Indolinone Derivatives Research Articles

Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase

Fighting bacterial resistance is a challenging task in the field of medicinal chemistry. DNA gyrase represents a validated antibacterial target and has drawn much interest in recent years. By a structure-based approach we have previously discovered compound 1, an indolinone derivative, possessing inhibitory activity against DNA gyrase. In the present paper, a detailed biophysical characterization of this inhibitor is described. Using mass spectrometry, NMR spectroscopy, and fluorescence experiments we have demonstrated that compound 1 binds reversibly to the ATP-binding site of the 24 kDa N-terminal fragment of DNA gyrase B from Escherichia coli (GyrB24) with low micromolar affinity. Based on these data, a plausible molecular model of compound 1 in the active site of GyrB24 was constructed. The predicted binding mode explains the competitive inhibitory mechanism with respect to ATP and forms a useful basis for further development of potent DNA gyrase inhibitors.

Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups

In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-beta on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)-positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)-or t(14;16)-positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups.

Identification of degradation products of diclofenac by electrospray ion trap mass spectrometry

The degradation products of diclofenac in aqueous dosage form in accelerated storage conditions were characterized by electrospray ionization–ion trap mass spectrometry (ESI–MS). Liquid chromatography (LC)–MS analyses revealed the presence of three degradation products. ESI–MS n spectra were used to study diclofenac fragmentation in detail and to characterize the structures of degradation products. A previously described degradation product, formed by a cyclization reaction of diclofenac producing the indolinone derivative, was found. As any hydroxylated product was found, no oxidation seems to occur in the dosage form used. On the contrary, two degradates have been detected and identified, leading to a primary alcohol structure or an aldehyde function in place of the acetate group of diclofenac.

Diclofenac Sodium Injection Sterilized by Autoclave and the Occurrence of Cyclic Reaction Producing a Small Amount of Impurity

A known impurity is formed in the production of a parenteral dosage form of diclofenac sodium if terminally sterilized by autoclave. This impurity has been detected as 1‐(2,6‐diclorophenyl) indolin‐2qone, which is also an intermediate from which diclofenac sodium is generally synthesized. It is only the condition of the autoclave method (i.e., 123 ± 2°C) that enforces the intramolecular cyclic reaction of diclofenac sodium forming the indolinone derivative and sodium hydroxide. The formation of this impurity has been found to depend on the initial pH of the formulation. The reaction follows first‐order kinetics, and the energy of activation is 5.34 kcal/mol. The other excipients in the formulation do not have a role in this reaction. The concentration of the impurity in the resultant product in the ampule goes beyond the limit of the raw materials in the pharmacopoeias. It is thus preferable to use an alternative sterilization method; that is, an aseptic filtration method in which the formation of this impurity can be avoided. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:541–544, 2001

Indolinone Derivatives Inhibit Constitutively Activated KIT Mutants and Kill Neoplastic Mast Cells

Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective against KIT with juxtamembrane activating mutations, whereas only SU6577 could suppress KIT containing either juxtamembrane or kinase domain activating mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.

Heterocyclization of 2-indolinone derivatives (A review)

Heterocyclization of 2-indolinone derivatives (A review)

Indolinone Derivatives as Potential Antimicrobial Agents

1-substituted aminomethyl-3-cyclohexylthiosemicarbazone-2-indolinones (I) were tested for their antibacterial activity against Bacillus pumilis, Bacillus brevis and Bacillus megaterium and antifungal activity against Aspergillus flavus, Aspergillus fumigatus and Aspergillus niger. The majority of the compounds were found to exhibit promising antibacterial and antifungal activities. These compounds were also screened for their antiviral action against tobacco mosaic virus in Nicotiana glutinosa plants in vivo as well as in vitro. Most of the compounds had shown significant antiviral activities both in vivo and in vitro.

Preparation electrochimique de derives de la quinoleine—I. Electroreduction de composes o-nitrobenzoyles monofonctionnalises

Controlled potential electrolysis at a mercury cathode, carried on at a working potential corresponding to the first polarographic wave of o-nitrobenzoyl compounds ( o-NO 2C 6H 4COCH 2Y) is a convenient way to prepare quinoline derivatives. o-Nitrobenzoylacetic acid (Y  CO 2H) or the parent methyl ester gives rise to a N-hydroxyquinoline. Nevertheless simultaneous formation of anthranil derivatives is observed when the reductions are carried out in an acidic media, whereas the latter is the sole product isolated at the term of electrolysis of the acid in a basic media. Quinoline N-oxides can be obtained by reduction of o-nitrobenzoylacetonitrile (Y  CN) or o-nitrobenzoylacetone (Y  COCH 3). Anthranil formation is again evidenced after electrolysis of the nitrile in acidic media, whereas reduction of the ketone in a basic media gives rise to simultaneous formation of the expected quinoline N-oxide and of an indolinone derivative.

Electrochemical and ESR studies on the reduction of some indolinone derivatives and of their N-oxides in DMF

2-Phenyl-3-oxo-3H-indole 4 and 3-imino-, 3-iminoxy-, derivatives, the corresponding N-oxide 3, and 2-phenyl- 5 and 2-(2'-pyridyl-) isatogen 6 have been reduced in DMF and in DMF in presence of proton donors, and followed by polarography, controlled potential coulometry, cyclic voltammetry, UV, and ESR. In aprotic media, compounds 1, 4, 5 and 6, are reduced via anion radical intermediates.