An Intercalating Isoxazole

Mosher, Michael; Natale, Nicholas R.; Vij, Ashwani

doi:10.1107/s0108270196005082

Cited by 15 publications

(17 citation statements)

References 4 publications

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“…This stereoelectronic effect was also previously observed in our crystallographic studies of isoxazole-3-anthracenes 9,13–17 and isoxazole-3-anthroquinones. 18 The isoxazole and ester are largely co-planar with the dihedral angle between the isoxazole mean plane and plane containing the ester carbonyl and ether atom being 10.89°.…”

supporting

confidence: 87%

“…30,31 In the current case it should be recalled that the AIMs are distinguished in every crystal structure and computation to date by a dihedral angle of 74–880° between the mean planes of the isoxazole to the anthracenyl moiety. 6,13–17 This conformation would be expected to have lower surface area and hence lower lipophilicity than an alternative conformation which is planar and conjugated. These properties may improve bioavailability and allow the AIMs to permeate cell membranes as well as the blood brain barrier.…”

mentioning

confidence: 99%

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AIMing towards improved antitumor efficacy

Weaver¹,

Kearns²,

Stump³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Using the structure-activity relationship emerging from previous reports, and guided by pharmacokinetic properties, new AIMs have been prepared with both improved efficacy against human glioblastoma cells and cell permeability as determined by fluorescent confocal microscopy. We present our first unambiguous evidence for telomeric G4-forming oligonucleotide anisotropy by NMR resulting from direct interaction with AIMs, which is consistent with both our G4 melting studies by CD, and our working hypothesis. Finally, we show that AIMs induce apoptosis in SNB-19 cells.

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supporting

confidence: 87%

mentioning

confidence: 99%

AIMing towards improved antitumor efficacy

Weaver¹,

Kearns²,

Stump³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…We had previously observed by NMR and that the ester group of 3-(9′-anthracenyl) 5-methyl 4-isoxazolcarboxylate is located proximal to the tricyclic aromatic system as evidenced by significant magnetic anisotropy 24. This has also been supported by subsequent x-ray studies.…”

Section: Chemistrymentioning

confidence: 54%

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Han

Mosher

et al. 2009

Bioorganic & Medicinal Chemistry

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The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs)¥ (22-33) is described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl 3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA, and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

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“…38 Scheme 4 Double Activation Syntheses of (6) and (7) Design and Synthesis of a Novel Intercalating Isoxazolyl Bis-lexitropsin Conjugate responding to anthracene in the 13 C nmr were observed also confirm this fact. The x-ray structure of a similar compound, ethyl 3-(9'-anthracenyl)-5-methyl-4-isoxazolecarboxylate, has already been reported by our laboratory [25], which in fact, adopts just such a conformation with isoxazole and anthracene orthogonal to each other. The two methyl groups (4-COOCH 3 and 5-COOCH 3 ) of (3) gave 1 H nmr resonances at δ = 3.42 ppm and 4.14 ppm respectively, since the 4-COOCH 3 adopts a conformation under the anthracene ring and is therefore shielded by the aromatic system.…”

supporting

confidence: 56%

Design and synthesis of a novel intercalating isoxazolyl bis‐lexitropsin conjugate

Han

Natale

2001

Journal of Heterocyclic Chem

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9‐Anthracene nitrile oxide directly generated from 9‐anthracenealdoxime and N‐chlorosuccinamide (NCS), reacts with dimethyl acetylenedicarboxylate (DMAD) and affords the corresponding 3‐(9′‐anthra‐cenyl)‐isoxazole‐4,5‐dicarboxylic acid ester (3) with good yield in a very short period. Double activation reaction between (3) and hydrogenated lexitropsin (5) in a 1:2 molar ratio, produced a bis‐lexitropsin product (6) (major product) and mono‐lexitropsin product (7).

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An Intercalating Isoxazole

Cited by 15 publications

References 4 publications

AIMing towards improved antitumor efficacy

AIMing towards improved antitumor efficacy

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Design and synthesis of a novel intercalating isoxazolyl bis‐lexitropsin conjugate

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