Preliminary biological evaluation and mechanism of action studies of selected 2-arylindoles against glioblastoma

Prabhu, Saurabh; Akbar, Zaheer; Harris, Frederick; Karakoula, Katherine; Lea, Robert; Rowther, FB; Warr, Tracy; Snape, Timothy J.

doi:10.1016/j.bmc.2013.01.032

Cited by 10 publications

(16 citation statements)

References 36 publications

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“…1) have anti-glioblastoma activity. 3 In the case of 1, the mechanism of this activity is consistent with the generation of reactive oxygen species (ROS) followed by autophagic cell death, which in some cases gave low micromolar EC 50 values against patient-derived shortterm cell cultures. 3,4 The research described herein expands on our previous programme of work and leads to the discovery of new and possibly improved scaffolds for further development into much needed glioblastoma treatments.…”

Section: Introductionmentioning

confidence: 80%

Towards identifying potent new hits for glioblastoma

et al. 2018

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Section: Introductionmentioning

confidence: 80%

Towards identifying potent new hits for glioblastoma

et al. 2018

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“…In a related research area, in 2013, Snape and Prabhu also found that I3C, as well as a small series of analogues (Figure 22), had activity against glioblastoma cell lines. [102] In particular, these analogues gave some indications as to the strucure-activity relationship of this class of indoles against glioblastoma, most notably that a protonated heteroatom (e.g. a hydroxyl group) is necessary for activity, as well as suggesting that phenyl groups at the 2-position of the indole nucleus improve activity.…”

Section: Ros Producersmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

139

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HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

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“…For example, fluvastatin is used to treat hypercholesterolemia as well as to prevent cardiovascular disease; 5‐chloro‐3‐{(3, 5‐dimethylphenyl)sulfunyl}‐4‐fluoro‐1 H ‐indole‐2‐carboximate and methyl (2‐carbamoyl‐5‐chloro‐1H‐indol‐3yl) (phenyl) phosphinate are potent inhibitors of HIV‐1 . Furthermore, Indole‐3‐Carbinol, a simple molecule present in wide range of plants, has modest activity against the glioma cell lines 132N1 and U87MG …”

Section: Introductionmentioning

confidence: 99%

Palladium‐catalyzed cyclization of 2‐alkynyl‐N‐ethanoyl anilines to indoles: synthesis, structural, spectroscopic, and mechanistic study

Hoque

Halim²,

Sarwar

et al. 2015

J of Physical Organic Chem

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This study reports a facial regio‐selective synthesis of 2‐alkyl‐N‐ethanoyl indoles from substituted‐N‐ethanoyl anilines employing palladium (II) chloride, which acts as a cyclization catalyst. The mechanistic trait of palladium‐based cyclization is also explored by employing density functional theory. In a two‐step mechanism, the palladium, which attaches to the ethylene carbons, promotes the proton transfer and cyclization. The gas‐phase barrier height of the first transition state is 37 kcal/mol, indicating the rate‐determining step of this reaction. Incorporating acetonitrile through the solvation model on density solvation model reduces the barrier height to 31 kcal/mol. In the presence of solvent, the electron‐releasing (–CH3) group has a greater influence on the reduction of the barrier height compared with the electron‐withdrawing group (–Cl). These results further confirm that solvent plays an important role on palladium‐catalyzed proton transfer and cyclization. For unveiling structural, spectroscopic, and photophysical properties, experimental and computational studies are also performed. Thermodynamic analysis discloses that these reactions are exothermic. The highest occupied molecular orbitallowest unoccupied molecular orbital gap (4.9–5.0 eV) confirms that these compounds are more chemically reactive than indole. The calculated UV–Vis spectra by time‐dependent density functional theory exhibit strong peaks at 290, 246, and 232 nm, in good agreement with the experimental results. Moreover, experimental and computed 1H and 13C NMR chemical shifts of the indole derivatives are well correlated. Copyright © 2015 John Wiley & Sons, Ltd.

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Preliminary biological evaluation and mechanism of action studies of selected 2-arylindoles against glioblastoma

Cited by 10 publications

References 36 publications

Towards identifying potent new hits for glioblastoma

Towards identifying potent new hits for glioblastoma

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Palladium‐catalyzed cyclization of 2‐alkynyl‐N‐ethanoyl anilines to indoles: synthesis, structural, spectroscopic, and mechanistic study

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