Structure of 6-azidotetrazolo[5,1-a]phthalazine, C8H4N8, isolated from the toxic dinoflaggelate Gymnodinium breve

Hossain, M. B.; Helm, D. van der; Sanduja, Radhika; Alam, Md. Morshedul

doi:10.1107/s0108270185007132

Cited by 18 publications

(21 citation statements)

References 3 publications

(4 reference statements)

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“…The proximity of the terminal nitrogen of the azidomethyl compounds 9 and 10 to the Asp339 carboxyl group also suggests an interaction that would be stabilized by the protonated form of Asp339 [i.e., C-N=N+=N"...H-O (Asp339)] although other modes of interaction are also possible. In small-molecule crystal structures, the nitrogen-nitrogen bond lengths of the azide group indicate the relative importance of alternative resonance forms may vary (Hossain et al, 1985;Biswas et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Glucose analog inhibitors of glycogen phosphorylase: the design of potential drugs for diabetes

Martin¹,

Veluraja²,

Ross³

et al. 1991

Biochemistry

130

125

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The T-state crystal structure of the glucose-phosphorylase b complex has been used as a model for the design of glucose analogue inhibitors that may be effective in the regulation of blood glucose levels. Modeling studies indicated room for additional atoms attached at the C1-beta position of glucose and some scope for additional atoms at the C1-alpha position. Kinetic parameters were determined for alpha-D-glucose: Ki = 1.7 mM, Hill coefficient n = 1.5, and alpha (synergism with caffeine) = 0.2. For beta-D-glucose, Ki = 7.4 mM, n = 1.5, and alpha = 0.4. More than 20 glucose analogues have been synthesized and tested in kinetic experiments. Most were less effective inhibitors than glucose itself and the best inhibitor was alpha-hydroxymethyl-1-deoxy-D-glucose (Ki = 1.5 mM, n = 1.3, alpha = 0.4). The binding of 14 glucose analogues to glycogen phosphorylase b in the crystal has been studied at 2.4-A resolution and the structure have been refined to crystallographic R values of less than 0.20. The kinetic and crystallographic studies have been combined to provide rationalizations for the apparent affinities of glucose and the analogues. The results show the discrimination against beta-D-glucose in favor of alpha-D-glucose is achieved by an additional hydrogen bond made in the alpha-glucose complex through water to a protein group and an unfavorable environment for a polar group in the beta pocket. The compound alpha-hydroxymethyl-1-deoxy-D-glucose has an affinity similar to that of glucose and makes a direct hydrogen bond to a protein group. Comparison of analogues with substituent atoms that have flexible geometry (e.g., 1-hydroxyethyl beta-D-glucoside) with those whose substituent atoms are more rigid (e.g., beta-azidomethyl-1-deoxyglucose or beta-cyanomethyl-1-deoxyglucose) indicates that although all three compounds make similar polar interactions with the enzyme, those with more rigid substituent groups are better inhibitors. In another example, alpha-azidomethyl-1-deoxyglucose was a poor inhibitor. In the crystal structure the compound made several favorable interactions with the enzyme but bound in an unfavorable conformation, thus providing an explanation for its poor inhibition. Attempts to utilize a contact to a buried aspartate group were partially successful for a number of compounds (beta-aminoethyl, beta-mesylate, and beta-azidomethyl analogues). The beta pocket was shown to bind gentiobiose (6-O-beta-D-glucopyranosyl-D-glucose), indicating scope for binding of larger side groups for future studies.

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Section: Discussionmentioning

confidence: 99%

Glucose analog inhibitors of glycogen phosphorylase: the design of potential drugs for diabetes

Martin¹,

Veluraja²,

Ross³

et al. 1991

Biochemistry

130

125

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“…8-azaguanine-3 N -β- d -ribofuranosyl ( 90 ) and 5′-phosphate-3 N -β- d -ribofuranosyl ( 91 ) are known as natural metabolites and showed anticancer activity against L-1210 lymphoid leukemia and adenocarcinoma 755, among other activities [ 101 ]. A toxic red-tide dinoflagellate, Gymnodinium breve , produced the antibiotic 6-azidotetrazolo[5,1-a]phthalazine ( 92 ) [ 102 ].…”

Section: Azo Metabolites Derived From Actinomycetes and Fungal Speciementioning

confidence: 99%

Pharmacological and Predicted Activities of Natural Azo Compounds

Dembitsky

Gloriozova

Poroikov

2017

Nat. Prod. Bioprospect.

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This paper describes research on natural azo compounds isolated from fungi, plant, bacteria, and invertebrates. More than 120 biologically active diazene containing alkaloids demonstrate confirmed pharmacological activity, including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of azo compounds are reviewed. Utilizing the computer program PASS, some structure–activity relationship new activities are also predicted, pointing toward possible new applications of these compounds. This article emphasizes the role of natural azo compounds as an important source of drug prototypes and leads for drug discovery.

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“…6-Azidotetrazolo[5,1- a ]phthalazine ( 15 ) is a metabolite of the dinoflagellate Gymnodinium breve , a protist implicated in the production of red tides . The only known tetrazole natural product, 15 , contains an unprecedented five contiguous nitrogen atoms separated by a single carbon atom from an azide group.…”

Section: Structural Typesmentioning

confidence: 99%

“…The only known tetrazole natural product, 15 , contains an unprecedented five contiguous nitrogen atoms separated by a single carbon atom from an azide group. This remarkable structure was assigned using X-ray crystallography . 6-Azidotetrazolo[5,1- a ]phthalazine ( 15 ) was reported to exhibit ichthyotoxicity (LD 100 of 0.4 μg mL –1 ), although no details were given regarding the names and/or numbers of fish species tested against …”

Section: Structural Typesmentioning

confidence: 99%