Efficient synthesis of a new bifunctional Cu(I) chelator

Abstract

a b s t r a c tHerein we report an efficient eight-step synthesis of N 1 -(3-(methylthio)propyl)-2-((3-(methylthio)propyl)thio)benzene-1,4-diamine (1) from 6-nitrobenzo [d]thiazole. Incorporation of a nitro rather than a hydroxyl functionality off the aromatic ring serves to enhance conversion during thia-and aza-conjugate additions. Ultimate reduction of the nitro substituent affords a bifunctional Cu(I) chelate in gram-scale quantities for subsequent sensing applications.Ó 2015 Elsevier Ltd. All rights reserved.As the third most abundant metal in biology, copper is intimately involved in the transport and activation of molecular oxygen. 1 This role is due in large part to its facile redox nature. However, the ability to access multiple oxidation states also renders this metal potentially toxic, with an increase in oxidative and nitrosative stress being linked with cancer 2 and neurodegeneration. 3 Monitoring this metal in a biological context is therefore necessary to elucidate the relationship between disruptions in metal-ion homeostasis and pathophysiology. The most attractive method for doing so is through the design and development of ligands that result in a measurable change in fluorescence upon metal-ion binding. 4 Fahrni and co-workers have developed a series of fluorescent pyrazolines exhibiting increased fluorescence in the presence of Cu(I) through inhibition of photoinduced electron transfer (PET) (Fig. 1). 5 Chelation of Cu(I) serves to lower the ligand's HOMO, thereby deactivating the PET process and restoring fluorescence. The authors quickly accessed these probes by first synthesizing a bifunctional N 1 S 3 ligand (2) that then underwent an aldol condensation with 4-acetylbenzonitrile. Subsequent condensation with one of five fluoro-substituted phenylhydrazine derivatives afforded the corresponding N 1 S 3 -functionalized pyrazolines (3). This ligand is extremely selective for Cu(I) over other interfering metal ions given the soft sulfur donors 6 and the propensity of this ligand to form a tetrahedral coordination environment, thus stabilizing Cu(I) relative to Cu(II). 5 Despite their elegant synthesis, these probes suffered from poor solubility in aqueous media in addition to high-energy excitation (346-391 nm) and emission profiles (432-486 nm) unsuitable for biological imaging.To improve tissue penetration, Chang and coworkers recently reported a near-infrared fluorescent sensor for monitoring biological Cu(I) also using PET. 7 They achieved this by developing a similar bifunctional N 1 S 3 ligand (4) that was then covalently attached to cyanine 7 to afford 5 (Fig. 1). Although this account demonstrated in vivo visualization of labile Cu(I), these 'turn-on' approaches toward metal-ion monitoring are incapable of providing quantitative measurements. Thus, sensors capable of modulating the ratio of multiple emission bands (ratiometric) are preferred in that they generate quantitative information. 8 However, few ratiometric sensors for copper exist, while most suffer from poor water solubility 9...

Rational design of a water-soluble, lipid-compatible fluorescent probe for Cu(i) with sub-part-per-trillion sensitivity

“…We previously demonstrated that this approach can generate excellent fluorescence turn-on responses for Cu(I)-probes in methanol, 20 and it was later adopted by others in the design of Cu(I)-selective fluorescent probes. 21,22 Compared to CTAP-2, probe 4 showed improvements in both contrast ratio (1:100) and fluorescence quantum yield (11%) upon saturation with Cu(I); however, the recovered quantum yield remained more than 5-times below that of reference compound 3 featuring the same fluorophore. Based on the crystal structure of the Cu(I) complex of a closely related acyclic ligand, 20 we suspected that the hydroxymethyl substituents may still produce steric congestion upon Cu(I) coordination, thus weakening the Cu(I)-N interaction.…”

Influence of PNIPAm on log Kf of a copolymerized 2,2′-bipyridine: revised bifunctional ligand design for ratiometric metal-ion sensing

“…Furthermore, this modular sensing platform enables any metal ion of any oxidation state to be accurately detected through rational design of the appropriate bifunctional ligand. 21…”