Synthesis of 3-Arylmethyl-2-oxindole Derivatives and Their Effects on Neuronal Cell Death

Abstract

Various 3-arylmethyl-2-oxindole derivatives were synthesized by the Knoevenagel condensation of oxindole and aromatic aldehydes followed by palladium-mediated hydrogenation or hydride-reduction. Further substituted derivatives at C-3 and/or N-1 of the oxindole skeleton were prepared from the condensation products. Their protective effect against neuronal cell death induced by oxidative stress was evaluated by lactate dehydrogenase assay. A structure-activity relationship study revealed that compounds with any of the dialkylamino, nitro or hydroxy groups on the 3-arylmethyl moieties elicit a superior potency to suppress cell death, while others are ineffective. Substitutions with less polar functional groups on the benzene or lactam ring of the oxindole skeleton positively, but not remarkably, affect the potency. In addition, the stereochemistry at C-3 of the oxindole core was not a crucial factor for the neuroprotective activity of the compounds.Key words oxindole derivative; synthesis; structure-activity relationship (SAR); neuronal cell death; oxidative stressLoss of neurons in specific areas of the brain due to neuronal cell death is a common feature of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. 1,2) Intracellular oxidative stress and endoplasmic reticulum (ER) stress are generally considered to play important roles in the death of neuronal cells. [3][4][5][6] In this context, the agents alleviating the oxidative and ER stresses and restore cellular homeostasis are expected to be potential therapeutic candidates for neurodegenerative diseases.In our continuous studies to elaborate small molecules with neuroprotective activities, we previously reported the design, synthesis and action mechanisms of artificial cyclopentenonetype prostaglandin analogs 1 and 2 7-10) (Fig. 1). These compounds exert their effects through covalent bond formation between the electrophilic conjugated-enone moiety and a cysteine residue of the target proteins, such as Keap1. 7,10) Unfortunately, these compounds induced cell death at higher doses presumably due to non-specific bindings to various proteins. 9) Strongly electrophilic compounds are known to inhibit the function of several proteins having cysteine residues and contribute to cell death. One possible approach to avoid this cytotoxic effect of the electrophilic compounds is to synthesize molecules of moderate electrophilicity. Based on this idea, we designed an α,β-unsaturated oxindole structure 3 (Fig. 2) in which the variable substituent Z can modulate the electrophilicity of the double bond. A preliminary study showed that some of the compounds 3, as expected, suppressed the oxidative stress-induced neuronal cell death without any cytotoxic effect. 11) However, further study has been suspended, because such compounds were already known as potent inhibitors for receptor tyrosine kinases. [12][13][14] Meanwhile, recent studies reported that rasagiline 4, a therapeutic agent for Parkinson's disease, exhibits a neuroprotective activity through not...

Novel Oxindole–Curcumin Hybrid Compound for Antioxidative Stress and Neuroprotection

“…GIF-0726-r and GIF-2165X-G1 were synthesized by the condensation of indolin-2-one with substituted benzaldehydes (followed by hydrogenation in the former case). , GIF compounds were dissolved in cell culture-grade dimethyl sulfoxide and stored in the dark at–20°C. 6-OHDA was obtained from Sigma-Aldrich (St. Louis, MO).…”

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones

“…A series of oxindole compounds (GIF-0852-r, -0854-r, -0856-r, -0876-r, -0877-r, -0890-r, -0935-r, -0976-r, -0978-r, -0979-r, -0991-r, -2001-r, -2004-r, -2005-r, -2068-r, and -2087-r) were synthesized from substituted or unsubstituted indolin-2-ones, either by condensation with aromatic aldehydes and subsequent reduction or base-mediated alkylation with arylalkyl halides. , The open-chain analogues (GIF-2015, -2023, and -2147) were prepared by acylation of appropriate amine derivatives. The test compounds, termed GIF compounds, were dissolved in cell culture-grade dimethyl sulfoxide (DMSO) and stored at −20 °C.…”

Continuous-Flow Regioselective Reductive Alkylation of Oxindole with Alcohols and Aldehydes in a Fast and Economical Manner

“…Oxindole (1; 400 mg, 3.00 mmol) was dissolved in the corresponding alcohol (10 mL) and the solution was pumped through the system under the opti- 9b 45 Me 96 9c 46 Et 77 9d 47 Pr 46 Batchwise synthesis of 3-alkyloxindoles via the Knoevenagel condensation of oxindole (1) and aldehydes followed by catalytic hydrogenation or hydride reduction of the C=C double bond is well known in the literature. [48][49][50] Therefore, we next turned our attention to the CF reductive 3-alkylation reaction of oxindole with aldehydes instead of alcohols, utilizing the same experimental setup applied with alcohols (Figure 2). The use of aldehydes as solvents is unreasonable, thus we decided to apply THF as the solvent since it proved to be inert in our earlier batch studies under similar conditions.…”

“…The use of aldehydes as solvents is unreasonable, thus we decided to apply THF as the solvent since it proved to be inert in our earlier batch studies under similar conditions. 14 Although the condensation between oxindole (1) and aldehydes does not necessitate very high temperatures, [48][49][50] in situ hydrogen generation does. Therefore, the conditions (temperature, pressure, flow rate) used were the same as those found to be optimal in the alkylation reaction performed with alcohols.…”