gaba(a) Subtypesmentioning

confidence: 99%

A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

Clayton

Rallapalli

Biawat

et al. 2015

International Journal of Medicinal Chemistry

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An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.

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Structures of two DNA minor-groove binders, based on pyrrolo[2,1-c][1,4]benzodiazepines

Cited by 8 publications

References 0 publications

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

Pharmacophore/Receptor Models for GABA_A/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

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Structures of two DNA minor-groove binders, based on pyrrolo[2,1-c][1,4]benzodiazepines

Cited by 8 publications

References 0 publications

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

Reduction ofortho-aminobenzoyl-proline fluorescence and formation of pyrrolobenzodiazepine-5,11-dione

Pharmacophore/Receptor Models for GABAA/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach

A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

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Product

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Pharmacophore/Receptor Models for GABA_A/BzR Subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a Comprehensive Ligand-Mapping Approach