Small molecule sensors

Rhodamine, a fluorescent molecule often used in small molecule sensors

Small-molecule sensors is jargon for chemicals that detect certain metal ions in solution.[1] Although many types exist, most small molecule sensors comprise a subunit that selectively binds to a metal that in turn induces a change in a fluorescent subunit. This change can be observed in the small molecule sensor's spectrum, which can be monitored using a detection system such as a microscope or a photodiode.[2] Different probes exist for a variety of applications, each with different dissociation constants with respect to a particular metal, different fluorescent properties, and sensitivities. They probe biological processes by monitoring metal ions at low concentrations in biological systems. More traditional bio-sensing are less effective or not suitable.[3] Most detection mechanisms involved in small molecule sensors involve fluorescence.[2][4]

Mechanisms of detection

Cartoon depicting a shift in spectrum of a small molecule sensor upon the binding of a metal

Fluorophores

Fluorophores are essential to some measurement of the metal binding event, and indirectly, metal concentration. There are many types, all with different properties that make them advantageous for different applications. Some work as small metal sensors completely on their own while others must be complexed with a subunit that can chelate or bind a metal ion. Rhodamine for example undergoes a conformation change upon the binding of a metal ion. In so doing it switches between a colorless, non-fluorescent spirocyclic form to a fluorescent, pink open cyclic form.[2][6] Quinoline based sensors have been developed that form luminescent complexes with Cd(II) and fluorescent ones with Zn(II). It is hypothesized to function by changing its lowest luminescent state from n–π* to π–π* when coordinating to a metal.[2][7][8] When the Dansyl group DNS binds to a metal, it loses a sulfonamide hydrogen, causing fluorescence quenching via a PET or reverse PET mechanism in which an electron is transferred either to or from the metal that is bound.[9]

Small molecule sensors for zinc have been reported.[4] One example is "ZX1", a compound comprising a dipicolylamine (DPA) Zinc binding subunit that has greater affinity for Zinc than other species found in solution such as Ca and Mg.[10] [11] GFZnP OMe is an alternate, GFP-based fluorescent Zn2+ sensor is published for two-photon microscopy and related biological and microscop application. It composed of an 8-methoxyquinoline scaffold. It has excellent photophysical characteristics including a 37-fold fluorescence enhancement with l(ex) = 440 nm and l(em) = 505 nm. The two-photon cross-section is as high as 73 GM at 880 nm.[12] GFZnP BIPY features a 2,2'-bipyridine chelator moiety. It was effective at physiologically relevant pH-range and excellent photophysical characteristics are reported, including a 53-fold fluorescence enhancement with excitation and emission maxima at 422 nm and 492 nm, respectively. High two-photon cross-section of 3.0 GM at 840 nm as well as excellent metal ion selectivity are reported. In vitro experiments on HEK 293 cell culture were carried out using two-photon microscopy demonstrating the applicability.[13]

For copper, the CTAP-1 sensor shows a response in the UV region when Cu(I) binds to an azatetrathiacrown motif that in turn excites a pyrazoline-based dye that is attached.[3][4] In Coppersensor-1 (CS1), a thioether-rich motif binds to Cu(I) causing the excitation of a boron-dipyrromethene (BODIPY) dye in the visible region.[3][4]

Iron sensors include Pryrene-TEMPO, in which the binding of iron to TEMPO quenches the fluorescence of pyrene when no Fe(II) is bound. Upon binding however, TEMPO is reduced and pyrene regains fluorescence. This probe is limited in that an analogous response can be generated by unwanted free radicals, and that it can only by used in acidic solution.[4][14] The DansSQ Fe(II)-binding system consists of a Dansyl group bound to styrylquinoline and operates by the disruption of intra-molecular charge transfer. It is limited in that it is only soluble in acetonitrile in 10% H2O.[4]

Cobalt sensors have been made that capitalize on the breaking of C-O bonds by Co(II) in a fluorescent probe known as Cobalt Probe 1 (CP1).[15]

A Sodium-Potassium pump that causes changing concentrations of metal ions in a biological system.

Potential applications can be envisioned for detecing mercury in fish.[16] Some mercury sensors (MS) are complexes of fluorescein and napthofluorescein. The MS1 probe increases its emission upon binding of Hg(II), while maintaining great affinity for mercury over other heavy metal ions.[3] The S3 sensor is based on a BODIPY complex which undergoes a significant increase in fluorescence upon the binding of Hg(II).[3][17] MF1 uses a soft thioether chelator for Hg(II) bound to a fluorescein-like xanthenone reporter. It has good contrast upon binding mercury and good selectivity. MF1 is sensitive enough that it has been proposed to be used to test fish for toxic levels of mercury.[3][16]

References

  1. ^ Tomat, Elisa; Lippard, Stephen J (April 2010). "Imaging mobile zinc in biology". Current Opinion in Chemical Biology. 14 (2): 225–230. doi:10.1016/j.cbpa.2009.12.010. PMC 2847655. PMID 20097117.
  2. ^ a b c d e f g h i j k Formica, Mauro; Fusi, Vieri; Giorgi, Luca; Micheloni, Mauro (January 2012). "New fluorescent chemosensors for metal ions in solution". Coordination Chemistry Reviews. 256 (1–2): 170–192. doi:10.1016/j.ccr.2011.09.010.
  3. ^ a b c d e f Domaille, Dylan W; Que, Emily L; Chang, Christopher J (March 2008). "Synthetic fluorescent sensors for studying the cell biology of metals". Nature Chemical Biology. 4 (3): 168–175. doi:10.1038/nchembio.69. PMID 18277978.
  4. ^ a b c d e f Carter, Kyle P.; Young, Alexandra M.; Palmer, Amy E. (23 April 2014). "Fluorescent Sensors for Measuring Metal Ions in Living Systems". Chemical Reviews. 114 (8): 4564–4601. doi:10.1021/cr400546e. PMC 4096685. PMID 24588137.
  5. ^ "Fluorescence Resonance Energy Transfer". UC Davis Chemwiki. UC Davis. 2 October 2013. Retrieved 12 March 2015.
  6. ^ Moon, Kyung-Soo; Yang, Young-Keun; Ji, Seunghee; Tae, Jinsung (June 2010). "Aminoxy-linked rhodamine hydroxamate as fluorescent chemosensor for Fe3+ in aqueous media". Tetrahedron Letters. 51 (25): 3290–3293. doi:10.1016/j.tetlet.2010.04.068.
  7. ^ Xue, Guoping; Bradshaw, Jerald S; Dalley, N.Kent; Savage, Paul B; Izatt, Reed M; Prodi, Luca; Montalti, Marco; Zaccheroni, Nelsi (June 2002). "The synthesis of azacrown ethers with quinoline-based sidearms as potential zinc(II) fluorophores". Tetrahedron. 58 (24): 4809–4815. doi:10.1016/S0040-4020(02)00451-9.
  8. ^ Miyamoto, Ryo; Kawakami, Jun; Takahashi, Shuko; Ito, Shunji; Nagaki, Masahiko; Kitahra, Haruo (2006). "Time-Dependent DFT Study of Emission Mechanism of 8-Hydroxyquinoline Derivatives as Fluorescent Chemosensors for Metal Ions". Journal of Computer Chemistry, Japan. 5 (1): 19–22. doi:10.2477/jccj.5.19.
  9. ^ Fabbrizzi, Luigi; Licchelli, Maurizio; Pallavicini, Piersandro; Perotti, Angelo; Sacchi, Donatella (17 October 1994). "An Anthracene-Based Fluorescent Sensor for Transition Metal Ions". Angewandte Chemie International Edition in English. 33 (19): 1975–1977. doi:10.1002/anie.199419751.
  10. ^ Pan, Enhui; Zhang, Xiao-an; Huang, Zhen; Krezel, Artur; Zhao, Min; Tinberg, Christine E.; Lippard, Stephen J.; McNamara, James O. (September 2011). "Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse". Neuron. 71 (6): 1116–1126. doi:10.1016/j.neuron.2011.07.019. PMC 3184234. PMID 21943607.
  11. ^ Csomos, Attila; Kovacs, Ervin; Madarasz, Miklos; Fedor, Flora; Fulop, Anna; Katona, Gergely; Balazs J., Rozsa; Mucsi, Zoltan (1 January 2024). "Two-Photon Fluorescent Chemosensors Based on the GFP-Chromophore for the Detection of Zn2+ in Biological Samples – From Design to Application". Sensors and Accuators B. 398 (1) 134753. doi:10.1016/j.snb.2023.134753. This article incorporates text from this source, which is available under the CC BY 3.0 license.
  12. ^ Csomos, Attila; Madarasz, Miklos; Turczel, Gábor; Levente, cseri; Bodor, Andrea; Matuscsak, Anett; Katona, Gergely; Kovacs, Ervin; Rozsa, Balazs J.; Mucsi, Zoltan (3 June 2024). "A GFP inspired 8-methoxyquinoline-derived fluorescent molecular sensor for the detection of Zn2+ by two-photon microscopy". Chemistry: A European Journal. 30 (31) e202400009. Bibcode:2024ChEuJ..30E0009C. doi:10.1002/chem.202400009. PMID 38446718.
  13. ^ Csomos, Attila; Madarász, Miklós; Turczel, Gábor; Cseri, Levente; Katona, Gergely; et al. (January 2024). "A Molecular Hybrid of the GFP Chromophore and 2,2′-Bipyridine: An Accessible Sensor for Zn2+ Detection with Fluorescence Microscopy". International Journal of Molecular Sciences. 25 (6): 3504. doi:10.3390/ijms25063504. ISSN 1422-0067. PMC 10971390. PMID 38542479. This article incorporates text from this source, which is available under the CC BY 4.0 license.
  14. ^ Chen, Jin-Long; Zhuo, Shu-Juan; Wu, Yu-Qing; Fang, Fang; Li, Ling; Zhu, Chang-Qing (February 2006). "High selective determination iron(II) by its enhancement effect on the fluorescence of pyrene-tetramethylpiperidinyl (TEMPO) as a spin fluorescence probe". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 63 (2): 438–443. Bibcode:2006AcSpA..63..438C. doi:10.1016/j.saa.2005.04.057. PMID 15996513.
  15. ^ Au-Yeung, Ho Yu; New, Elizabeth J.; Chang, Christopher J. (2012). "A selective reaction-based fluorescent probe for detecting cobalt in living cells". Chemical Communications. 48 (43): 5268–70. doi:10.1039/c2cc31681a. PMID 22531796.
  16. ^ a b Yoon, Sungho; Albers, Aaron E.; Wong, Audrey P.; Chang, Christopher J. (November 2005). "Screening Mercury Levels in Fish with a Selective Fluorescent Chemosensor". Journal of the American Chemical Society. 127 (46): 16030–16031. Bibcode:2005JAChS.12716030Y. doi:10.1021/ja0557987. PMID 16287282.
  17. ^ Guo, Xiangfeng; Qian, Xuhong; Jia, Lihua (March 2004). "A Highly Selective and Sensitive Fluorescent Chemosensor for Hg in Neutral Buffer Aqueous Solution". Journal of the American Chemical Society. 126 (8): 2272–2273. Bibcode:2004JAChS.126.2272G. doi:10.1021/ja037604y. PMID 14982408.
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