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4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid: Synthesis, bioactivity and toxicity

Mar 15，2023

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4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid can be sy nthesized by single step according to the previous work [1]. Benzhydrylamine copolystyrene-1% divinylbenzene cross-linked resin (10.0 g, 9.3 mequiv, 100-200 ASTM mesh, Advanced ChemTech) was swelled in 100 mL CH₂Cl₂, filtered and washed successively with 100 ml each of CH₂Cl₂, 6% DIPEA/CH₂Cl₂ (two times), CH₂Cl₂ (two times). The resin was treated with p-((R, S)-α-(1-(9H-fluoren-9-yl)-methoxyformamido)-2,4-dimethoxybenzyl)-phenoxyacetic acid (Fmoc-Linker) (7.01 g, 13.0 mmole), N-hydroxybenzotriazole (2.16 g, 16.0 mmole), and diisopropyl-carbodiimide (2.04 ml, 13.0 mmol) in 100 mL 25% DMF/CH2Cl2 for 24 hours at room temperature. The resin was filtered and washed successively with 100 ml each of CH2Cl2 (two times), isopropanol (two times), DMF, and CH2Cl2 (three times). A Kaiser Ninhydrin analysis was negative. The resin was dried under vacuum to yield 16.12 g of Fmoc-Linker-BHA resin. A portion of this resin (3.5 mg) was subjected to Fmoc deprotection and quantitative UV analysis which indicated a loading of 0.56 mmol/g.

The 4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid can be analyzed by the method of Time-of-flight secondary ion mass spectrometry (TOF-SIMS) according to the previous work [2]. Briefly, crown samples analyzed by TOF-SIMS were cut out directly from the pins with a razor blade to obtain thin slices, which were then immediately placed on a stainless-steel grid. TOF-SIMS measurements were performed on a TRIFT I spectrometer (PHI-Evans). Spectra were recorded using a pulse (1 ns, 12 kHz) liquid metal source (69Ga, 15 keV) operating in the bunched mode of operation in order to provide good mass reolution (m/δm = 2000 measured at m/z 43). Owing to large charge effects on such insulating materials, charge compensation was needed for all samples and was achieved by a pulsing electron flood (Ek = 20 eV) at a rate of one electron pulse per five ion pulse. The analyzed surfaces were squares of 100 × 100 μm. All positive and negative spectra were acquired in 10 min with a fluence of less than 10¹² ions cm^-2, ensuring static conditions on the sample slices.

Bioactivity

Toxicity

As a preliminary assessment of toxicity, the viability assays for the 4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxyacetic acid which inhibited ALR2 to greater than 50% at 50 μM [3]. The

[2]Aubagnac et al. Application of time-of-flight secondary ion mass spectrometry to in situ monitoring of solid-phase peptide synthesis on the Multipin (TM) system. Journal of Mass Spectrometry, 1998, 33(11): 1094-1103.

[3]Wang et al. Discovery of New Selective Human Aldose Reductase Inhibitors through Virtual Screening Multiple Binding Pocket Conformations. Journal of Chemical Information and Modeling, 2013, 53(9): 2409-2422.

[4]Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E. Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications. J. Med. Chem. 1985, 7, 841? 849.

[5]Kinoshita, J. H.; Nishimura, C. The involvement of aldose reductase in diabetic complications. Diabetes Metab. Rev. 1988, 4, 323?337.

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