WO2015134969A1

WO2015134969A1 - Optimized synthetic receptors for the detection of analytes in complex water-based media

Info

Publication number: WO2015134969A1
Application number: PCT/US2015/019441
Authority: WO
Inventors: Robert E. Hanes; Eric V. Anslyn
Original assignee: Beacon Sciences, Llc
Priority date: 2014-03-07
Filing date: 2015-03-09
Publication date: 2015-09-11

Abstract

The present invention relates in general to a synthetic receptor core composition with a moiety that is capable of interacting with an analyte. Further, the binding event may be detected optically in a complex water-based fluid in order to return meaningful output. The binding event's optical output may be sent to a data analysis algorithm that returns the mathematical relationship between the change in optical signal with the chemical behavior of the system, so as to provide meaningful data, such as the concentration in a complex fluid. Complex fluids may be analyzed directly, subjected to a pretreatment and/or diluted to achieve a signal in a range which may be optically detected by a detection system.

Description

OPTIMIZED SYNTHETIC RECEPTORS FOR THE DETECTION OF ANALYTES IN

COMPLEX WATER-BASED MEDIA

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates in general to a synthetic receptor core composition with a moiety that is capable of interacting with an analyte. Further, the binding event may be detected optically in a complex water-based fluid in order to return meaningful output.

Description of the Relevant Art

A common objective when developing synthetic receptors is high binding affinity and specificity for an analyte. This may be challenging when targeting a complex analyte in a competitive crude medium such as water that may or may not contain organic media such as oils, fats, lipids or hydrocarbons.

Traditionally, synthetic receptors with specific binding functionalities prepared by synthetic organic chemistry have limited commercial interest due to cost and complexity of preparation. The present embodiment overcomes this limitation through the use of a chemical design algorithm based upon the use of synthetically accessible scaffold which can be coupled with specific analyte binding groups for targeted species.

SUMMARY OF THE INVENTION

The embodiments described herein provide improved and optimized synthetic receptor core compositions that have a moiety which is capable of interacting with an analyte. Further, the binding event can be optically detected and measured so that meaningful data specific to the analyte desired for quantification can be obtained, even in a complex water-based fluid.

In one embodiment, the present disclosure relates to compositions and methods for detecting ions, molecular ions or neutral molecular species in a sample using a synthetic receptor core molecule appended with analyte binding groups and a method for signaling such an event.

Thus the present disclosure teaches how to readily access multifunctional chemical entities and improve upon commercially available binding agents. These novel binding agents can then be screened against targeted analyte species via a chemometric algorithm to identify chemical species of interest in complex aqueous fluids. In one embodiment, scaffold groups are appended with groups containing phenolic binding groups pre-organized in three dimensional space. However the method applies to other binding groups that also are arranged in three dimensional space, such as alcohols, amines, carboxylic acids, amides, ethers, sulfonamides, N- sulfonyloxyacetamides, phophonates, sulfonates and boronates.

Thus by the benefit of this disclosure, one can perform a chemometric screening on the periodic table and identify complementary binding agents for the targeted species. In one preferred embodiment, the system was tested against borate, a water soluble analyte that is difficult to detect by conventional means as well as by enzyme or antibody assays. Thus, the approach is applicable to analytes known to have challenges in detection directly in aqueous media.

In one embodiment, the current disclosure was optimized to detect borate and iron ions in produced water from fracking operations. Once the binding group screen was completed, the system was optimized for produced water using organic synthesis to append to a scaffold. The system allows for matching complementary synthetic receptors with the chemical species of choice, then applying a signaling strategy. Once demonstrated in control fluids, the system is formulated to work directly with a complex fluid. The change in optical signal is measured, either by the human eye or, in another embodiment, the output is analyzed by an algorithm to return physical data such as concentration in a complex fluid. Deployment of the system allows for the detection of chemical species of interest. This system automates detection and reporting in such a way that is currently not possible without highly trained people and equipment. Thus the purpose of the invention is to provide meaningful data by adding unknown mixtures to the system. Current state of the art methods to solve the detection of analytes in complex media require a lab fitted with capital equipment, or the use of rudimentary methods in portable kits that are highly susceptible to error.

BRIEF DESCRIPTION OF THE DRAWINGS

Advantages of the present invention will become apparent to those skilled in the art with the benefit of the following detailed description of embodiments and upon reference to the accompanying drawings in which:

FIG. 1 shows a flow chart detailing the process by which synthetic receptors are optimized;

FIG. 2 shows diagrams of synthetic receptor screening libraries prepared from molecular modeling studies;

FIG. 3 shows a graph depicting a comparison of empirical data with model data demonstrating a fit of theoretical model to actual data, as the Measure Absorbance vs.

Concentration is equal to the predicted results from the theoretical model; FIG. 4 shows a graph depicting an enhancement of absorbance as a result of adding a surfactant to the alizarin/borate binding assay;

FIG. 5 shows a line graph depicting Fell and Felll concentration in the presence of iron receptor versus absorbance demonstrating the detection of both species by Structure 2;

FIG. 6 shows a line graph depicting the calibration curve of Felll used to test water samples from a mineral recovery operation using Structure 2; and

FIG. 7 shows a line graph depicting the calibration curve of boron used to test water samples from a mineral recovery operation using Structure 1.

While the invention may be susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. The drawings may not be to scale. It should be understood, however, that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but to the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is to be understood the present invention is not limited to particular compounds, devices or methods, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include singular and plural referents unless the content clearly dictates otherwise. Furthermore, the word "may" is used throughout this application in a permissive sense (i.e., having the potential to, being able to), not in a mandatory sense (i.e., must). The term "include," and derivations thereof, mean "including, but not limited to." The term "coupled" means directly or indirectly connected.

According to an embodiment of this disclosure, binding and signaling chemistries are formulated to be dehydrated for the purpose of being added in a stable form to the form factor of choice, with a preferred embodiment being a well plate possessing 8-1536 wells for rapid analysis with a conventional commercial reader device for this purpose.

Synthetic receptor core scaffolds are represented by the following Formula (I):

Where COR

Where A is: -C(0)-NR«-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-0-P(0)(OH)-0-.

Where each R_1; R₂, and R₃ are independently -H, -OH, -OC(0)Re; - (R₆)2; where at least one of Ri, R2, and R3 is not -H.

Where Re is -H or Ci-C₆ alkyl.

Where n is 0-10

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (la):

(Ia)

Where A, R_{1 ;} R₂, R3 and n are as defined above for Formula (I). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (lb)

Xi is O or R₆. Ri, R₂, R3 and R6 are as defined above for Formula (I).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ic)

Where R₉ is -H or -C(0)CH₃.

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Id)

Where A, Ri, R₂, R₃ and n are as defined above for Formula (I).

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ie):

Xi is O or R6. Ri, R₂, R3 and R6 are as defined above for Formula (I).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (If)

Where R₉ is -H or -C(0)CH₃.

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ig):

Where A, R_{1 ;} R₂, R3 and n are as defined above for Formula (I).

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ih)

(Ih)

Xi is O or Re. Ri, R₂, R3 and R6 are as defined above for Formula (I).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ii)

Where R₉ is -H or -C(0)CH₃.

According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (II):

(II)

Where each R is Ci-C₆ alkyl or -H.

Where each R₈ is -H; -(CH₂)_n-OR₆; -(CH₂)_n-N(R₆) or -(CH₂)_n-A-Ar; and where at least is -(CH₂)_n-A-Ar.

Where A is: -C(0)-NR₄-; -NR₄-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-;

Where Ar is:

Where each Ri, R₂, and R₃ are independently -H, -OH, -OC(0)Re; or -Ν^)₂; where at least one of R], R₂, and R₃ is not -H.

Where Rg is -H or C C₆ alkyl.

Where n is 0-10.

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ila)

Where A, R_{l 5} R₂, R3, R₇, and n are as defined above for Formula (II).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (lib)

Ri ^R1 (lib) is O or NR<5. Ri, R₂, R3, Re, and R7 are as defined above for Formula (II).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (lie)

Where R₉ is -H or -C(0)CH₃ and R₇ is Me

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (lid)

Where A, Ri, R₂, R₃, R7, and n are as defined above for Formula (II). R₁₀ is H; (CH₂)_n-OR₆; or -(CH₂)_n-N(R₆).

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (He):

Xi is O or NR5. Ri, R₂, R3, R6, and R7 are as defined above for Formula (II). Rio is -H;

-(CH₂)_n-OR₆; or -(CH^-N^) In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ilf):

Where R₉ is -H or -C(0)CH₃; R₇ is Me or Et; and Rio is -H; -(CH₂)_n-OR6; or -(CH₂)_n-N(R6). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ilg)

Where A, Ri, R₂, R3, R₇, and n are as defined above for Formula (II). Ri₀ is -H; -(CH₂)_n-OR<5;

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Hh)

Xi is O or Re. Ri, R₂, R3, R6, and R7 are as defined above for Formula (II). Rio is -H; -(CH₂)_n-OR₆; or -CCHz NCRe).

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Hi):

Where R₉ is -H or -C(0)CH₃ and R₇ is Me According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (III):

-0-P(0)(OH)-0-.

Where ¾ is H or Ci-C₅ alkyl and where n is 0-10.

Dye may be any dye that undergoes a change in absorption in the presence of the analyte. In some embodiments, Dye may be a heteroanthracene dye or an anthraquinone dye.

As used herein a "heteroanthracene dye" is defined as a dye having an anthracene core structure where one or more of the anthracene carbon atoms are substituted by a heteroatom (e.g., O, N or S). Exemplary heteroanthracene dyes include, but are not limited to: Acridine Orange, Azure A, Azure B; Azure C, Basic Blue 3, Brilliant Cresyl Blue; Celestine Blue, Eosin Methylene Blue, Gallocyanine, Giemsa stain, Methylene Blue, Methylene Green, Methylene Violet, Neutral Red, Pyronin B, Pyronin Y, Resorufm, Rhodamine 6G, Rhodamine B, Rose bengal, Thionin, Toluidine Blue O, and Violamine R.

As used herein an anthraquinone dye has an anthraquinone core structure. Exemplary anthraquinone dyes include, but are not limited to: Acid Blue 25; Alizarin Red S;

Anthrapurpurin; Carminic acid; l,4-Diamino-2,3-dihydroanthraquinone; 1,3- Dihydroxyanthraquinone; 1 ,4-Dihydroxyanthraquinone; Disperse Red 9; Disperse Red 11;

Indanthrone blue; Morindone; Oil Blue 35; Oil Blue A, Parietin, Quinizarine Green SS; Remazol Brilliant Blue R; Solvent Violet 13; 1,2,4-Trihydroxyanthraquinone; Vat Orange 1; Vat Yellow 1; and Vat Yellow 4. In one embodiment, a heteroanthracene dye is represented by the following Formula (IVa):

Where X is N or CH and Y is N, NR₆, O, or S.

Where each R_x, R₂, and R₃ are independently -H, -OH, -OC(0)R<5; or -Ν^)₂; where at least one of Ri, R₂, and R3 is not -H. embodiment, an anthracene dye is represented by the following Formula (IVb):

Where each Ri, R₂, and R3 are independently -H, -OH, -OC(0)R6; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not -H. a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ilia)

(Ilia)

Where A, R_1; R₂, R3 and n are as defined above for Formula (HI) and X and Y are as defined above for Formula (IV). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Illb)

Xi is O or NRg. Ri, R₂, R3 and R6 are as defined above for Formula (III) and X and Y are as defined above for Formula (IV). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (IIIc)

(IIIc)

Where R₉ is -H or -C(0)CH₃ and R₆ is Me or Et. a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Hid)

(Hid)

Where A, Ri, R2, R3 and n are as defined above for Formula (III) and X and Y are as defined above for Formula (IVa).

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Hie):

Xi is O or R₆. Ri, R₂, R3 and R6 are as defined above for Formula (III) and X and Y are as defined above for Formula (IVa). In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Illf):

(Illf)

Where R₉ is -H or -C(0)CH₃ and R₆ is Me a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Illg):

(nig)

Where A, R_1; R₂, R3 and n are as defined above for Formula (III) and X and Y are as defined above for Formula (IVa). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Illh)

Xi is O or NRg. Ri, R₂, R3 and R6 are as defined above for Formula (III) and X and Y are as defined above for Formula (IVa).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Illi)

Where R₉ is -H or -C(0)CH₃ and R₆ is Me

According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (V):

Where each R₇ is Ci-Ce alkyl or -H;

Where R₈ is -H; -(CH₂)_n-OR₅; -(CH₂)„-N(R₆) or -(CH₂)_n-A-Dye; and wherein at least one R₈ is -(CH₂)_n-A-Dye

Where A is: -C(0)-NRs-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-0-P(0)(OH)-0-.

Where R^ is -H or Ci-C₆ alkyl and where n is 0-10.

The Dye may be a heteroanthracene dye or an anthraquinone dye, as defined above. A heteroanthracene dye may have the structure set forth in Formula (IVa), while an anthraquinone dye may have the structure set forth in Formula (IVb).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Va)

(Va)

Where A, Ri, R₂, R3, R7, and n are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vb)

Xi is O or i e. Ri, R2, R3, Rs, and R7 are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vc)

c)

Where R₉ is -H or -C(0)CH₃ and R₇ is Me

In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vd):

Where A, Ri, R₂, R3, R₇, and n are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa). Rio is -H; -(CH₂)„-OR₆; or -(CH₂)_n-N(R6). In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Ve):

Xi is O or R6- Ri, R2, R3, R , and R7 are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa). R₁₀ is -H; -(CHz ORe; or -(CH₂)_n-N(R₆) a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vf)

(Vf)

Where R₉ is -H or -C(0)CH₃; R₇ is Me or Et; and Rio is -H; -(CH₂)n-OR6; or -(CH₂)„-N(R6).

a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vg)

Where A, Ri, R₂, R₃, R7, and n are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa). Ri₀ is -H; -(CH₂)„-OR₆; or -(CH₂)_n-N(R6). a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vh)

Xi is O or R₆. Ri, R₂, R₃, R6, and R₇ are as defined above for Formula (V) and X and Y are as defined above for Formula (IVa). R₁₀ is -H; -(CH₂)_n-OR6; or -(CH₂)„-N(R₆). In a specific embodiment, a synthetic receptor core scaffold has the structure of Formula (Vi):

Where R₉ is -H or -C(0)CH₃ and R₇ is Me or Et. R₁₀ is -H; -(CH₂)_n-OR₆; or -(CH₂)_n-N(R₆). According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (VI):

Where COR

Where A is: -C(0)-NR₆-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-0-P(0)(OH)-0-;

Where each Z is independently: -C(0)-NR₆-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-;

-Se-; -0-; or -0-P(0)(OH)-0-;

Where L is -(CH₂)_m- or -(CH₂0)_m- Where each R₂ and R3 are independently -H, -OH, -OC(0)R6; or -N(Re)₂; where at least one of R₂ and R3 is not H;

Where R6 is -H or Ci-C₆ alkyl, where n is 0-10, and where m is 1-10. According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (VII):

Where each R₇ is C1-C6 alkyl or -H;

Where R₈ is H or -(CH₂)_n-A-Ar;

Where A is: -C(0)-NR4-; -NR₄-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-0-P(0)(OH)-0-;

Where each Z is independently: -C(0)-NR₆-; -NR₆-C(0) -; -C(0)-0-; -O-C(O)

-Se-; -0-; or -0-P(0)(OH)-0- Where L is -(C

Where Ar is:

Where each R₂ and R₃ are independently -H, -OH, -OC(0)R5; -N(Rg)₂; where at least one of R₂

Where Rg is -H or C C₆ alkyl. Where n is 0-10 and m is 1-10. According to another specific example embodiment of this disclosure, synthetic receptor cores are provided that are represented by the following Formula (VIII):

Where A is: C(0)-NR<5 ; NR₆-C(0) ; C(0)-0 ; O-C(O) ; S ; -Se ; O ; or

-0-P(0)(OH)-0-;

-Se-; -0-; or -0-P(0)(OH)-0-;

Where L is -(CH₂)_m- or -(CH₂0)_m-.

Where ¾ is H or C i-C₆ alkyl. Where m is 1 - 10.

With the synthetic receptor core scaffolds in mind, optimization of analyte binding group proceeds from the choice of element on the periodic table. One skilled in the art recognizes that columns of the table typically show trends between the elements of that group. For the purposes of this disclosure, the following elements are contemplated as targets for this chemometric system: Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Fe¹¹, Fe^m, Mn, Cu, Co, Ti, Zr, B, Al, Pb, P, As, S, Se, F, CI, Br and I. Accordingly, one skilled in the art recognizes the preferred aqueous species each of these elements tend to adopt and therefore complementary binding pockets to these elements can be conceived.

In order to rapidly identify color change agents that may directly react with analytes to change color under buffered conditions, a prescreening is performed plus or minus 1 pKa unit of the pKa of a color changing dye. Through the addition of analytes to an array of dyes on a 96 well plate, direct color changes may often be observed to the human eye, but more often shifts in the lambda max of the dye are also observed in a typical absorption spectrum plotting absorbance versus wavelength. Using this method, it was observed the dye alizarin red S changes color in the presence of boron compounds when buffered around its pKa of 6.5, as well as other alizarin dyes. One skilled in the art can observe that others have used alizarin red S to measure boron concentration, but that is usually performed by following the changing in the fluorescence emission.

In this work, in the presence of surfactants, buffers and secondary chelators, it was determined the stoichiometry of the complex between the boron compound (e.g., a borate) and the dye was unexpectedly observed to be 1 :2 (dye to boron compound) when the change in absorbance wavelength was observed at 520. Further, through the choice of an appropriate surfactant, the magnitude of change in the color of the dye is proportion to the dye concentration. Thus through the correct selection of surfactant, the signal change relative to concentration can be enhanced.

Once an appropriate color change agent is identified, designing a synthetic receptor to directly or indirectly detect the desired analyte may be implemented using molecular modeling. Molecular modeling programs, such as Gaussian '03 are capable of mathematical predictions of energy based on the structure may be used to determine quantitative analysis. A combination of molecular mechanics, semi-empirical and ab initio calculations are combined to determine structures minimized for energy. In a typical example, the scaffold is minimized, followed by the analyte binding group. Then the analyte is modeled with its preferred water ligand sphere and geometry. Finally, the energy of the scaffold with designated analyte binding group is determined with and without the analyte. This process is iteratively repeated until satisfied that the complex is lower in energy than the free components themselves.

After modeling, the lead candidate compounds then are screened against the analytes looking for an optical modulation in the UV or visible part of the spectrum. In the event that fluorescence is operative, that band of energy can be used to excite the complex and look for the resultant photon emission.

Once lead candidates are matched with analytes, a signaling method is chosen. In a preferred embodiment, complementary dyes that form weak complexes to the scaffold-analyte binding group ensemble are chosen. In preferred embodiments, the weak interaction between the scaffold-analyte binding group ensemble results in a color change, or change in UV absorption or fluorescence.

Ideally, this docking phenomenon between the dye and the scaffold-analyte binding group results in a reverse of the color changes once the analyte of choice is docked. Finally, when the scaffold-analyte binding group ensemble - analyte chemical analysis system is complete, the system is tested against complex waters with mixtures of analytes.

This process (summarized in the flow chart depicted in FIG. 1) results in an iterative optimization cycle screening for interferences, and formulation for dehydration. The use of buffers is key to prevent color change or false binding events based upon changes in pH.

Secondary chelators are deployed to mask interferences such that the preferred scaffold-analyte binding group ensemble- analyte interaction is maximized. Maximum binding events often can be graphically visualized by the slope of the curve as it relates to absorbance (or fluorescence) and concentration of the analyte. Often, the greater the slope, the greater the binding. Binding events characterized by flat slopes tend to indicate weak relationships that lead to more interference and difficulty in quantitation. Finally, surfactants may be utilized to amplify the optical signal. These amplification events are often caused by the perturbation of the microenvironment of the dye such that water may be excluded or minimized. Water often is an excellent quencher of dye behavior. In order to overcome this quenching, an organic solvent may be added to the water. The dye, in the presence of an organic solvent, generally gives a greater signal than the dye in water. Each of these components must be optimized for performance and freeze drying. Ideally, the freeze dried sample rapidly rehydrates in less than 5 minutes, preferably, less than 2 minutes.

Finally, with the scaffold-analyte binding group ensemble, chosen analyte, and optimized formulated data, one uses mathematical models of binding behavior to determine the best fit of the data to the theoretical behavior. While linear or polynomial fits are often sufficient, a preferred embodiment of this disclosure uses chemical equilibrium models of host - guest binding events such as 1 :1, 1 :2, 2:1 stoichiometries as well as the newer indicator displacement behavior. Solving these complex mathematical models of chemical behavior has become feasible with the processing power of the average computer.

The process described above may be implemented in an end form of a multi-well plate. Water samples may be added directly to the plate, diluted and or treated with solid media, including, but not limited to activated carbon, silica gel, aluminum oxide, cellulose, ion exchange media and celite to pretreat the sample. Once the water has been added to the test plate, the samples are tested by a well plate reader. The raw data is sent to the chemometric algorithm above, and meaningful data is returned, such as the relationship between optical property and concentration of analyte in the sample. Still another embodiment uses digital imaging technology to measure changes in color by measuring the RGB values as determined by software such as Adobe Photoshop. These RGB values can be mathematically related to absorbance. In a preferred embodiment, samples are photographed with a portable device (e.g., a smartphone) and the data is analyzed by the processer in the device or sent (by the device) to a central database. In another embodiment, the dehydrated chemistries are added to lateral flow membrane papers and or paper strips.

According to another specific embodiment of this disclosure, a synthetic receptor scaffold core is provided that is composed of a molecule with at least one analyte binding group.

According to another specific example embodiment of this disclosure, synthetic receptors are provided that comprise a synthetic receptor scaffold core; and an analyte binding group, wherein the analyte binding group is capable of complexion with an analyte. Systems are provided that comprise a sample chamber comprising: a sample disposed within the sample chamber; and a plurality of synthetic receptor molecules disposed within the sample chamber, wherein the plurality of synthetic receptor molecules comprise: a synthetic receptor core; and an analyte binding group, wherein the analyte binding group is capable of complexion with an analyte; a photon source disposed operative with the sample chamber to provide photons to the sample chamber; and a photon detector disposed operative with the sample chamber to provide detection of photons from the sample chamber.

According to another specific embodiment of this disclosure, kits are provided that comprise a synthetic receptor, wherein the synthetic receptor comprises: a synthetic receptor core; and an analyte binding group, wherein the analyte binding group is capable of complexion with an analyte; a container for a sample; one or more containers for combining the synthetic receptor and the sample.

According to another specific embodiment of this disclosure, synthetic receptor cores and synthetic receptors may be fluorimetric. Such compositions may be used in methods for the detection of an analyte.

According to another specific example embodiment of this disclosure, synthetic receptor cores and synthetic receptors may absorb uv-visible light or be fluorimetric. Such compositions may be used in, among other things, methods for the detection of an analyte in a sample, for example an industrial water stream. Such methods may be advantageous in that they may have minimal sample and synthetic receptor requirements for testing, as well as be a rapid and efficient method for analyte detection or quantification or both. Current methods using enzymes or antibodies are limited to known systems, require expensive development for new analytes and are subject to environmental changes such as pH, temperature. Synthetic receptors overcome this limitation.

In one embodiment, the development of synthetic receptors may be based on a synthetic core receptor which is transformed to allow high binding affinity and specificity for an analyte while retaining the core elements of the receptor (for example, absorption or fluorescent properties). Transformation may involve chemical derivation of the core receptor molecule so as to alter the molecular spacing of the target binding portions of the molecule.

The present disclosure, in one embodiment, adopts this approach to provide for compositions and methods useful for specific binding and detection of metal ions in a sample using uv-visible chromophores and/or fluorescent receptor molecules.

The synthetic receptor cores of the present disclosure represented by Formulas (I)-(VIII) may be derivatized by replacing one or more of the benzene rings with napthoic acid or other common substituted aromatic carboxylic acids including but not limited to phthalic anhydride, trimellitic anhydride, naphthalic anhydride and derivatives by coupling via an esterification, amidation or condensation to form a dye after appended to a synthetic receptor core scaffold.

According to another embodiment, the synthetic receptor cores of the present disclosure may be covalently bound to a solid phase support. Such compositions may be useful, among other things, to form materials for screening chemical libraries using, for example, combinatorial chemistry. Examples of suitable solid phase supports include, but are not limited to: silica gels, resins, derivatized plastic films, multi-well assay plates, glass, glass beads, fiber optics, cotton, plastic beads, alumina gels, synthetic antigen-presenting matrices, cells, and liposomes.

In a preferred embodiment, the chemical libraries represented by formulas (I)-(VIII) were

screened against Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Fe¹¹, Fe^m, Mn, Cu, Co, Ti, Zr, B, Al, Pb, P, As, S, Se, F, CI, Br and I.

In some examples, in which the synthetic receptor core comprises a compound according to Formula I, the solid phase support may be covalently bound to one or more of Rl, R2, and R3.

As mentioned above, the synthetic receptor cores of the present disclosure may be used to form synthetic receptors. Such synthetic receptors generally comprise a synthetic receptor core and an analyte binding group. The analyte binding group may be capable of forming a complex with a desired analyte, for example, borate.

In some examples, in which the synthetic receptor core comprises a compound according to any of Formulas (I) and (III), the solid phase support may be covalently bound to one or more of CORE structures (e.g., by modifying the core to include a functional handle). In Formulas (II) and (V), for example, the core aromatic pendant groups R₇ may be used to couple the synthetic receptor to a solid phase support.

Synthetic receptors of the present disclosure may be used to detect the analyte, for example, through fluorescence quenching or a change in the UV-Vis spectrum. For example, the binding of an analyte (e.g., borate) with a synthetic receptor that comprises a binding group capable of forming a complex with the analyte may cause a decrease in the emission spectra of the synthetic receptor, which may result in a near complete quenching of the synthetic receptor's emission spectrum. This may be manifested as a disappearance or change in color of the solution containing the synthetic receptor in the presence of the analyte.

One example of a synthetic receptor of the present disclosure is the synthetic receptor represented by FIG. 2, structure 1. This synthetic receptor may be capable of forming a complex with borate, and may have an absorption or fluorimetric spectrum that may be detectably altered upon formulation of a complex comprising the receptor and a borate molecule. Accordingly, this synthetic receptor may be used to detect borate in a sample, as describe herein.

In another example, compounds based on Formula (II) were found to respond to Fe^m.

For example, structure 1 (of FIG. 2) changed color in the presence of Fe^m from purple to blue.

According to another embodiment, the synthetic receptors of the present disclosure may be used in methods for detecting an analyte in a sample. Such methods may comprise providing a sample that may comprise an analyte; contacting a synthetic receptor to the sample; allowing the formation of a synthetic receptor-analyte complex; and identifying the formation of the synthetic receptor-analyte complex.

The sample may be industrial in origin, for instance a mining operation. The sample also may be obtained from industrial water. For synthetic receptors having a fluorescent emission, the change in absorption or fluorescent emission that may occur upon complexation with an analyte may be detected and compared to a standard to, for example, determine the concentration of the analyte in the sample being tested. According to another embodiment, the synthetic receptors of the present disclosure may be used in methods for detecting an analyte in a sample in which the synthetic receptor is derivatized or immobilized onto a solid phase support, such as the well of a multiwall plate.

By way of explanation, and not of limitation, binding of borate with a synthetic receptor represented by Formula (II) may cause a change in the absorption spectra, resulting from interaction of borate with the a portion of the Dye molecule.

A system for detecting analytes may include a sample chamber in which a sample that includes the analyte is disposed within. The sample chamber includes a plurality of synthetic receptor molecules disposed within the sample chamber; a photon source disposed operative with the sample chamber to provide photons to the sample chamber; and a photon detector disposed operative with the sample chamber to provide detection of photons from the sample chamber. In some embodiments these systems also may comprise a photomultiplier tube, a computer, or both. The present disclosure, according to certain embodiments, also provides kits for, among other things the detection of analytes. Such kits may comprise a synthetic receptor molecule, a container for a sample; and one or more containers for combining the synthetic receptor and the sample. To facilitate a better understanding of the present invention, the following examples of specific embodiments are given. In no way should the following examples be read to limit or define the entire scope of the invention.

Example 1 : Binding of Alizarin Red S to Borate - 1 :2 Binding Stoichiometry

Using a 1 :2 binding model for host (alizarin red s, "ARS", an anthraquinone dye) and guest (borate) a 1 :2 binding stoichiometry was observed by plotting the experimental data versus the model predicted absorbance and the model predicted concentration. This was accomplished by using the Newton's method for finding nonlinear roots. See Figure 3.

Example 2: Signal enhancement of alizarin red s - borate complex with surfactants

As an exemplary embodiment, the signal of alizarin red s could be enhanced through the use of surfactants. Nonionic, neutral, anionic and cationic surfactants were evaluated to determine increases in absorbance from the effect of the surfactant alone. The most dramatic increase in absorbance from surfactant was observed in the presence of a non-ionic defoamer. See Figure 4.

Example 3 : Improving the binding to borate through the use of a borate enhancement ligand chemically attached to ARS.

Through the attachment of a tertiary amino alcohol to alizarin red s, a new borate binding site was prepared. By adding this chelating ligand, the alizarin red s specificity and sensitivity to borate was observed. This is explained by thermodynamics, the improved ligand sphere allowed for stronger binding with more entropy than satisfying the ligand sphere of borate with ARS and water.

Example 4: Stripping of Borate from alizarin red s

Finally, demonstrating the improved binding constant for borate for the synthetic receptor versus alizarin red s, a 1 : 1 complex of ARS and borate was prepared. By adding in increasing quantities of the synthetic receptor, the color change was reversed. Under buffered conditions, this demonstrates a greater binding for the synthetic receptor versus alizarin alone. Thus using the algorithm for synthetic receptor core screening and identification, an improved ligand for borate was discovered. Detection of boron (specifically water soluble species of elemental boron) such as boric acid or a metal borate, or sodium borate, was studied using the compounds described herein. Those skilled in the art recognize that when reporting boron values, these values are with respect to elemental boron, although the actual species of interest is usually a derivative of boric acid. Structure 1, a preferred enablement of Formula (I), was designed to detect the tetrahedral form of boric acid, borate anion. However it was found that Structure 1 oxidized very quickly in air, as evidenced by the appearance of a dark brown color.

Solving the solubility and oxidation problem described previously was achieved through an investigation of formations which could solve both problems simultaneously. The oxidation problem proved dominant, because long term stability and analytical fidelity are lost upon oxidation of structures such as Structure 1. To this end, when the L group is changed to an ester protected function on each hydroxyl group, stability to oxidation is observed. In a preferred embodiment, the ester of choice is acetate, but this is not limiting and one skilled in the art recognizes that any ester group that hydrolyzes under assay conditions is suitable, as this is a temporary group. While acetate is preferred, any ester that hydrolyzes faster or within a time frame similar to that of the acetate would be suitable for the end assay. In aging studies, the ligands were stable when kept in a sealed container. Unexpectedly, the binding of the targeted ligand, boron for Structure 1 , was achieved without prior removal of the protecting groups. Thus the ability to prepare the ligand depicted as Structure 1 , as a protected compound, eliminates a synthetic step and protects the ligand from undesired oxidation.

The choice of buffer and pH are adjusted to optimize the final formulation. While the unprotected ligand (Ac replaced by H, in Structure 1) had greater water solubility, the protected ligand (Structure 1 , -OAc ) was water soluble with a single additive, namely a solution of polyethyleneglycol in water, achieving similar water solubility with the protecting groups intact. In an example of the working formulation of polyethylene glycol for this detection scheme, the preferred concentration was 17%, but a range of 1% to 25% is acceptable. Balancing the ligand solubility with appropriate buffer and pH required additional formulation. For instance, the buffer TRIS tris(hydroxymethyl)aminomethane was found to interfere with the sensitivity of Structure 1 , acting as a competing ligand for boron. Switching to the buffer HEPES (4-(2- hydroxyethyl)-l-piperazineethanesulfonic acid) fixed the problem for the competition with the target analyte boron, and maintained pH at 7.8.

The pH of the detection solution was also used to optimize the formulation. pH's above 9.5 lead to rapid hydrolysis of the protected ligand (Structure 1) and aided subsequent oxidation. A pH which was too low caused the assay to be slow to respond to the target analyte. To protect against cross-interfering metal ions, EDTA was added to the solution at a concentration of 100 mM with a preferred range of 25 mM to 250 mM. Further aiding the solubility of the ligand and the detection and sensitivity of the assay to the target analyte, a formulation could include one or more of the following ingredients: 2-butoxyethanol in a range of 0.1% to 10% with a preferred concentration of about 1%; Tween-20 in a range of 0.1% to 10% with a preferred concentration of about 1%; and triton x- 100 at 1% concentration with a range of 0.1% to 10% possible.

Finally, the ligand Structure 1 with acetate protecting groups can be included in a formulation ranging from 0.1% to 2.5% with a preferred embodiment being 0.4% by weight. Thus, the formulation as described above is suitable for the detection of boron in complex water such as those extracted during mineral operations.

Detection of iron (specifically water soluble species of elemental iron) was studied using the compounds described herein. Those skilled in the art recognize that when reporting iron values, these values are with respect to elemental iron, although the actual species of interest is usually a derivative of iron. Structure 2, a preferred enablement of Formula (II), was designed to detect the Feⁿ Surprisingly, it was discovered that Structure 2 may also be used to detect Fe^m.

While working well under ideal conditions, or simulated frac waters, in actual waters several problems were observed: 1) solubility of the ligands described by Formula (II) was lower in real water compared with simulated water 2) oxidation of the hydroxyl groups (phenols of the hydroxybenzoic acids) hampered precise detection of targeted analytes. Solving the solubility and oxidation problem described previously was achieved through an investigation of formations for which both problems were solved simultaneously. The oxidation problem proved more important, for long term stability and analytical fidelity are lost upon oxidation of structures such as Structure 2. To this end, when the L group is changed to an ester protected function on each hydroxyl group, stability to oxidation is observed. In a preferred embodiment, the ester of choice is acetate, but this is not limiting and one skilled in the art recognizes that any ester group that hydro lyzes under assay conditions is suitable, as this is a temporary group. While acetate is preferred, any ester that hydrolyzes faster or within a time frame similar to that of the acetate would be suitable for the end assay. In aging studies, the ligands were stable when kept in a sealed container. Unexpectedly, the binding of the targeted analyte, iron in the case of Structure 2, was achieved without prior removal of the protecting groups. Thus the ability to prepare the ligand as in Formula II, Structure 2 as a protected compound eliminates a synthetic step and protects the ligand from undesired oxidation.

With the oxidation problem solved and compatible with analytical detection of analytes, the choice of buffer and pH are next studied to optimize the formulation. Further complicating the detection of iron resides with the fact iron commonly exists in two oxidation states, namely Fe¹¹ and Fe^m. The compound, Structure 2, detects both Fe¹¹ and Fe^m simultaneously. Current methods usually detect Fe¹¹, then calculate Fe¹¹¹ from the difference of total iron and Fe¹¹, with the remainder being the amount of Fe^m. As iron will react with oxygen and many complex solution species may exist, liberation of iron is necessary to properly detect it in complex produced water. Thus, raw, untreated water samples were subjected to 0.1 N nitric acid for digestion. This sample was then buffered back to the working range of the receptor with appropriate buffer. The preferred buffer was MES (2-(N-morpholino)ethanesulfonic acid) at 100 mM with a range of 25 mM to 500 mM possible.

While the unprotected ligand Structure 2 (no Ac) had greater water solubility, the protected ligand Structure 2 (as shown) was water soluble with a single additive, namely a solution of polyethyleneglycol in water. In an example of the working formulation of polyethylene glycol for this detection scheme, the preferred concentration was 17%, but a range of 1% to 25% is acceptable. Balancing the ligand solubility with appropriate buffer and pH required formulation. The buffer MES (2-(N-morpholino)ethanesulfonic acid), did not interfere with Structure 2, maintained pH at 5.6, and balanced the pH from the nitric acid digestion.

The pH of the detection solution was also used to optimize the formulation. pH's greater than 7 lead to rapid hydrolysis of the protected ligand (Structure 2) and aided subsequent oxidation. Too low of a pH caused the assay to be slow to respond to the target analyte. Further aiding the solubility of the ligand and the detection and sensitivity of the assay to the target analyte, a formulation could include one or more of the following ingredients: 2-butoxyethanol in a range of 0.1% to 10% with a preferred concentration of about 1%; Tween-20 in a range of 0.1% to 10% with a preferred concentration of about 1%; and triton x-100 at 1% concentration with a range of 0.1% to 10% possible. Finally, the ligand, Structure 2, with acetate protecting groups can be included in a formulation ranging from 0.1% to 2.5% with a preferred

embodiment being 0.4% by weight. Thus, the formulation as described above is suitable for the detection of iron in complex water such as those extracted during mineral operations. Analysis of the Receptors 1 and 2 in Distilled Water to Verify Detection of Fe¹¹ and Feⁿⁱ

Recipes for the preparation of the assay solution are as described above with the exception of using distilled water in place of the produced water, then adding the known concentration of analyte to achieve a Beer's Law plot.

To validate the function of the Structures 1 and 2, identical waters were tested with the formulations described for the respective analyte receptors then sent to a third party lab for testing. Samples were evaluated for iron and boron content. To meet this objective, the samples were sent to a third-party laboratory, for independent determination of these analyte

concentrations. The requested analyses were iron (II), iron (III) and boron. Given the actual concentrations and working ranges of the iron and boron sensors, the iron test was performed on undiluted sample water, while the boron sensor was tested with a sample of the diluted water sent to the third party lab.

Produced water sample 006 was tested for total iron and borate using the assays described above and the concentrations were determined to be 30.8 mg/L and 36.1 mg/L, respectively, which compares to the values determined by a third party lab using ICP-MS of 29.3 mg/L and 21.3 mg/L.

The data and results collected in these tests are shown in FIGS. 5-7. FIG. 5 shows a line graph depicting Fe¹¹ and Fe^m concentration in the presence of iron receptor versus absorbance demonstrating the detection of both species by Structure 2. FIG. 6 shows a line graph depicting the calibration curve of Fe^m used to test water samples from a mineral recovery operation using Structure 2. FIG. 7 shows a line graph depicting the calibration curve of boron used to test water samples from a mineral recovery operation using Structure 1.

Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments.

Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A synthetic receptor core scaffold having the Formula (I):

where CORE

where A is: C(0)-NRs ; NR₆-C(0) ; C(0)-0 ; O-C(O) ; S ; Se ; O ; or

-0-P(0)(OH)-0-;

where each R_{l s} R₂, and R₃ are independently -H, -OH, -OC(0)R6;or - (R₆)₂; where at least one of Ri, R₂, and R3 is not -H;

where R6 is -H or C₁-C6 alkyl; and.

where n is 0-10.

2. The synthetic receptor core scaffold of claim 1, wherein the synthetic receptor core scaffold has the structure of Formula (la):

3. The synthetic receptor core scaffold of claim 1 , wherein the synthetic receptor core scaffold has the structure of Fo

(lb) where Xi is O or NR-6.

4. The synthetic receptor core scaffold of claim 1 , wherein the synthetic receptor core scaffold has the structure of Formula (Ic):

where R₉ is -H or -C(0)CH₃.

5. The synthetic receptor core scaffold of claim 1, wherein the synthetic receptor core scaffold has the s

6. The synthetic receptor core scaffold of claim 1, wherein the synthetic receptor core scaffold has the structure of Formula (Ie):

where Xi is O or R₆.

7. The synthetic receptor core scaffold of claim 1, wherein the synthetic receptor core scaffold has the structure of Formula (If):

where R₉ is -H or -C(0)CH₃.

8. The synthetic receptor core scaffold of claim 1, wherein the synthetic receptor core scaffold has the structure of Formula (Ig):

9. The synthetic receptor core scaffold of claim 1 , wherein the synthetic receptor core scaffold has the structure of Formula (Ih):

where Xi is O or NR.6

10. The synthetic receptor core scaffold of claim I, wherein the synthetic receptor core scaffold has the structure of Formula (Ii):

where R₉ is -H or -C(0)CH₃

11. A synthetic receptor core scaffold having the Formula (II):

where each R is Ci-C6 alkyl or -H;

where each R₈ is -H; -(CH₂)_n-OR₆; -^Η₂)_η-Ν(¾) or -(CH₂)_n-A-Ar; and where at least is -(CH₂)_n-A-Ar;

where Ar is:

where each Ri, R₂, and R₃ are independently H, -OH, -OC(0)R or - (Re)₂; where at least one of Ri, R₂, and R3 is not -H;

where R6 is -H or Ci-C alkyl;

where n is 0-10.

12. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (Ila):

(Ila).

13. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (lib)

where Xi is O or NR-6.

14. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (lie):

where R₉ is -H or -C(0)CH₃ and R₇ is Me

15. The synthetic receptor core scaffold of claim 1 1 , wherein the synthetic receptor core scaffold has the structure of Formula (II d):

(lid) where Rio is -H; -(CH^-ORe; or -(CH₂)_n-N(R₆).

16. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (He):

where Xi is O or NR₆ and R_i0 is -H; -(CH₂)„-OR₆; or -(CH₂)_n-N(R6).

17. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (Ilf):

where R₉ is -H or -C(0)CH₃; R₇ is Me or Et; and R_w is -H; -(CH₂)_n-OR₆; or -(CH₂)_n-N(Re).

18. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the s

where R₁₀ is -H; -(CH^-ORe; or -(0½)_η-Ν^).

19. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (Ilh):

where Xi is O or NR₆; and io is -H; -(CH₂)_n-OR₆; or -(CH₂)„-N(R6).

20. The synthetic receptor core scaffold of claim 11, wherein the synthetic receptor core scaffold has the structure of Formula (Hi)

where R₉ is -H or -C(0)CH₃ and R₇ is Me A synthetic receptor core scaffolds having the Formula (III):

where CORE is:

where A is: -C(0)-NR«-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-; or

-0-P(0)(OH)-0-;

where R6 is -H or C1-C6 alkyl and where n is 0-10.

where Dye is a dye that undergoes a change in absorption in the presence of a predetermined analyte.

22. The synthetic receptor core scaffold of claim 21, wherein the Dye is a heteroanthracene dye

23. The synthetic receptor core scaffold of claim 21, wherein the Dye is selected from the group consisting of: Acridine Orange, Azure A, Azure B; Azure C, Basic Blue 3, Brilliant Cresyl Blue; Celestine Blue, Eosin Methylene Blue, Gallocyanine, Giemsa stain, Methylene Blue, Methylene Green, Methylene Violet, Neutral Red, Pyronin B, Pyronin Y, Resorufm, Rhodamine 6G, Rhodamine B, Rose bengal, Thionin, Toluidine Blue O, and Violamine R.

The synthetic receptor core scaffold of claim 21, wherein the Dye has the structure:

where X is N or CH and Y is N, Rs, O, or S; and

where each R_ls R₂, and R₃ are independently H, -OH, OC(0)R<5; or -N(¾)₂; where at least one of Ri, R₂, and R3 is not -H.

25. The synthetic receptor core scaffold of claim 21, wherein the Dye is an anthraquinone dye.

26. The synthetic receptor core scaffold of claim 21, wherein the Dye is selected from the group consisting of: Acid Blue 25; Alizarin Red S; Anthrapurpurin; Carminic acid; l ,4-Diamino-2,3- dihydroanthraquinone; 1 ,3-Dihydroxyanthraquinone; 1 ,4-Dihydroxyanthraquinone; Disperse Red 9; Disperse Red 1 1 ; Indanthrone blue; Morindone; Oil Blue 35; Oil Blue A, Parietin, Quinizarine Green SS; Remazol Brilliant Blue R; Solvent Violet 13; 1,2,4- Trihydroxyanthraquinone; Vat Orange 1 ; Vat Yellow 1; and Vat Yellow 4.

The synthetic recep the structure:

where each R_{l s} R₂, and R₃ are independently -H, -OH, -OC(0)Rg; or - (Re)₂; where at least one of Ri, R₂, and R₃ is not -H.

28. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Ilia):

(Ilia)

where each R_{l s} R₂, and R₃ are independently -H, -OH, -OC(0)R6; or - (Re)₂; where at least one of Ri, R₂, and R₃ is not H; and wherein X is N or CH and Y is N, NR₆, O, or S.

29. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Illb):

(Illb) where Xi is O or NR-6;

where each R R₂, and R₃ are independently -H, -OH, -OC(0)Re; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not -H; and

where X is N or CH and Y is N, NRe, O, or S.

30. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor

scaffolds has the structure of Formula (IIIc):

where R₉ is -H or -C(0)CH₃ and R₆ is Me

31. The synthetic receptor core scaffold of claim 21 , wherein the synthetic receptor core scaffolds has the structure of Formula (Hid):

(Hid)

where each Ri, R₂, and R₃ are independently -H, -OH, -OC(0)Re; or - (Re)₂; where at least one of Ri, R₂, and R₃ is not -H; and wherein X is N or CH and Y is N, NRg, O, or S.

32. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Hie):

where X₁ is O or NR₆;

where each Ri, R₂, and R₃ are independently -H, -OH, -OC(0)Re; or - (Re)₂; where at least one of Ri, R₂, and R₃ is not -H; and wherein X is N or CH and Y is N, NR₆, O, or S.

33. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Illf) :

where R₉ is -H or -C(0)CH₃ and R₆ is Me or Et.

34. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Illg):

(nig)

where each R_ls R₂, and R3 are independently -H, -OH, -OC(0)R_<5; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not -H; and wherein X is N or CH and Y is N, NR₆, O, or S.

35. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor scaffolds has the structure of Formula (Illh):

where Xi is O or NR-6; and

where each R_ls R₂, and R₃ are independently -H, -OH, -OC(0)R6; or - (Re)₂; where at least one of Ri, R₂, and R₃ is not -H; and wherein X is N or CH and Y is N, NR₆, O, or S.

36. The synthetic receptor core scaffold of claim 21, wherein the synthetic receptor core scaffolds has the structure of Formula (Illi):

A synthetic receptor core scaffold having the Formula (V)

where each R₇ is C1-C5 alkyl or -H;

where Rg is -H; -(CH₂)_n-OR₆; -(CH )_n-N(R₆) or -(CH₂)_n-A-Dye; and wherein at least one Rg is -(CH₂)_n-A-Dye;

where A is: -C(0)-NRe-; -NR₆-C(0) -; -C(0)-0-; -O-C(O) -; -S-; -Se-; -0-;

-0-P(0)(OH)-0-;

where R₆ is -H or Ci-C₆ alkyl;

where n is 0-10;

38. The synthetic receptor core scaffold of claim 37, wherein the Dye is a heteroanthracene dye. 39. The synthetic receptor core scaffold of claim 37, wherein the Dye is selected from the group consisting of: Acridine Orange, Azure A, Azure B; Azure C, Basic Blue 3, Brilliant Cresyl Blue; Celestine Blue, Eosin Methylene Blue, Gallocyanine, Giemsa stain, Methylene Blue, Methylene Green, Methylene Violet, Neutral Red, Pyronin B, Pyronin Y, Resorufin, Rhodamine 6G, Rhodamine B, Rose bengal, Thionin, Toluidine Blue O, and Violamine R.

The synthetic recep the structure:

where X is N or CH and Y is N, R₆, O, or S; and

where each R_ls R₂, and R₃ are independently -H, -OH, -OC(0)Rg; or -N(Re)₂; where at least one of Ri, R₂, and R₃ is not -H.

41. The synthetic receptor core scaffold of claim 37, wherein the Dye is an anthraquinone dye.

42. The synthetic receptor core scaffold of claim 37, wherein the Dye is selected from the group consisting of: Acid Blue 25; Alizarin Red S; Anthrapurpurin; Carminic acid; l,4-Diamino-2,3- dihydroanthraquinone; 1,3-Dihydroxyanthraquinone; 1 ,4-Dihydroxyanthraquinone; Disperse Red 9; Disperse Red 11; Indanthrone blue; Morindone; Oil Blue 35; Oil Blue A, Parietin, Quinizarine Green SS; Remazol Brilliant Blue R; Solvent Violet 13; 1,2,4- Trihydroxyanthraquinone; Vat Orange 1; Vat Yellow 1; and Vat Yellow 4.

The synthetic receptor core scaffold of claim 37, wherein the Dye has the structure:

where each R R₂, and R₃ are independently -H, -OH, -OC(0)R5; or -N(Re)₂; where at least one of Ri, R₂, and R₃ is not -H.

44. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Va):

(Va)

where each R R₂, and R₃ are independently -H, -OH, -OC(0)Re; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not H; and

wherein X is N or CH and Y is N, NR₆, O, or S.

45. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vb):

(Vb)

where Xi is O or NR^;

where each R_ls R₂, and R₃ are independently -H, -OH, -OC(0)R<5; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not -H; and

wherein X is N or CH and Y is N, NR₆, O, or S.

46. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vc):

(VC) where R₉ is -H or -C(0)CH₃ and R₇ is Me

47. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vd):

(Vd)

where each R_{l s} R₂, and R3 are independently -H, -OH, -OC(0)R6; or -N(Re)₂; where at least one of Ri, R₂, and R₃ is not H; and

wherein X is N or CH and Y is N, NR₆, O, or S.

48. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Ve):

where Xi is O or NR₆;

where each Ri, R₂, and R3 are independently -H, -OH, -OC(0)R6; or - (R₆)₂; where at least one of Ri, R₂, and R₃ is not -H; and

where X is N or CH and Y is N, NRe, O, or S.

49. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vf):

where R₉ is -H or -C(0)CH₃; R₇ is Me or Et; and R_w is -H; -(CH₂)_n-OR₆; or -(ΟΗ₂)_η-Ν^).

50. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vg):

where each R_ls R₂, and R3 are independently -H, -OH, -OC(0)R<5; or -N(Re)₂; where at least one of Ri, R₂, and R3 is not -H; and

where X is N or CH and Y is N, Re, O, or S.

51. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor core scaffolds has the structure of Formula (Vh):

where Xi is O or NR₆;

where each Ri, R₂, and R3 are independently -H, -OH, -OC(0)R6; or -N(R6)₂; where at least one of Ri, R₂, and R₃ is not -H; and

where X is N or CH and Y is N, NRe, O, or S.

52. The synthetic receptor core scaffold of claim 37, wherein the synthetic receptor scaffolds has the structure of Formula (Vi):

where R₉ is -H or -C(0)CH₃ and R₇ is Me or Et. R₁₀ is -H; -(CH₂)_n-OR₆; or -(CH₂)_n-N(R6).

53. A composition comprising one or more synthetic receptor core scaffolds as described in any one of claims 1-52 and a solvent for the one or more synthetic receptor core scaffolds,

54. The composition of claim 53, wherein the solvent comprises water and an alcohol.

55. The composition of claim 53, wherein the solvent comprises polyethylene glycol.

56. The composition of claim 53, further comprising a buffer. 57. The composition of claim 53, further comprising a surfactant.

58. A method of detecting an analyte comprising:

obtaining a sample comprising the analyte;

contacting the sample with the composition of any one of claims 53-57 to form a mixture; detecting changes in light absorption of the mixture.

59. The method of claim 58, wherein the synthetic receptor core scaffold has a light absorption that is altered in the presence of an analyte, and wherein the method comprising determining the change in light absorbance of the mixture after the analyte sample is added to the composition.

60. The method of claim 58, wherein the composition further comprises a dye capable of reversibly binding with the analyte, wherein the synthetic receptor core scaffold has a stronger binding constant to the analyte compared to the binding constant of the dye to the analyte. 61. The method of claim 60, wherein the method further comprises adding a dye to the composition; wherein the synthetic receptor core scaffold competes with the dye such that the synthetic receptor core scaffold removes the analyte from the dye to alter the light absorption of the dye. 62. The method of claim 60, wherein the synthetic receptor core scaffolds are bound to a solid support.

63. The method of claim 60, wherein the synthetic receptor core scaffolds are bound to a microtiter plate.

64. The method of claim 60, wherein the sample comprises borate ions, and wherein the one or more synthetic receptor core scaffolds interact with borate ions to produce a change in the light absorption of the mixture.

65. The method of claim 64, wherein the one or more synthetic receptor core scaffolds comprise a compound having the structure (If):

where R₉ is -H or -C(0)CH₃.

66. The method of claim 64, wherein the sample is a sample obtained from frac water.

67. The method of claim 60, wherein the sample comprises iron ions, and wherein the one or more synthetic receptor core scaffolds interact with iron ions to produce a change in the light absorption of the mixture.

68. The method of claim 67, wherein the iron ions comprise Fe¹¹ and Fe^m ions.

69. The method of claim 67, wherein the one or more synthetic receptor core scaffolds comprise a compound having the structure (He):

where R₉ is -H or -C(0)CH₃ and R₇ is Me or Et.

70. The method of claim 67, wherein the one or more synthetic receptor core scaffolds comprise a compound having the structure (Vi):

(Vi) where R₉ is -H or -C(0)CH₃; R₇ is Me or Et; and Rio is -H; -(CH₂)_n-OR₆; or -(CH₂)_n-N(R6).

71. The method of claim 67, wherein the sample is a sample obtained from frac water.

72. The method of claim 58, further comprising calculating the concentration of the anal the sample based on the change in light absorption of the mixture.