CN115768745A

CN115768745A - Sulfated columnar arenes, methods of making same, and uses thereof

Info

Publication number: CN115768745A
Application number: CN202180031334.3A
Authority: CN
Inventors: 莱尔·戴维·艾萨克斯; 薛伟剑
Original assignee: University of Maryland at College Park
Current assignee: University of Maryland at College Park
Priority date: 2020-02-27
Filing date: 2021-03-01
Publication date: 2023-03-07
Also published as: EP4110757A1; WO2021174209A1

Abstract

Sulfated columnar arenes, methods of making and methods of using the same are provided. The pillar arene has a macrocyclic core with a plurality of aryl groups connected (e.g., covalently bonded) to adjacent methylene groups in para-substitution. The pillar arene has a hydrophobic cavity. The hydrophobic cavity can be used to sequester various materials or deliver materials sequestered therein.

Description

Sulfated pillararene, method for producing the same and use thereof

Cross Reference to Related Applications

This application claims priority to U.S. provisional application No. 62/982,460, filed on day 27, 2020, and U.S. provisional application No. 63/013,336, filed on day 21, 2020, the disclosures of which are incorporated herein by reference.

Statement regarding federally sponsored research

The present invention was made with government support under contract number CHE-1404911 awarded by the National Science Foundation (National Science Foundation). The government has certain rights in the invention.

Background

Several classes of molecular container compounds are known, including cyclodextrins, calixarenes, cyclophanes, pillararenes, and cucurbiturils. These molecular containment compounds bind to their target molecules in solution and thereby modulate the properties of the target, including optical properties, solubility, odor, and even biological activity. Previous workers in the field of column [ n ] arenes have synthesized container molecules characterized by hydrophobic cavities and carboxylic acid solubilizing groups, and have shown that they bind with good affinity to cationic targets in water. The challenge in this field is how to create new molecular containers or modify existing molecular containers such that they maintain good solubility in water and at the same time enhance their binding affinity to their target.

Disclosure of Invention

The present disclosure provides sulfated pillar arenes. The present disclosure also provides a method of making sulfated column aromatics and uses thereof.

In the present disclosure, it is demonstrated, for example, that locating anionic solubilizing groups (e.g., sulfate groups) at the edges of the pillar arene cavity significantly enhances their binding affinity for cationic targets in water, and thereby their ability to act as chelating agents for various applications.

In one aspect, the present disclosure provides compounds. These compounds are sulfated pillar arenes. Sulfated columnar arenes comprise a macrocyclic core comprising a plurality of aryl groups, wherein adjacent aryl groups are linked via an alkyl linkage (e.g., -CH) ₂ A group) is covalently linked (e.g. bonded). The alkyl linking group is para to the aryl group (e.g., a 1, 4-phenyl linkage). These bonds may be on different phenyl rings of the aryl group, andif the different benzene rings overlap, they correspond to the para bond. In many instances, one or more or all of the adjacent aryl groups are not covalently linked through an alkyl linking group at a meta position on the aryl group (e.g., a 1, 3-phenyl linkage (in the case where the linkages are on different phenyl rings or aryl groups, these linkages do not correspond to meta linkages if the different phenyl rings overlap)). Non-limiting examples of sulfated pillararomatics are provided herein. Provided herein are non-limiting examples of methods of making sulfated pillar aromatic hydrocarbons.

In one aspect, the present disclosure provides a composition comprising one or more sulfated pillar arenes. Non-limiting examples of compositions are described herein.

The composition may comprise one or more sulfated pillar arenes and one or more agents. In various examples, the pharmaceutical agent comprises one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

In one aspect, the present disclosure provides the use of sulfated pillar arenes. Non-limiting examples of uses of sulfated pillar arenes are provided herein.

Sulfated pillar arenes can be used to chelate various materials, which can be chemical compounds. In various non-limiting examples, one or more sulfated pillararomatics are used to chelate one or more neuromuscular blockers (such as, for example, rocuronium (rocuronium), tubocurarine (tubocurarine), atracurium (atracurium), (cis) atracurium besylate, mevalonium (mivacurium), gallamine (gallamine), pancuronium (pancuronium), vecuronium (vecuronium), and rapaconium (rapacuuronium), among others); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (e.g., ketamine (or the like)), short-acting anesthetics (e.g., etomidate (or the like)), or the like); one or more agents (such as, for example, a drug (e.g., an anticoagulant, such as, for example, hexadimethrine) and the like) Drugs of abuse (e.g., methamphetamine (methamphetamine), cocaine (cocaine), fentanyl (fentanyl), carfentanil (carfentanil), etc.); one or more insecticides (such as, for example, paraquat (paraquat), diquat (diquat), organochlorines (e.g., DDT, aldrin (aldrin), etc.), neonicotinoids (e.g., permethrin, etc.), organophosphates (e.g., malathion (malathion), glyphosate (glyphosate), etc.), pyrethroids, triazines (e.g., atrazine, etc.); one or more dyes (such as, for example, methylene blue, nile red, crystal violet, thioflavin T, thiazole orange, proflavine, acridine orange, methylene violet, azure a, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27, etc.), coumarin, congo red, etc.); one or more malodorous compounds (such as, for example, low molecular weight thiols (e.g., C) ₁ -C ₄ Mercaptans), low molecular weight amines (e.g., triethylamine, putrescein, cadaverine, etc.); or one or more chemical warfare agents such as, for example, nitrogen and sulfur mustards (e.g., bis (2-chloroethyl) ethylamine, bis (2-chloroethyl) methylamine, tris (2-chloroethyl) amine, bis (2-chloroethyl) sulfide, bis (2-chloroethylthioethyl) ether, and the like) (bis (2-chloroethylthioethyl) ether), nerve agents (such as, for example, those from the G, GV and V series of nerve agents (e.g., tabun (tabun), sarin (sarin), soman (soman), cyclosalin (cyclosporine), 2- (dimethylamino) ethyl N, N-dimethylfluoronate (GV), november (novichagent), VE, VG, phosphoramide, VM, VX, and the like), or combinations thereof.

Drawings

For a fuller understanding of the nature and objects of the present disclosure, reference should be made to the following detailed description taken together with the accompanying figures.

Figure 1 shows an example of a host (sulfated pillar arene).

Fig. 2 shows an example of a cationic guest.

Figure 3 shows an example of a drug of abuse.

Figure 4 shows an example of a neuromuscular blocking agent.

Fig. 5 shows binding constants of complexes of an exemplary host and cationic guest.

Fig. 6 shows binding constants of complexes of exemplary hosts with drugs of abuse.

Figure 7 shows binding constants for complexes of exemplary subjects and neuromuscular blockers.

FIG. 8 shows what is recorded for ¹ H NMR Spectroscopy (500MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS, b) methamphetamine, c) P6]An equimolar mixture of AS and methamphetamine (0.5 mM), and d) methamphetamine (1 mM) and P [6]]AS (0.5 mM) 2.

FIG. 9 shows what is recorded for ¹ H NMR Spectroscopy (500MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[6]AS, b) Motor 2, c) rocuronium bromide, d) P [6]]An equimolar mixture of AS and rocuronium bromide, e) an equimolar mixture of Motor 2 and rocuronium bromide, f) Motor 2 and rocuronium bromide followed by addition of P [6]Mixtures of AS g) P6]AS and rocuronium bromide were then added to the mixture of Motor 2.

FIG. 10 shows the crystal structure of P [6] AS.

FIG. 11 shows a) CB [ n ]]And the structure of M2. b) Column [ n ]]MaxQ(P[5]AS–P[7]AS) and P [5]]Preparation of ACS and WP [ n ]]The structure of (1). Conditions are as follows: a) Py. SO ₃ Pyridine, 90 ℃; b) Propane sultone, naOH, acetone, 8%.

FIG. 12 shows the recorded solutions for ¹ H NMR Spectroscopy (600MHz, D) ₂ O，298K)：a)P[6]AS (1 mM), b) guest 25 (1 mM), c) P [6]]A mixture of AS (1 mM) and guest 25 (1 mM); d) P6]Mixture of AS (1 mM) and guest 25 (2 mM).

FIG. 13 shows the X-ray crystal structure of P [6] AS and P [5] ACS. a) P [6] AS in the unit cell is an oblique stereoview of one molecule (cross-oriented stereo). A view of the stacking of P [6] AS in the crystal along the b) z-axis and c) y-axis. d) P [5] in the unit cell is an oblique perspective view of one molecule of ACS.

FIG. 14 shows a) P [6] from 20 (1 mM) pair wells in a syringe]DP vs time for titrations of mixtures of AS (100. Mu.M) and 17 (500. Mu.M).b) Δ H relative to P [6]]A plot of the AS to 20 molar ratio; the solid line represents the best fit of data to the competitive binding model implemented in the PEAQ-ITC data analysis software, where K _a ＝(1.20±0.06)×10 ¹¹ M ^-1 And Δ H = -17.1. + -. 0.033kcal mol ^-1 。

FIG. 15 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, D) ₂ O，RT)：a)P[6]AS (1 mM), b) M2 (0.5 mM), c) rocuronium bromide (0.5 mM), d) P [6]AS rocuronium bromide (0.5 mM), e) M2 rocuronium bromide (0.5 mM), and f) from a reaction with 1 equivalent of P [6]]Part e of the solution after AS treatment. For M2, P [6]]Proton labels for AS and rocuronium bromide are given in fig. 11 and fig. 4.

FIG. 16 shows the data for P [5]]Recorded by ACS ¹ H NMR Spectroscopy (400MHz, D) ₂ O，RT)。

FIG. 17 shows the data for P [5]]Recorded by ACS ¹³ C NMR spectroscopy (150MHz, D) ₂ O, etOH as internal reference, RT).

FIG. 18 shows the data for P [5]]AS recorded ¹ H NMR Spectroscopy (600MHz, D) ₂ O，RT)。

FIG. 19 shows the data for P [5]]AS recorded ¹³ C NMR Spectroscopy (150MHz, D ₂ O, etOH as internal reference, RT).

FIG. 20 shows a graph for P [6]]AS recorded ¹ H NMR Spectroscopy (600MHz, D) ₂ O，RT)。

FIG. 21 shows a graph for P [6]]AS recorded ¹³ C NMR Spectroscopy (150MHz, D ₂ O and CD ₃ OD 10:1，RT)。

FIG. 22 shows the data for P [7]]AS recorded ¹ H NMR Spectroscopy (600MHz, D) ₂ O，RT)。

FIG. 23 shows a graph for P [7]]AS recorded ¹³ C NMR Spectroscopy (150MHz, D ₂ O, dioxane as external reference, RT).

FIG. 24 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[5]ACS，b)17，c)P[5]An equimolar mixture of ACS and 17 (1 mM), and d) 17 (2 mM) and P [5]]2 of ACS (1 mM)And (3) mixing.

FIG. 25 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]ACS，b)21，c)P[5]An equimolar mixture of ACS and 21 (1 mM), and d) 21 (2 mM) and P [5]]2 of ACS (1 mM).

FIG. 26 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS，b)23，c)P[5]An equimolar mixture of AS and 23 (1 mM), and d) 23 (2 mM) and P [5]]2.

FIG. 27 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS，b)21，c)P[5]An equimolar mixture of AS and 21 (1 mM), and d) 21 (2 mM) and P [5]]2.

FIG. 28 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS，b)22，c)P[5]Equimolar mixture of AS and 22 (1 mM) and d) 22 (2 mM) and P [5]]2]3]AS (1 mM) 4.

FIG. 29 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS，b)12，c)P[5]An equimolar mixture of AS and 12 (1 mM), and d) 12 (2 mM) and P [5]]2]3]AS (1 mM) 4.

FIG. 30 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[5]AS，b)25，c)P[5]An equimolar mixture of AS and 25 (0.5 mM), d) 25 (1 mM) and P [5]]2]3-mixture of AS (0.5 mM), and f) 25 (2 mM) and P [5]]AS (0.5 mM) of 4.

FIG. 31 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[5]AS，b)26，c)P[5]ASAnd 26 (0.5 mM), d) 26 (1 mM) and P [5]]2-1 mixture of AS (0.5 mM), and e) 26 (1.5 mM) and P [5]]3 of AS (0.5 mM).

FIG. 32 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS，b)23，c)P[6]An equimolar mixture of AS and 23 (1 mM), and d) 23 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 33 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[6]AS，b)17，c)P[6]An equimolar mixture of AS and 17 (1 mM), and d) 17 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 34 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS，b)24，c)P[6]An equimolar mixture of AS and 24 (1 mM), and d) 24 (2 mM) and P [6]]2.

FIG. 35 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS，b)11，c)P[6]An equimolar mixture of AS and 11 (1 mM), and d) 11 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 36 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[6]AS，b)12，c)P[6]An equimolar mixture of AS and 12 (1 mM), and d) 12 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 37 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[6]AS，b)21，c)P[6]An equimolar mixture of AS and 21 (1 mM), and d) 21 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 38 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS，b)22，c)P[6]An equimolar mixture of AS and 22 (1 mM), and d) 22 (2 mM) and P [6]]2 of AS (1 mM).

FIG. 39 shows a table for each of the followingThe items being recorded ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS，b)26，c)P[6]An equimolar mixture of AS and 26 (0.5 mM), and d) 26 (1 mM) and P [6]]AS (0.5 mM) 2.

FIG. 40 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS，b)11，c)P[7]An equimolar mixture of AS and 11 (0.5 mM), and d) 11 (1 mM) and P [7]]AS (0.5 mM) 2.

FIG. 41 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS，b)17，c)P[7]An equimolar mixture of AS and 17 (0.5 mM), and d) 17 (1 mM) and P [7]AS (0.5 mM) 2.

FIG. 42 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS，b)23，c)P[7]An equimolar mixture of AS and 23 (0.5 mM), and d) 23 (1 mM) and P [7]2 mixture of AS (0.5 mM).

FIG. 43 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[7]AS，b)21，c)P[7]An equimolar mixture of AS and 21 (0.5 mM), and d) 21 (1 mM) and P [7]2 mixture of AS (0.5 mM).

FIG. 44 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[7]AS，b)22，c)P[7]An equimolar mixture of AS and 22 (0.5 mM), and d) 22 (1 mM) and P [7]AS (0.5 mM) 2.

FIG. 45 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[5]AS, b) acetylcholine, c) P5]An equimolar mixture of AS and acetylcholine (0.5 mM), and d) acetylcholine (1 mM) and P [5]]AS (0.5 mM) 2.

FIG. 46 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS, b) rocuronium bromide, c) P5]AS and LuoAn equimolar mixture of Cocuronium bromide (0.5 mM), d) rocuronium bromide (1 mM) and P [5]]AS (0.5 mM) 2]3 of AS (0.5 mM).

FIG. 47 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS, b) vecuronium bromide, c) P [5]]Equimolar mixture of AS and vecuronium bromide (0.5 mM), d) vecuronium bromide (1 mM) and P [5 mM%]AS (0.5 mM) 2]3 of AS (0.5 mM).

FIG. 48 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[5]AS, b) pancuronium bromide, c) P [5]Equimolar mixture of AS and pancuronium bromide (0.5 mM), d) pancuronium bromide (1 mM) and P [ 5mM ]]AS (0.5 mM) 2]3 of AS (0.5 mM).

FIG. 49 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS, b) vecuronium bromide, c) P [6]]An equimolar mixture of AS and vecuronium bromide (0.5 mM), and d) vecuronium bromide (1 mM) and P [6]]AS (0.5 mM) 2.

FIG. 50 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS, b) acetylcholine, c) P6]An equimolar mixture of AS and acetylcholine (0.5 mM), and d) acetylcholine (1 mM) and P [6]]2 mixture of AS (0.5 mM).

FIG. 51 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[6]AS, b) rocuronium bromide, c) P [6]]An equimolar mixture of AS and rocuronium bromide (0.5 mM), and d) rocuronium bromide (1 mM) and P [6]]2 mixture of AS (0.5 mM).

FIG. 52 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[6]AS, b) pancuronium bromide, c) P [6]]An equimolar mixture of AS and pancuronium bromide (0.5 mM), and d) pancuronium bromide (1 mM) and P [6]]2A compound (I) is provided.

FIG. 53 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS, b) vecuronium bromide, c) P7]An equimolar mixture of AS and vecuronium bromide (0.5 mM), and d) vecuronium bromide (1 mM) and P [ 7%]AS (0.5 mM) 2.

FIG. 54 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS, b) rocuronium bromide, c) P7]An equimolar mixture of AS and rocuronium bromide (0.5 mM), and d) rocuronium bromide (1 mM) and P [7]]AS (0.5 mM) 2.

FIG. 55 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate-buffered D) ₂ O)：a)P[7]AS, b) pancuronium bromide, c) P [7]]An equimolar mixture of AS and pancuronium bromide (0.5 mM), and d) pancuronium bromide (1 mM) and P [7]]AS (0.5 mM) 2.

FIG. 56 shows what is recorded for ¹ H NMR Spectroscopy (600MHz, RT,20mM phosphate buffered D ₂ O)：a)P[7]AS, b) cis atracurium, c) cis atracurium (0.125 mM) and P [7]]1]1]An equimolar mixture of AS and cisatracurium (0.5 mM).

FIG. 57 shows the case for the subject P [5]]Recorded AS dilutions (20.0-0.1 mM) of AS ¹ H NMR Spectroscopy (600MHz, D) ₂ O, 298K). Body P [5]]AS is weakly self-associated in water, AS evidenced by the high field chemical shift variation of the aromatic region at 7.33-7.40ppm protons.

FIG. 58 shows P [5]]AS vs [ P [5]]AS]A graph of chemical shifts of (a). The solid line represents the best non-linear fit of the data to a 2-fold self-association model, where K _a ＝19.7M ^-1 。

FIG. 59 shows for the body P [6]]Dilutions (20.0-0.1 mM) of AS recorded ¹ H NMR Spectroscopy (600MHz, D) ₂ O, 298K). Body P [6]]AS is weakly self-associated in water, which is due to the high field chemistry of the aromatic region at 7.34-7.38ppm protonsThe shift change was confirmed.

FIG. 60 shows P [6]]AS vs [ P [6]]AS]A graph of chemical shifts of (a). The solid line represents the best non-linear fit of the data to the 2-fold self-association model, where K _a ＝16.2M ^-1 。

FIG. 61 shows the equation for Rim-P [5]]AS recorded ¹ H NMR spectrum (400MHz, D) ₂ O)。

FIG. 62 shows a graph for Rim-P [5]]AS recorded ¹³ C NMR Spectroscopy (150MHz, D ₂ O, etOH as internal reference).

Fig. 63 shows HepG2 toxicology assays. AK (a, C) and MTS assays (B, D) were performed after the cells had been incubated with the indicated containers for 24 h. UT = untreated control; stx = staurosporine (staurosporine).

Figure 64 shows HEK293 toxicology assays. AK (a, C) and MTS assays (B, D) were performed after the cells had been incubated with the indicated containers for 24 h. UT = untreated control; stx = staurosporine.

FIG. 65 shows the MTD study performed on P [6] AS. Female Swiss Webster mice (n =5 per group) were dosed with different concentrations of P [6] as or Phosphate Buffered Saline (PBS) via the tail vein on day 0 and day 2 (indicated by). Normalized mean weight change for each study group is indicated. Error bars represent SEM.

FIG. 66 shows the reversal of methamphetamine-induced excitatory autonomic activity (hypercommenion) by P [6] AS in vivo. Mean autonomic activity counts for male Swiss Webster mice (n =8; mean body weight (g) ± SD:39 ± 2.203) were plotted as a function of treatment. The treatment sequence was cancelled over several days (counter balanced) and mice received treatment only once per day. In a six consecutive day test, mice each received PBS (PBS; 0.01M 0.2mL, infused), P [6] AS only (P [6] AS 4mM, 0.178mL, infused), methamphetamine only (METH; 0.5mg/kg;0.022mL, infused), a premixed solution of P [6] AS and methamphetamine (premixed;. About.7 1P 6] AS. Bars represent average autonomic activity counts. Error bars represent standard error of the mean (SEM). Dots represent counts per mouse (n = 8). The presented p-values are only used for post hoc comparisons of significant (p < 0.05) Tukey-corrections.

Figure 67 shows the effect of reversing methamphetamine-induced excitatory autonomic activity observed in vivo after a 5 minute delay between treatment with methamphetamine and P [6] as administration. On

days

7 and 8, mice (n = 8) received methamphetamine followed by a 0.01M PBS infusion (REV-C; 0.022mL Meth,0.2mL PBS, infused) administered 5 minutes later, or methamphetamine followed by P [6] AS administered in a counteracting fashion (REV-5. Administration of P [6] as 5 minutes after methamphetamine exposure reduced excitatory autonomic activity (paired t-test, t (7) =2.757, P = 0.0282). Bars represent average autonomic activity counts. Error bars represent standard error of the mean (SEM). Dots represent counts per mouse (n = 8).

Figure 68 shows the chemical structures of MDMA, methoprene (mephedron), heroin and methamphetamine.

FIG. 69 shows a) MDMA from use in syringes (1.00 mM) at 20mM NaH ₂ PO ₄ Buffer (pH7.4) for the molecular container P6 in the pool]DP vs time for titrations of AS (100. Mu.M) and 1, 3-propanediammonium chloride (150. Mu.M); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(3.92±0.20)×10 ⁷ M ^-1 ，ΔH＝-13.3±0.1kcal/mol，-TΔS＝2.95kcal/mol)。

FIG. 70 shows a) Methoxylin (100. Mu.M) in 20mM NaH from the use of a syringe ₂ PO ₄ Buffer (pH 7.4) to the molecular Container P6 in the cell]DP vs time for titration by AS (10 μ M); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (Ka = (1.91 ± 0.19) × 10) of the data to the 1 ⁷ M ^-1 ，ΔH＝-12.6±0.11kcal/mol，-TΔS＝2.68kcal/mol)。

FIG. 71 shows a) heroin (100. Mu.M) in 20mM NaH from use of syringe ₂ PO ₄ Buffer (pH7.4) for the molecular container P6 in the pool]DP vs time for titration by AS (10 μ M); b) Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(5.78±0.02)×10 ⁵ M ^-1 ，ΔH＝-11.9±0.11kcal/mol，-TΔS＝4.01kcal/mol)。

FIG. 72 shows a) a sample from a molecular container P [6]]AS (100. Mu.M) and 17 (500. Mu.M) were treated with rocuronium bromide (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(6.33±0.08)×10 ¹¹ M ^-1 ，ΔH＝-24.9±0.177kcal/mol，-TΔS＝8.79kcal/mol)。

FIG. 73 shows a) the output from the molecular reservoir P [6]]AS (100. Mu.M) and 17 (500. Mu.M) were prepared using vecuronium bromide (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(1.00±0.34)×10 ¹² M ^-1 ，ΔH＝-18.5±0.095kcal/mol，-TΔS＝2.10kcal/mol)。

FIG. 74 shows a) the sample from the molecular container P [6]]AS (100. Mu.M) and 17 (150. Mu.M) were treated with pancuronium bromide (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(7.35±1.23)×10 ¹⁰ M ^-1 ，ΔH＝-16.5±0.216kcal/mol，-TΔS＝1.63kcal/mol)。

FIG. 75 shows a) the sample from the molecular container P [7]]AS (10. Mu.M) and using cis atracurium (0.05 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the data in combination with 1Best nonlinear fit (K) of the model _a ＝(1.52±0.12)×10 ⁷ M ^-1 ，ΔH＝-35.0±0.396kcal/mol，-TΔS＝25.2kcal/mol)。

FIG. 76 shows a) the sample from the molecular container P [6]]AS (100. Mu.M) and propane-1, 3-diammonium (150. Mu.M) were treated with methamphetamine (1.00 mM) in 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(9.90±0.39)×10 ⁶ M ^-1 ，ΔH＝-10.4±0.040kcal/mol，-TΔS＝0.833kcal/mol)。

FIG. 77 shows a) the sample from the molecular container P [6]]AS (100. Mu.M) and propane-1, 3-diammonium (1.00 mM) with fentanyl (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(1.02±0.03)×10 ⁸ M ^-1 ，ΔH＝-15.0±0.052kcal/mol，-TΔS＝4.02kcal/mol)。

FIG. 78 shows a) the sample from the molecular container P [6]]AS (100. Mu.M) and with cocaine (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(1.92±0.06)×10 ⁶ M ^-1 ，ΔH＝-15.6±0.047kcal/mol，-TΔS＝7.07kcal/mol)。

FIG. 79 shows a) the output from the molecular container P [6]]AS (100. Mu.M) and using ketamine (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(1.52±0.25)×10 ⁵ M ^-1 ，ΔH＝-22.0±1.02kcal/mol，-TΔS＝14.9kcal/mol)。

FIG. 80 shows a) the sample from a molecular container P [6]]AS (100. Mu.M) and propane-1, 3-diammonium (150. Mu.M) were treated with Phencyclidine (1.00 mM) in 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the competitive binding model _a ＝(5.85±0.47)×10 ⁷ M ^-1 ，ΔH＝-12.4±0.076kcal/mol，-TΔS＝1.84kcal/mol)。

FIG. 81 shows a) the sample from the molecular container P [6]]AS (100. Mu.M) and morphine (1.00 mM) in 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(1.36±0.07)×10 ⁶ M ^-1 ，ΔH＝-12.9±0.073kcal/mol，-TΔS＝4.49kcal/mol)。

FIG. 82 shows a) the output from the molecular container P [6]]AS (100. Mu.M) and using hydromorphone (1.00 mM) at 20mM NaH ₂ PO ₄ Graph of DP versus time for titrations in buffer (pH 7.4); b) Graph of Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(1.31±0.04)×10 ⁶ M ^-1 ，ΔH＝-11.9±0.042kcal/mol，-TΔS＝3.55kcal/mol)。

FIG. 83 shows a) a sample from a molecular container P [6]]AS (100. Mu.M) and using oxycodone (1.00 mM) at 20mM NaH ₂ PO ₄ DP against time plot for titrations performed in buffer (pH 7.4); b) Δ H as a function of molar ratio. The solid line represents the best non-linear fit (K) of the data to the 1 _a ＝(9.52±0.36)×10 ⁴ M ^-1 ，ΔH＝-8.62±0.097kcal/mol，-TΔS＝1.83kcal/mol)。

Detailed Description

While the claimed subject matter will be described in terms of certain examples, other examples, including examples that do not provide all of the benefits and features set forth herein, are also within the scope of this disclosure. Various structural, logical, and process step changes may be made without departing from the scope of the disclosure.

Ranges of values are disclosed herein. These ranges specify a lower limit and an upper limit. Unless otherwise indicated, these ranges include the lower limit, the upper limit, and all values between the lower limit and the upper limit, including but not limited to all values to the minimum (whether lower or upper limit).

As used herein, unless otherwise specified, the term "group" refers to a chemical entity that is monovalent (i.e., has one terminus that can be covalently bonded to other chemical species), divalent, or multivalent (i.e., has two or more termini that can be covalently bonded to other chemical species). The term "group" also includes free radicals (e.g., monovalent and multivalent, such as, for example, divalent, trivalent, etc. radicals). Illustrative examples of groups include:

as used herein, unless otherwise indicated, the term "aryl group" means C ₅ To C ₁₈ (including all integer numbers of carbons and ranges of carbons therebetween) aromatic or partially aromatic carbocyclic groups (e.g. C) ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ 、C ₁₂ 、C ₁₃ 、C ₁₄ 、C ₁₅ 、C ₁₆ 、C ₁₇ And C ₁₈ ). The aryl group may also be referred to as an aromatic group. Aryl groups may include polyaryl groups such as, for example, fused ring or biaryl groups. An aryl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and-I), azide groups, aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, hydroxyl groups, alkoxide groups (alkoxide groups), carboxylate groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, and the like, and combinations thereof. The substituent may be or further include a sulfonate group or a sulfate group. Examples of aryl groups include, but are not limited to, phenyl groupsBiaryl groups (e.g., biphenyl groups, etc.) and fused ring groups (e.g., naphthyl groups, anthracene groups, pyrenyl groups, etc.), which may be unsubstituted or substituted.

As used herein, unless otherwise indicated, the term "heteroaryl group" refers to a C containing one or two aromatic rings ₁ To C ₁₈ Monocyclic, polycyclic or bicyclic group (e.g., aryl group) which one or both aromatic rings contain at least one heteroatom (e.g., nitrogen, oxygen, sulfur, etc.) in the aromatic ring, including all integer carbon numbers and ranges of carbon numbers therebetween (e.g., C) ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ 、C ₁₂ 、C ₁₃ 、C ₁₄ 、C ₁₅ 、C ₁₆ 、C ₁₇ And C ₁₈ ). Heteroaryl groups may be substituted or unsubstituted. Examples of heteroaryl groups include, but are not limited to, benzofuranyl groups, thienyl groups, furanyl groups, pyridyl groups, pyrimidinyl groups, oxazolyl groups, quinolinyl (quinolyl) groups, thienyl (thiophenyl) groups, isoquinolinyl groups, indolyl groups, triazinyl groups, triazolyl groups, isothiazolyl groups, isoxazolyl groups, imidazolyl groups, benzothiazolyl groups, pyrazinyl groups, pyrimidinyl groups, thiazolyl groups, thiadiazolyl groups, and the like. Examples of substituents include, but are not limited to, halogens (-F, -Cl, -Br, and-I), aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, alkoxide groups, amine groups, carboxylate groups, carboxylic acids, ether groups, alcohol groups, alkyne groups (e.g., ethynyl groups, etc.), and the like, and combinations thereof.

As used herein, unless otherwise specified, the term "aliphatic" refers to a branched or unbranched hydrocarbon group optionally containing one or more degrees of unsaturation. The unsaturation may be from, but is not limited to, a cyclic aliphatic group. For example, the aliphatic group/moiety is C ₁ To C ₄₀ Aliphatic group, including all integer numbers of carbons and carbon number ranges therebetween: (For example, C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ 、C ₁₂ 、C ₁₃ 、C ₁₄ 、C ₁₅ 、C ₁₆ 、C ₁₇ 、C ₁₈ 、C ₁₉ 、C ₂₀ 、C ₂₁ 、C ₂₂ 、C ₂₃ 、C ₂₄ 、C ₂₅ 、C ₂₆ 、C ₂₇ 、C ₂₈ 、C ₂₉ 、C ₃₀ 、C ₃₁ 、C ₃₂ 、C ₃₃ 、C ₃₄ 、C ₃₅ 、C ₃₆ 、C ₃₇ 、C ₃₈ 、C ₃₉ And C ₄₀ ). Aliphatic groups include, but are not limited to, alkyl groups, alkenyl groups, and alkynyl groups. An aliphatic group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and-I), azide groups, aliphatic groups (e.g., alkyl groups, alkene groups, alkyne groups, and the like), aryl groups, hydroxyl groups, alkoxide groups, carboxylate groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, and the like, and combinations thereof.

As used herein, unless otherwise specified, the term "alkyl group" refers to a branched or unbranched saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, n-propyl groups, and isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, tert-butyl groups, and the like. For example, the alkyl group may be C ₁ To C ₁₂ This includes all integer carbon numbers and carbon number ranges therebetween (e.g., C) ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ And C ₁₂ ). An alkyl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogens (-F, -Cl, -Br, and-I), azide groups, aliphatic groupsGroups (e.g., alkyl groups, alkene groups, alkyne groups, etc.), aryl groups, hydroxyl groups, alkoxide groups (-OR, where R is an alkyl group), carboxylate groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, and the like, and combinations thereof.

The present disclosure provides sulfated column arenes. The present disclosure also provides a method of making sulfated pillared aromatics and uses thereof.

In the present disclosure, it has been shown, for example, that locating anionic solubilizing groups at the edges of the pillar arene cavity significantly enhances their binding affinity for cationic targets in water, and thereby their ability to act as chelators for a wide variety of applications.

In one aspect, the present disclosure provides compounds. The compound is a sulfated pillar arene. Sulfated columnar arenes comprise a macrocyclic core comprising a plurality of aryl groups, wherein adjacent aryl groups are linked via an alkyl linkage (e.g., -CH) ₂ A group) is covalently linked (e.g. bonded). The alkyl linking group is para to the aryl group (e.g., a 1, 4-phenyl linkage). The bonds may be on different phenyl rings of the aryl group and, if the different phenyl rings overlap, correspond to para bonds. In many instances, one or more or all of the adjacent aryl groups are not covalently linked through an alkyl linking group at a meta position on the aryl group (e.g., a 1, 3-phenyl linkage (in the case where the linkages are on different phenyl rings or aryl groups, these linkages do not correspond to meta linkages if the different phenyl rings overlap)). Non-limiting examples of sulfated pillar arenes are provided herein. Provided herein are non-limiting examples of methods of making sulfated pillar aromatic hydrocarbons.

In various examples, the sulfated pillar arene has the following structure:

wherein Ar is para-substituted to an adjacent methylene group (e.g., a 1, 4-phenyl group bond)An aryl group attached (e.g., covalently bonded), which can be part of a larger aryl group; each R is independently selected from-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (TRIS), -OS (O) ₂ OH, non-sulfate anionic groups (such as, for example, sulfonate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m S(O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (TRIS)/-O (CH) ₂ ) _m S(O) ₂ OH, wherein m is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), -C ₆ H ₅ S(O) ₂ OH, etc., and such groups in which the terminal O is removed), carbonate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m C(O)O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ² ⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS)/-O (CH) ₂ ) _m C (O) OH, wherein n is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), and the like, such as, for example, -OCH ₂ CO ₂ ^– M ⁺ /-OCH ₂ CO ₂ H groups and the like and such groups in which the terminal O is removed), phosphonate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m P(O)(OH) ₂ ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (TRIS)/-O (CH) ₂ ) _m P(O)(OH) ₂ Wherein m is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), etc., such as, for example, -O (CH) ₂ ) ₂ P(O)(OH) ₂ Etc. and such groups in which the terminal O is removed), a phosphate group-OP (O) (OH) ₂ Etc.), substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, O-alkyl groups (including alkyl groups), azide groups, -H, substituted or unsubstituted alkyl groups, halogens (e.g., -Br, -F, -I, -Cl), amide groups, cyano groups, substituted or unsubstituted sulfur-containing aliphatic groups (e.g., -S-alkyl and polythioethers, etc.), nitro groups, amino groups, substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups including secondary and/or tertiary amines, etc.), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, carbamate groups, imine groups, aldehyde groups, -SO groups ₃ H group, -SO ₃ Na group, -OSO ₂ F group, -OSO ₂ CF ₃ Group, -OSO ₂ OR '"groups (wherein R'" is a substituted OR unsubstituted aryl group OR a substituted OR unsubstituted alkyl group), and the like, and combinations thereof; x is 0, 1,2 or 3; and y is independently at each occurrence 0, 1,2,3, or 4, provided that at least one y is 1 and at least one R group is-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ ) or-OS (O) ₂ OH, or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer or mixture thereof. One or more R groups may be located anywhere on the aryl group. In the case of aryl groups having multiple R groups, a single R group may be that of the aryl groupAny combination of locations. In various examples, all aryl groups contain an R group that is independently-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic forms of ethylenediamine, piperazine and TRIS (TRIS) or-OS (O) ₂ And (5) OH. In various examples, at least one aryl group does not include an R group, which R group is-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) or-OS (O) ₂ And (5) OH. In various embodiments, the aryl group can be further substituted with various substituents such as, for example, -H, alkyl groups, aliphatic groups, polyethylene glycol groups, and the like, or combinations thereof.

In certain embodiments, M ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine, or TRIS (hydroxymethyl) aminomethane (TRIS).

In certain embodiments, M ⁺ Is Na ⁺ 、K ⁺ And H ₄ N ⁺ . In certain embodiments, M ⁺ Is Na ⁺ 。

The sulfated pillar arene may comprise various aryl groups. The aryl groups may all be the same or at least two of the aryl groups may be different. Non-limiting examples of aryl groups are independently selected at each occurrence from phenyl groups, fused ring groups (e.g.Naphthyl groups, anthracenyl groups, phenanthrenyl groups, tetracenyl groups, pentacenyl groups, and the like), biaryl groups (e.g., biphenyl groups, and the like), terphenyl groups, and the like, as well as combinations thereof. For the avoidance of doubt, unless otherwise stated, when the phenyl group is not part of a larger aryl group, it is C ₆ H ₄ A group. The phenyl group may be referred to as a phenylene group.

Adjacent aryl groups may be bonded through various linkages. These bonds are para-attached phenyl group bonds. In various examples, at least a portion or all of these bonds are 1, 4-phenyl group bonds. Non-limiting examples of para-linked phenyl group linkages include:

and combinations thereof. These are illustrative examples. Other para-linked phenyl group linkages are within the scope of the present disclosure. In many examples, the key is not an interval key.

The aryl group may comprise one or more phenyl groups. In a number of non-limiting examples, at least two, at least three, or at least 4, or all of the one or more phenyl groups in the one or more aryl groups comprised by the cyclic core of the compound have at least 1 or at least 2R groups independently selected from-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) and-OS (O) ₂ And (5) OH. All aryl groups (one or more or all of which may be phenyl groups) may beTo contain a sulfate group-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) or-OS (O) ₂ And (5) OH. In various examples, at least one aryl group (which can be a phenyl group) does not comprise a sulfate group (e.g., -OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) or-OS (O) ₂ OH)。

In various examples, the sulfated pillar arene has the following structure:

in various examples, each R is-OS (O) ₂ O–M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) and-OS (O) ₂ OH。

In various examples, the sulfated pillar arene has the following structure:

in various examples, 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently-OS (O) ₂ O ^– M ⁺ Group (wherein M ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) or-OS (O) ₂ An OH group.

The composition may comprise one or more sulfated pillar arenes, one or more pharmaceutical carriers, and optionally one or more pharmaceutical agents. The compositions described herein may have one or more pharmaceutically acceptable carriers. Suitable pharmaceutically acceptable carriers are known in the art. Some non-limiting examples of pharmaceutically acceptable carriers can be found in: remington The Science and Practice of Pharmacy (2005), 21st edition, philadelphia, PA. Lippincott Williams &Wilkin. In many instances, the drug carrier is pure water or a buffer, such as PBS buffer or the like.

Compositions comprising one or more sulfated columnar arenes (which can form guest-host complexes) in combination with one or more pharmaceutical agents can be prepared using any suitable technique, at any point in time prior to use of the composition. The compound-agent complex may be formed, for example, by mixing the compound and agent in a suitable solvent. It is desirable that the compound and the pharmaceutical agent be soluble in the solvent such that the compound and the pharmaceutical agent form a non-covalent complex. Any suitable solvent may be used. In certain examples, the solvent is an aqueous solution, which includes, but is not necessarily limited to, water and various buffers (e.g., PBS buffer, etc.). Non-aqueous solvents (e.g., meOH, etOH, and other organic solvents, and combinations thereof) can also be used, which are then removed, and if desired, the composition can be re-dissolved in aqueous solution for application. In general, a solution of one or more compounds may be provided at a known concentration, examples of which include, but are not limited to, 0.1 to 90mM (inclusive and including all integers to the tenth decimal place therebetween), and an agent desired to enhance solubility is added to the solution. The one or more pharmaceutical agents may be provided, for example, in solid form. The combination may be shaken or stirred for a period of time and the amount of dissolved medicament monitored. If all of the added agent goes into solution, more agent can be added until some detectable portion thereof remains undissolved (e.g., a solid). The soluble compound-agent complex may then be separated and analyzed by any suitable technique, such as by recovering the centrifuged fraction and analyzing it by NMR to determine the concentration of the agent in solution. In various examples, the compound is provided in a composition comprising the drug in a ratio of at least 1 to 1 relative to the compound-agent stoichiometry (e.g., a ratio of pillar arene to drug). In various examples, the ratio of the pillararene (e.g., pillararene sulfate) to drug is from 1 to 1, including all ratio values and ranges therebetween (e.g., 100, 1,2, 1,3, 1,4 or 1.

The composition may be prepared at the patient's bedside or by the pharmaceutical manufacturer. In the latter case, the composition may be provided in any suitable container, such as, for example, a sealed sterile vial, ampoule, or the like, and may be further packaged to include instructions for use by a pharmacist, physician, other healthcare provider, or the like (the combination of which may be referred to as a kit). The composition may be provided in liquid form or in lyophilized or powder form (which may be reconstituted at the time of preparation for use, if desired). In particular, the compositions may be provided in combination with any suitable delivery form or vehicle, examples of which include, but are not limited to, liquids, caplets, capsules, tablets, inhalants or aerosols, and the like. The delivery device may comprise components that facilitate release of the agent over a particular period and/or interval and may comprise compositions that enhance drug delivery, such as nanoparticle, microsphere, or liposome formulations, a wide variety of which are known in the art and are commercially available. In addition, each composition described herein may comprise one or more pharmaceutical agents.

The compositions of the present disclosure may comprise more than one agent. Likewise, the compositions may comprise different host-guest complexes. For example, a first composition comprising one or more sulfated pillar arenes and a first agent can be prepared separately from a composition comprising the same compound and a second agent, and such preparations can be mixed to provide a dual (or more) way of achieving the desired prevention or treatment in an individual. Further, the compositions can be prepared using mixed formulations of any of the sulfated columnar aromatic compounds disclosed herein.

The solid substrate may comprise one or more sulfated pillar aromatic hydrocarbons disposed on (e.g., chemically bonded to) at least a portion of the surface of the substrate. At least a portion or all of the sulfated pillar arene may be chemically bonded to at least a portion of the surface by a covalent bond, a non-covalent bond, or a combination thereof. Methods of conjugating sulfated pillar arenes to solid surfaces are known in the art. In various examples, the sulfated pillar arene is conjugated to the surface via covalent and/or non-covalent bond forming reactions (including, but not limited to, amide bond formation, azide alkyne cycloaddition, gold thiol interactions, silanol condensation, and the like, and combinations thereof).

The solid substrate may comprise (or be) a variety of materials. In a number of non-limiting examples, the solid substrate includes or is silica (such as, for example, silica particles), polymer beads, polymer resins (such as, for example, polystyrene, polynipam, polyacrylic acid, metal nanoparticles (e.g., gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold, etc.), and the like, or combinations thereof.

In one aspect, the present disclosure provides the use of sulfated pillar arenes. Non-limiting examples of uses of sulfated pillarafins are provided herein, for example, non-limiting examples of uses of sulfated pillarafins are described in the statements and examples.

Sulfated pillar arenes can be used to chelate various materials, which can be chemical compounds. In various non-limiting examples, one or more sulfated pillararomatics are used to chelate one or more neuromuscular blocking agents (such as, for example, rocuronium bromide, tubocurarine, atracurium (cis) benzenesulfonate, mevinocurium, galantamine, pancuronium bromide, vecuronium bromide, and lapachylammonium, and the like); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (e.g., ketamine, etc.), short-acting anesthetics (e.g., etomidate, etc.); one or more pharmaceutical agents (such as, for example, drugs (e.g., anticoagulants such as, for example, hypromellose, and the like), drugs of abuse (e.g., methamphetamine, cocaine, fentanyl, carfentanil, PCP, MDMA, heroin, and the like); one or more insecticides (such as, for example, paraquat, diquat, organochlorines (e.g., DDT, aldrin, etc.), neonicotinoids (e.g., permethrin, etc.), organophosphates (e.g., malathion, glyphosate, etc.), pyrethroids, triazines (e.g., atrazine, etc.); one or more dyes (such as, for example, methylene blue, nile red, crystal violet, thioflavin T, thiazole orange, proflavine, acridine orange, methylene violet, azure a, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27, etc.), coumarin, congo red, etc.); one or more malodorous compounds (such as, for example, low molecular weight thiols (e.g., C) ₁ -C ₄ Thiols), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.)Etc.); or one or more chemical warfare agents (such as, for example, nitrogen and sulfur mustards (e.g., bis (2-chloroethyl) ethylamine, bis (2-chloroethyl) methylamine, tris (2-chloroethyl) amine, bis (2-chloroethyl) sulfide, bis (2-chloroethylthioethyl) ether, and the like), nerve agents (such as, for example, those from the G, GV and V series of nerve agents (e.g., tabun, sarin, soman, cyclosaline, 2- (dimethylamino) ethyl N, N-dimethylphosphamide-yl-fluoroacetate (GV), novigco, VE, VG, VM, VX, and the like); one or more hallucinogens (e.g., ergolines, lysergic acid diethylamide (LSD), silopic acid diamides, siloxibin (psilocybin), tryptamines (Tryptamines), dimethyltryptamine (DMT), phenethylamines (phenylethyylamines), mescaline (mescaline), mortalium (ayahuasca), dextromethorphan (dextromethorphan), etc.), one or more toxins (e.g., dioxins, perfluoroalkylsulfonates (PFAS), perfluorooctanoic acid (PFOA), decabromodiphenyl Ether (DECA), heavy metals (e.g., mercury), muscarine (muscaranine), tyramine, strychnene (strychnine), tetrodotoxin (tetrodotoxin), saxitoxin (saxitoxin), etc., cholesterol, deoxycholic acid, N-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine (1, 2,3, 6-tetrahydropyridine), etc., cholesterol, deoxycholic acid, N-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine, etc, phenylalanine, tyrosine, arginine, histamine); one or more metabolites (e.g., toxic metabolites such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4- (methylnitrosoamino) -1- (3-pyridyl) -1-butanone); or a combination thereof.

The material, which may be a chemical compound, may contain one or more cationic groups. In various examples, the material, which may be a chemical compound, contains one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

In various examples, a method for sequestering one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or the like, or a combination thereof, comprises contacting one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof, with one or more sulfated pillar arenes and/or one or more compositions, wherein the one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more sulfated pillar arenes, one or a combination thereof, is comprised of one or more compounds, one or a combination thereof.

One or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof may be present in an aqueous sample, in a solid sample (such as, for example, a soil sample), in a gaseous sample, and the like. An aqueous sample can be obtained (e.g., via extraction or other methods for isolating one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof) from a solid sample. The aqueous sample can be a wastewater sample (e.g., a municipal wastewater sample, an industrial wastewater sample, etc.), an industrial water sample (e.g., water used to manufacture a commercial product such as, for example, a reagent, a solvent, etc.), a municipal water sample, and the like.

The composition may comprise one or more pharmaceutically active agents. In various non-limiting examples, at least a portion (or all) of the one or more compounds have one or more pharmaceutically active agents disposed in a cavity of the one or more compounds. Without intending to be bound by any particular theory, it is believed that the complex (which may be referred to as a guest-host complex) is formed by, for example, one or more interactions (e.g., one or more non-covalent interactions formed therebetween, such as, for example, one or more non-covalent bonds) between the compound (which may be referred to as a host) and one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents (which may be one or more pharmaceutical agents with undesirable (e.g., low) water solubility), one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof (which may be referred to as one or more guests). Thus, a guest-host complex can be viewed as an organized chemical entity resulting from the association of one or more agents (guest (s)) and a host held together (e.g., by non-covalent intermolecular forces).

The composition may comprise various pharmaceutically active agents. Non-limiting examples of pharmaceutical agents include drugs. The one or more pharmaceutically active agents may have different water solubilities. The pharmaceutically active agent may have hydrophobic, hydrophilic or amphiphilic properties.

The complex may be removed from an aqueous sample, a solid sample, a gas sample, and the like. In various examples, one or more neuromuscular blocking agents, one or more anesthetics, one or more medicants, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are removed from an aqueous sample, a solid sample, a gaseous sample, or the like using a solid surface having one or more sulfated heteroarenes disposed thereon.

Sulfated pillar arenes can be used to chelate various materials in an individual. In various non-limiting examples, one or more neuromuscular blocking agents, one or more anesthetics, one or more medicants, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in the individual, and contacting comprises administering one or more compounds and/or one or more compositions to the individual.

The sulfated pillar arene may be used to reverse drug-induced neuromuscular blockade and/or anesthesia and/or the effect of one or more drugs, which may be drugs of abuse, in an individual.

In various non-limiting examples, a method for reversing drug-induced neuromuscular blockade and/or anesthesia and/or the effect of one or more agents (e.g., one or more drugs of abuse) in or on a subject includes administering one or more sulfated pillararenes and/or one or more compositions to a subject in need of reversing neuromuscular blockade and/or reversing anesthesia and/or reversing the effect of one or more agents (e.g., one or more drugs of abuse). The subject may need to reverse drug-induced neuromuscular blockade. The individual may need to reverse anesthesia. The individual may need to reverse drug-induced neuromuscular blockade and anesthesia. The subject may need to reverse the effects of one or more agents, such as, for example, one or more drugs (which may be one or more drugs of abuse). The individual may have been exposed to one or more drugs of abuse (e.g., carfentanil, etc.) from a terrorist attack.

The sulfated pillar arene compound may be used as a vessel for dissolving chemical compounds. Improving the solubility of a compound, for example, in an aqueous solution, is desirable for studying pharmaceutical compounds and for improving the bioavailability of the drug for purposes such as, for example, therapeutic and/or prophylactic purposes. For example, sulfated pillararomatics are used to enhance the stability of a drug in water, solid state, or both (e.g., reduce degradation, increase shelf life, etc.).

In certain examples, sulfated pillared arene compounds can be used to rescue promising drug candidates with undesirable solubility and bioavailability, and thus mitigate the depletion during drug development for anticancer agents and agents intended to treat other diseases. The container can be used for targeted delivery of a drug to a particular cell type, such as, for example, a tumor cell, or the like, to increase the effectiveness of an existing drug, reduce one or more toxic side effects thereof, or both.

In various examples, the composition includes one or more sulfated columnar arenes and one or more agents. Such compositions may be provided as pharmaceutical formulations as described herein.

It is important to emphasize that there is no particular limitation on the agent or agents that may be included in the composition comprising the sulfated pillar arene or agents and the agent or agents. In certain examples, the one or more agents in combination with the one or more sulfated columnar arenes are one or more agents that are poorly water soluble. In certain other examples, the one or more agents in combination with the one or more sulfated columnar arenes are water soluble one or more agents.

The solubility of any particular agent can be determined using any of a variety of techniques well known to those skilled in the art, if desired. Solubility can be determined at any pH (e.g., physiological pH) and/or at any desired temperature, if desired. Suitable temperatures include, but are not necessarily limited to, 4 ℃ to 70 ℃ (inclusive) and include all integer ℃ values therebetween.

With respect to poorly soluble or low solubility agents suitable for use in the present disclosure, such agents are considered to be those agents having a solubility in water or aqueous buffer of less than 100 μ M in a number of examples.

In a number of other examples, poorly soluble agents are considered to include compounds that are Biopharmaceutical Classification System (BCS) class 2 or class 4 drugs. BCS is well known to those skilled in the art and is based on the water solubility of drugs reported in readily available references, and for drugs administered orally, it includes a correlation with human intestinal membrane permeability (see, e.g., takagi et al, (2006) Molecular pharmaceuticals, vol.3, no.6, pp.631-643). The skilled artisan can readily identify a drug as a member of BCS class 2 or class 4 from published literature, or can test a drug with an unknown BCS or other solubility value to determine if it has characteristics consistent with any of these classifications, or is otherwise suitable for use in the present disclosure. In one example, the solubility is determined according to the parameters listed in this matrix:

solubility in water	The parts of solvent required for 1 part of solute	Solubility Range (mg/mL)
			Is very soluble in water	<1	≥1000
Is easy to dissolve	1 to 10	100-1000
			Soluble in water	10 to 30	33-100
Slightly soluble	30 to 100	10-33
			Slightly soluble	100 to 1000	1-10
Very slightly soluble	1000 to 10000	0.1-1
			Practically insoluble	≥10000	<0.1

Thus, for the purposes of this disclosure, a poorly soluble agent that may be combined with one or more sulfated columnar arenes may be any agent falling within the classes of sparingly soluble, very sparingly soluble, and practically insoluble in the matrices described above.

Again, it should be emphasized that there is no limitation to the agents that may be combined with one or more sulfated pillar arenes, other than being characterized as having low solubility in aqueous solutions. In this regard, at least one utilization of the present disclosure is the combination of one or more of a wide variety of different agents with one or more sulfated pillararomatics and the solubility of the one or more agents is increased as a result of combining these compounds with the one or more agents. In various examples, the types of agents suitable for solubilization include, but are not limited to, mitotic inhibitors (e.g., paclitaxel (taxol), a mitotic inhibitor for cancer chemotherapy, etc.); nitrogen mustard alkylating agents (e.g., melphalan (Melphalan), tradename Alkeran for chemotherapy, etc.); benzimidazoles (e.g., albendazole (Albendazole), marketed as Albenza, eskazole, zentel, and Andazol, for the treatment of a wide variety of helminth infections, etc.); an antagonist of an estrogen receptor (e.g., tamoxifen (Tamoxifen), which is an estrogen receptor antagonist when metabolized to its active form of hydroxytamoxife (hydroxyneoxamine), etc.) in breast tissue for the treatment of breast cancer; antihistamines (e.g., cinnarizine (Cinnarizine), marketed as Stugeron and sturonone, for controlling the symptoms of motion sickness, etc.); thienopyridine anti-platelet agents (e.g., clopidogrel (Clopidogrel), marketed as Plavix for inhibiting thrombosis and the like in coronary artery disease and other diseases); and antiarrhythmic drugs (e.g., amiodarone (Amiodarone), for the treatment of tachyarrhythmias, etc.). Other agents not specifically listed herein are also included within the scope of the present disclosure. Some examples of such agents include, but are not limited to, adjuvants for enhancing immune responses, analgesics, detectably labeled reagents for diagnostic imaging, and the like. Any combination of these exemplary agents may be used. Sulfated pillar arenes can be combined with and improve the solubility of agents that are members of a distinct class of compounds characterized by disparate chemical structures and biological activities.

The compositions of the present disclosure can be administered to any human or non-human animal in need of treatment or prevention of one or more conditions for which the agent is intended to provide a prophylactic or therapeutic benefit. Thus, an individual may be diagnosed with, suspected of having, or at risk of developing any of a variety of conditions for which a reduction in severity is desired. Non-limiting examples of such disorders include cancer, which includes solid tumors, blood cancers (e.g., leukemia, lymphoma, myeloma, etc.). Specific examples of cancers include, but are not limited to, fibrosarcoma (fibrosarcoma), myxosarcoma (myxosarcoma), liposarcoma (liposarcoma), chondrosarcoma (chondrosarcoma), osteogenic sarcoma (osteoprogenic sarcoma), chordoma (chordoma), angiosarcoma (angiosarcoma), endothelial sarcoma (endoheliosarcoma), lymphangiosarcoma (lymphangiosarcoma), peritoneopseudomyxoma (pseudomyxoma peritonie), lymphangiosarcoma (lymphangiosarcoma), synovioma (synovioma), mesothelioma (mesothelioma), ewing's tumor (Ewing's tumor), leiomyosarcoma (leiomyosarcoma), rhabdomyosarcoma (rhabdomyosarcoma), colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, basal cell carcinoma, squamous cell carcinoma, head and neck cancer sweat gland cancer (sweat gland carcinoma), sebaceous gland cancer (seborrhoea gland carcinoma), papillary carcinoma (papillary carcinoma), papillary adenocarcinoma (papillary adenocarinomas), cystic adenocarcinoma (cystadenocarinoma), medullary carcinoma (medullary carcinoma), bronchial carcinoma, renal cell carcinoma, hepatoma (hepatoma), bile duct carcinoma, choriocarcinoma (choriocarcinoma), seminoma (seminoma), embryonic carcinoma (embroynal carcinoma), ns 'tumor (Wilns' tumor), cervical carcinoma, testicular tumor (testicular tumor), lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioblastoma (neuroblastoma), ependymoma (pineblastoma), neuroblastoma (pineblastoma), hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, thymoma, waldenstrom's macroglobulinemia, heavy chain disease, and the like.

In addition to various malignancies, the compounds of the present disclosure are also suitable for providing benefits to cardiovascular related conditions, examples of which include, but are not limited to, angina, arrhythmia, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary artery thrombosis, myocardial infarction, hypertension, hypercholesterolemia/hyperlipidemia, mitral valve prolapse, peripheral artery disease, stroke, thrombosis, embolism, other forms of ischemic injury, and the like.

In addition, the compositions of the present disclosure may be used in connection with the treatment of a wide variety of infectious diseases. It is contemplated that a wide variety of agents for treating and/or inhibiting infectious diseases caused by, for example, bacteria, protozoa, helminths, fungal sources, viral sources, and the like, can be facilitated by the use of the compositions of the present disclosure.

Various methods known to those skilled in the art can be used to introduce the compounds and/or compositions of the present disclosure into an individual. These methods include, but are not limited to, intravenous, intramuscular, intracranial, intrathecal, intradermal, subcutaneous, oral routes, and the like, as well as combinations thereof. The composition comprising the doses of the compound and agent will necessarily depend on the needs of the individual to whom the composition is to be administered. These factors include, but are not necessarily limited to, body weight, age, sex, medical history, and the nature and stage of the disease for which a therapeutic or prophylactic effect is desired. The compositions may be used in combination with any other conventional treatment modalities designed to ameliorate the disease for which a desired therapeutic or prophylactic effect is expected, non-limiting examples of which include surgical intervention and radiation therapy. The composition may be administered once, or in a series of administrations at different intervals as determined using one of ordinary skill in the art, and provides the benefit of the present disclosure.

The methods of the present disclosure may be used on a variety of individuals. In various examples, the individual is a human or non-human mammal. Examples of non-human mammals include, but are not limited to, farm animals such as, for example, cattle, pigs, sheep, and the like, and pets or sport animals such as, for example, horses, dogs, cats, and the like. Other non-limiting examples of individuals include, but are not limited to, rabbits, rats, mice, and the like.

The steps of the methods described in the various examples disclosed herein are sufficient to implement the methods of the present disclosure. Thus, in one example, the method consists essentially of a combination of the steps of the methods disclosed herein. In another example, the method consists of such steps.

In one aspect, the present disclosure provides an article of manufacture comprising a compound of the present disclosure.

The article may be an article of manufacture. Non-limiting examples of articles include wipes (wipes) impregnated with one or more compounds of the present disclosure. For example, such wipes are used to decontaminate surfaces from any material that can be sequestered by a compound (e.g., a pillared arene of the present disclosure). For example, the wipes are used to decontaminate surfaces that have or have been previously exposed to toxins, drugs of abuse, and the like, or combinations thereof.

The following statements illustrate various embodiments of the present disclosure.

Statement 1. A compound having the structure:

wherein Ar is an aryl group, wherein the adjacent aryl groupsGroups are bonded via para-bonded phenyl group bonds (e.g., one or more 1, 4-phenyl group bonds) (e.g., the aryl group is connected to an adjacent methylene group with para substitution), which may be part of a larger aryl group; each R is independently selected from-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS), and-OS (O) ₂ OH, non-sulfate anionic groups (such as, for example, sulfonate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m S(O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (TRIS)/-O (CH) ₂ ) _m S(O) ₂ OH, wherein n is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), -C ₆ H ₅ S(O) ₂ OH, and the like, and such groups wherein the terminal O is removed), carboxylate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m C(O)O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (TRIS)/-O (CH) ₂ ) _m C (O) OH, wherein m is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), and the like, such as, for example, -OCH ₂ CO ₂ ^– M ⁺ /-OCH ₂ CO ₂ H group, etc., and the one in which the terminal O is removedAnalogous groups), phosphate (and corresponding acid) groups (e.g., -O (CH) ₂ ) _m P(O)(OH) ₂ ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or the cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS)/-O (CH) ₂ ) _m P(O)(OH) ₂ Wherein m is 1 to 8 (e.g., 1,2,3, 4, 5, 6, 7, 8), etc., such as, for example, -O (CH) ₂ ) ₂ P(O)(OH) ₂ Etc., and such groups in which the terminal O is removed), phosphate group-OP (O) (OH) ₂ Etc.), substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, O-alkyl groups (including alkyl groups), polyether groups (e.g., polyethylene glycol (PEG) groups), azide groups, -H, substituted or unsubstituted alkyl groups, halogens (e.g., -Br, -F, -I, -Cl), amide groups, cyano groups, substituted or unsubstituted sulfur-containing aliphatic groups (e.g., -S-alkyl and polythioethers, and the like), nitro groups, amino groups, substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups comprising secondary and/or tertiary amines, and the like), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, carbamate groups, imine groups, aldehyde groups, -SO groups ₃ H group, -SO ₃ Na group, -OSO ₂ F group, -OSO ₂ CF ₃ Group, -OSO ₂ OR '"groups (wherein R'" is a substituted OR unsubstituted aryl group OR a substituted OR unsubstituted alkyl group), and the like, and combinations thereof; x is 0, 1,2 or 3; and y is independently at each occurrence 0, 1,2,3, or 4, provided that at least one y is 1 and at least one R group is-OS (O) ₂ O ^– M ⁺ (wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS) or-OS (O) ₂ OH, or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer or mixture thereof. The one or more R groups may be at any one or more positions on the aryl group. In the case of an aryl group with multiple R groups, the individual R groups can be at any combination of positions on the aryl group. In various embodiments, the aryl group can be further substituted with various substituents.

Statement 2. The compound according to statement 1, wherein the aryl group, at each occurrence, is independently selected from a phenyl group, a fused ring group (e.g., a naphthyl group, an anthracenyl group, a phenanthrenyl group, a tetracenyl group, a pentacenyl group, etc.), a biaryl group (e.g., a biphenyl group, etc.), a terphenyl group, and the like.

Statement 3. The compound according to

statement

1 or 2, wherein the cyclic core of the compound comprises at least two, at least three or at least four or all of the one or more phenyl groups of the one or more aryl groups having at least 1 or at least 2 substituents independently selected from-OS (O) ₂ O ^– M ⁺ and-OS (O) ₂ R group of OH.

Statement 4. The compound according to statement 3, wherein the compound has the following structure:

in various examples, each R is-OS (O) ₂ O ^– M ⁺ and-OS (O) ₂ OH。

Statement 5. Compounds according to any of the preceding statements, wherein all aryl groups comprise independently are-OS (O) ₂ O ^– M ⁺ or-OS (O) ₂ R group of OH.

Statement 6. Compounds according to any of statements 1 to 3, wherein at least one aryl groupNot including being-OS (O) ₂ O ^– M ⁺ or-OS (O) ₂ R group of OH.

Statement 7. The compound according to statement 1, wherein the compound has the following structure:

statement 8. The compound according to statement 7, wherein 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently-OS (O) ₂ O ^– M ⁺ Radical or-OS (O) ₂ An OH group.

Statement 9. Compounds according to

statement

7 or 8, wherein the cyclic core of the compound comprises at least 1 or at least 2 phenyl groups each independently selected from-OS (O) ₂ O ^– M ⁺ and-OS (O) ₂ R group of OH.

Statement 10. Compounds according to any of statements 7 to 9, wherein at least one phenyl group does not comprise is-OS (O) ₂ O ^– M ⁺ or-OS (O) ₂ R group of OH.

Statement 11. A composition comprising one or more compounds according to any of the preceding statements.

Statement 12. The composition according to statement 11, further comprising a pharmaceutical carrier.

Statement 13. The composition according to statement 11, wherein the one or more compounds are disposed (e.g., chemically bonded) to at least a portion of the solid substrate.

Statement 14. The composition according to statement 13, wherein the solid substrate comprises (or is) silica (such as, for example, silica particles), polymeric beads, polymeric resins (such as, for example, polystyrene, polynipam, polyacrylic acid), metal nanoparticles (such as, for example, gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold, and the like), or the like, or combinations thereof.

Statement 15. The composition according to any of statements 11-14, wherein at least a portion (or all) of the one or more compounds have the one or more pharmaceutically active agents disposed in a cavity of the one or more compounds (e.g., non-covalently complexed with the one or more compounds).

Statement 16. A method for sequestering: one or more neuromuscular blocking agents (such as, for example, rocuronium bromide, tubocurarine, atracurium (cis) benzenesulfonate, mevinocurium, galantamine, pancuronium bromide, vecuronium bromide, lapachylammonium, and the like); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (e.g., ketamine, etc.), short-acting anesthetics (e.g., etomidate, etc.); one or more pharmaceutical agents (such as, for example, drugs (e.g., anticoagulants such as, for example, hypromellose, and the like), drugs of abuse (e.g., methamphetamine, cocaine, fentanyl, carfentanil, PCP, MDMA, heroin, and the like); one or more insecticides (such as, for example, paraquat, diquat, organochlorines (e.g., DDT, aldrin, etc.), neonicotinoids (e.g., permethrin, etc.), organophosphates (e.g., malathion, glyphosate, etc.), pyrethroids, triazines (e.g., atrazine, etc.); one or more dyes (such as, for example, methylene blue, nile red, crystal violet, thioflavin T, thiazole orange, proflavine, acridine orange, methylene violet, azure a, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27, etc.), coumarin, congo red, etc.); one or more malodorous compounds (such as, for example, low molecular weight thiols (e.g., C) ₁ -C ₄ Mercaptans), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.); or one or more chemical warfare agents (such as, for example, nitrogen mustard and sulfur mustard (e.g., bis (2-chloroethyl) ethylamine, bis (2-chloroethyl) methylamine, tris (2-chloroethyl) amine, bis (2-chloroethyl) sulfide, bis (2-chloroethylthioethyl) ether, and the like), nerve agents (such as, for example, those from the G, GV, and V series of nerve agents (e.g., tabun, sarin, soman, cycloserine, 2- (dimethylamino) ethyl N, N-dimethylphosphamide (GV), novokir, VE, VG, VM, VX, and the like), one or more hallucinogen agents (e.g., ergoline, lysergic acid diethylamide (LSD), cecropin, and the like)Loxabine, tryptamine, dimethyltryptamine (DMT), phenethylamine, mescaline, dead vine, dextromethorphan, and the like); one or more toxins (e.g., dioxin, perfluoroalkyl sulfonate (PFAS), perfluorooctanoic acid (PFOA), decabromodiphenyl Ether (DECA), heavy metals (e.g., mercury), muscarine, tyramine, strychnine, tetrodotoxin, saxitoxin, etc., cholesterol, deoxycholic acid, N-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine, phenylalanine, tyrosine, arginine, histamine); one or more metabolites (e.g., toxic metabolites such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4- (methylnitrosoamino) -1- (3-pyridyl) -1-butanone); etc., or combinations thereof, chelated by one or more compounds according to any one of statements 1-10 and/or one or more compositions according to any one of statements 11-14.

Statement 17. The method according to statement 16, wherein the one or more neuromuscular blocking agents, the one or more anesthetic agents, the one or more pharmaceutical agents, the one or more pesticide agents, the one or more dye agents, the one or more malodorous compounds, the one or more chemical warfare agents, the one or more hallucinogen agents, the one or more toxin agents, the one or more metabolite(s), or combinations thereof are present in an aqueous sample, in a solid sample (such as, for example, a soil sample), in a gas sample, on a solid surface, or the like.

Statement 18. The method according to statement 17, wherein the aqueous sample is a wastewater sample (e.g., a municipal wastewater sample, an industrial wastewater sample, etc.), an industrial water sample (e.g., water used to manufacture a commercial product such as, for example, a reagent, a solvent, etc.), a municipal water sample, or the like.

Statement 19. The method according to any of statements 16-18, wherein a complex is formed by one or more compounds and one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof (e.g., one or more interactions therebetween (e.g., one or more non-covalent bonds formed therebetween)).

Statement 20. The method according to any of statements 16-19, wherein the complex is removed from an aqueous sample, a solid sample, a gas sample, or the like.

Statement 21. The method according to statement 16, wherein one or more neuromuscular blocking agents, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in and/or on the individual, and the contacting comprises administering one or more compounds and/or one or more compositions to the individual.

Statement 22. The method according to statement 21, wherein the subject is a human or non-human mammal.

Statement 23. A method for reversing drug-induced neuromuscular blockade and/or anesthesia and/or the effect of one or more agents (e.g., one or more drugs of abuse) in an individual comprising administering to the individual in need of reversing neuromuscular blockade and/or reversing anesthesia and/or reversing the effect of one or more agents (e.g., one or more drugs of abuse) one or more compounds according to any one of statements 1-10 and/or one or more compositions according to any one of statements 11-14.

Statement 24. The method according to statement 23, wherein the individual is in need of reversal of drug-induced neuromuscular blockade.

Statement 25. The method according to statement 23, wherein the subject is in need of reversal of anesthesia.

Statement 26. The method according to statement 23, wherein the subject is in need of reversal of drug-induced neuromuscular blockade and anesthesia.

Statement 27. The method according to statement 23, wherein the individual is in need of reversal of the effect of one or more agents selected from one or more drugs of abuse, one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, and/or one or more metabolites. In one example, an individual is exposed to one or more drugs of abuse (e.g., carfentanil, etc.), one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites (in the event of a terrorist attack), and combinations thereof.

Statement 28. The method according to any of statements 23-27, wherein the individual in need thereof is a human.

Statement 29. The method according to any of statements 23-27, wherein the individual in need thereof is a non-human mammal.

Statement 30. A method for preventing and/or treating a disorder in an individual, comprising administering to an individual in need of prevention and/or treatment one or more compounds according to any one of statements 1-10 and one or more agents, wherein the one or more compounds and the one or more agents are present as a complex (or a composition comprising one or more of said complexes, which may be a pharmaceutical composition), wherein after administration, treatment and/or prevention of the disorder in the individual is performed.

Statement 31. The method of statement 30, wherein the one or more of the one or more pharmaceutical agents has a solubility in the aqueous solvent of less than 100 μ Μ.

Statement 32. A compound according to any one of statements 1 to 10, a composition according to any one of statements 11 to 15 or a method according to any one of statements 16 to 31, wherein M ⁺ Is Na ⁺ 、K ⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ 。

Statement 33. A compound according to any one of statements 1 to 10, a composition according to any one of statements 11 to 15, or a method according to any one of statements 16 to 31, wherein M ⁺ Is Na ⁺ 。

The following examples are provided to illustrate the present disclosure. They are not intended to be limiting in any way.

Example 1

This example provides a description of the compounds of the present disclosure, methods of making the compounds, characterization of the compounds, and use of the compositions.

General experimental details. The starting materials were purchased from commercial suppliers and used without further purification, or were prepared by literature procedures. Melting points were measured in open capillaries on a Meltemp apparatus and were not corrected. IR spectra were recorded on a JASCO FT/IR 4100 spectrometer and in cm ^-1 And (6) reporting. ¹ H NMR spectra were measured on a Bruker instrument for ¹ H operates at 400 or 600MHz and for ¹³ C operates at 100 MHz. Mass spectrometry was performed using a JEOL AccuTOF electrospray instrument (ESI). ITC data were collected on a Malvern Microcal PEAQ-ITC instrument.

Synthesis procedure and characterization data.

Body P [5] AS.

The first two compounds (2 and 3) were synthesized by using methods adapted from methods known in the art. The procedure used for the last step was: to a mixture of compound 3 (0.200g, 0.328mmol) and pyridine sulfur trioxide complex (1.050g, 6.56mmol) was added anhydrous pyridine (10 mL). The resulting mixture is stirred under N ₂ Stirring was continued at 90 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The product precipitated from solution and was collected by filtration. The solid was slurried in water (5 mL) and slurried by slow addition of saturated NaHCO ₃ The aqueous solution adjusted the pH to 8.4. After addition of EtOH (35 mL), the crude product was collected by centrifugation at 7000rpm × 7 min. The precipitate was suspended in ethanol (20 mL × 2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (2 ml) and used

The G25 resin (30 mm. Times.200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction (front fractions). After drying under high vacuum, compound P5 is obtained]AS, white solid (0.374 g,0.229mmol,70% yield). And (M.p).>310 deg.C (decomposed). IR (ATR, cm) ^-1 )：3490w,1630m,1497m,1399m,1234s,1116s,1042s,995m,941m,858m,806m。 ¹ H NMR(600MHz，D ₂ O)：7.31(s,10H),4.00(s,10H)。 ¹³ C NMR(150MHz，D ₂ O, etOH as internal reference): 147.4,134.1,125.6,30.8.MS (ESI): m/z 791.78179 ([ M-2Na ]] ^2- ) The theoretical value is 791.79597.

Host P [5] ACS.

P5 is]A solution of A (0.200g, 0.28mmol) in NaOH (10 wt%, 2 mL) was treated dropwise with a solution of propane sultone (0.687 g, 5.63mmol) in acetone (4 mL). This solution was stirred at room temperature for 5 days (d), then EtOH (25 mL) was added to the mixture to give the crude product as a precipitate. The precipitate is obtained by filtration and the solid is dissolved in H ₂ O (0.5 mL) and then reprecipitated by adding EtOH (5 mL) to give P [5]]ACS as a pale yellow solid (45mg, 0.022mmol, 8%). And (M.p).>300 deg.C (decomposed). IR (ATR, cm) ^-1 )：3452w,2936w,1725m,1625m,1479m,1471m,1406m,1181s,1035s,951w,798m,756m。 ¹ H NMR(400MHz，D ₂ O)：6.76(s,10H),3.90(m,10H),3.86(s,10H),3.68(m,10H),3.05(m,20H),2.08(m,20H)。 ¹³ C NMR(150MHz，D ₂ O, etOH as internal reference): Δ 150.9,129.8,116.7,68.5,49.1,31.1,25.5.HR-MS (ESI): m/z 1002.03215 ([ M-2Na ]] ^2- ) The theoretical value is 1002.03072.

Body P [6] AS.

The first two compounds (7 and 8)) were synthesized using methods adapted from those known in the art. The procedure used for the last step was: to a mixture of compound 8 (0.200g, 0.27mmol) and pyridine sulfur trioxide complex (1.090g, 6.83mmol) was added anhydrous pyridine (10 mL). Mixing the obtained mixtureCompound in N ₂ Stirring was continued at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The product precipitated from solution and was collected by filtration. The solid was slurried in water (5 mL) and slurried by slow addition of saturated NaHCO ₃ The aqueous solution adjusted the pH to 8.4. After addition of EtOH (35 mL), the crude product was collected by centrifugation at 7000rpm × 7 min. The precipitate was suspended in ethanol (20 mL × 2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (2 ml) and used

The G25 resin (30 mm. Times.200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P6 is obtained]AS was a white solid (0.352g, 0.18mmol,66% yield). And (M.p).>290 deg.c (decomposed). IR (ATR, cm) ^-1 )：3509w,1712m,1630m,1498m,1364m,1237m,1113s,1045s,995m,942m,861m,813m。 ¹ H NMR(600MHz，D ₂ O)：7.35(s,12H),4.11(s,12H)。 ¹³ C NMR(150MHz，D ₂ O and CD ₃ OD 10:1)：δ148.1,133.6,125.6,31.5.MS(ESI)：m/z 954.7593([M-2Na] ^2- ) The theoretical value is 954.7537.

Main body P [6] A8S.

The first three compounds were synthesized by using methods adapted from those known in the art. The procedure for the last step was: to a compound octahydroxy column [6]]Anhydrous pyridine (5 mL) was added to a mixture of arene (0.100g, 0.15mmol) and pyridine sulfur trioxide complex (0.479g, 3mmol). The resulting mixture is stirred under N ₂ Stirring was continued at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The product precipitated from solution and was collected by filtration. The solid was slurried in water (4 mL) and saturated Na was added slowly ₂ CO ₃ The aqueous solution adjusted the pH to 8.4. After addition of EtOH (10 mL), the crude product was purified byThe mixture was collected by ultracentrifugation at 7000rpm × 7 min. The precipitate was suspended in ethanol (10 mL × 2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (0.5 ml) and used

The G25 resin (30 mm. Times.200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P6 is obtained]A8S (10) as a white solid (0.075g, 0.051mmol,33% yield). And (M.p).>285 deg.C (decomposed). IR (ATR, cm) ^-1 )：3491w,1630m,1440s,1234s,1078m,1043s,941m,878m,800m,667m。 ¹ H NMR(600MHz，D ₂ O)：7.39(s,4H),7.25(s,4H),7.04(s,8H),4.07(s,4H),3.99(s,8H)。 ¹³ C NMR(150MHz，D ₂ O, etOH as internal reference): Δ 147.7,147.6,138.7,134.2,133.2,129.2,125.3,125.1,35.7,31.1.MS (ESI): m/z 718.88334 ([ M-2 Na)] ^2- ) The theoretical value is 718.88632.

Body P [7] AS.

The first two compounds were synthesized by using methods adapted from those known in the art. The procedure used for the last step was: to compound (HO) ₁₄ Column [7]]Anhydrous pyridine (3 mL) was added to a mixture of arene (0.020g, 0.023mmol) and pyridine sulfur trioxide complex (0.375g, 2.34mmol). The resulting mixture is taken up in N ₂ Stirring was continued at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The product precipitated from solution and was collected by filtration. The solid was slurried in water (1 mL) and saturated Na was added slowly ₂ CO ₃ The aqueous solution adjusted the pH to 8.4. After addition of EtOH (10 mL), the crude product was collected by centrifugation at 7000rpm × 7 min. The precipitate was suspended in ethanol (10 mL × 2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (0.5 ml) and used

The G25 resin (30 mm. Times.200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P [7] is obtained]AS, AS a white solid (0.025g, 0.011mmol,46% yield). And (M.p).>290 deg.c (decomposed). IR (ATR, cm) ^-1 )：3494w,1624m,1444s,1244m,1102s,1049s,995m,875m,807m,614s。 ¹ H NMR(600MHz，D ₂ O)：7.29(s,14H),4.14(s,14H)。 ¹³ C NMR(150MHz，D ₂ O, dioxane as external reference): δ 147.6,132.8,124.7,30.8.MS (ESI): m/z547.36023 ([ M-4 Na)] ^4- ) The theoretical value is 547.36080.

Rim-P[5]AS。

The starting material, 2- (benzyloxy) -5-methoxybenzyl alcohol, was synthesized based on methods known in the art. Synthesis of a PentaHydroxy column [5] by Using methods known in the art]An aromatic hydrocarbon compound. To a pentahydroxy column [5]]Anhydrous pyridine (10 mL) was added to a mixture of aromatic hydrocarbon (0.200g, 0.328mmol) and pyridine sulfur trioxide complex (1.050g, 6.56mmol). The resulting mixture is stirred under N ₂ The mixture was stirred at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The product precipitated from solution and was collected by filtration. The solid was slurried in water (5 mL) and slurried by slow addition of saturated NaHCO ₃ The aqueous solution was adjusted to pH 9. Addition of EtOH (EtOH/H) ₂ O v/v = 2) resulted in a precipitate which was removed by centrifugation (7000 rpm × 10 min). The filtrate was collected as crude product and redissolved in a minimum amount of water (2 mL) and used

The G25 resin (5 cm. Times.50 cm) was purified by size exclusion chromatography using water as eluent. The front fraction eluted from the column contained pure product. After drying under high vacuum, rim-P5 is obtained]AS, white solid (0.374g,0.229mmol,67% yield, content: about 92% by using sodium 2-bromoethanesulfonate as ¹ Determined from H NMR internal standard). And (M.p).>300 deg.C (decomposed). ¹ H NMR(400MHz，D ₂ O)：7.21(s,5H),6.56(s,5H),3.90(s,10H),3.24(s,15H)。 ¹³ C NMR(150MHz，D ₂ O, etOH as internal reference): 155.3,143.2,134.5,129.6,124.7,114.9,56.7,30.6.

And (4) measuring the solubility.

P[5]Determination of the solubility of AS in water. Reacting the compound P [5]]AS was added in excess to 0.5mL of deuterium oxide. The suspension was magnetically stirred at room temperature overnight and then centrifuged (4500 rpm) twice for 10 minutes each. The supernatant (50. Mu.L) was mixed with sodium 3- (trimethylsilyl) propionate-2, 3-d ₄ (TMSP) (10mM, 50. Mu.L at D ₂ O) was added to 0.4mL of deuterium solvent. P5]Concentration utilization of AS ¹ H NMR measurements and use of sodium 3- (trimethylsilyl) propionate-2, 3-d ₄ (TMSP) was calculated as an internal reference.

P[6]Determination of the solubility of AS in water. Reacting the compound P [6]]AS was added in excess to 0.5mL of deuterium oxide. The suspension was magnetically stirred at room temperature overnight and then centrifuged (4500 rpm) twice for 10 minutes each. The supernatant (50. Mu.L) was mixed with sodium 3- (trimethylsilyl) propionate-2, 3-d ₄ (TMSP) (10mM, 50. Mu.L at D ₂ O) was added to 0.4mL of deuterium solvent. P6]Concentration utilization of AS ¹ H NMR measurements and use of sodium 3- (trimethylsilyl) propionate-2, 3-d ₄ (TMSP) was calculated as an internal reference.

Determination of K between various subjects and cationic guests or drugs of abuse or neuromuscular blockers using Isothermal Titration Calorimetry (ITC) _a . All ITC experiments were performed in a 200 μ L working volume of the sample cell of the PEAQ ITC instrument. We used a 40 μ L capacity syringe. In each case, the host and guest solutions were prepared at 20mM NaH ₂ PO ₄ Buffer (pH 7.4). The sample cell was filled to capacity (200 μ Ι _ with host solution) and the guest solution was titrated (first injection =0.4 μ Ι _, followed by 18 injections =2 μ Ι _). Data combination in MicroCal PEAQ-ITC analysis softThe fitting was performed using a 1. In which K is _a In the case of too large to be determined by direct titration, competitive ITC titrations were performed with known K _a Competitive objects with Δ H are included in the ITC cell along with the host, who then uses the K to determine it _a The object of (1) is titrated.

WP5, WP6 and the following compounds were used in the comparative examples:

of the drug selected with the subject ¹ H NMR spectrum. FIG. 8 shows the drug (methamphetamine) and the host (P6)]AS) of ¹ An example of an H NMR spectrum.

Competitively binding ¹ H NMR spectrum. FIG. 9 shows P [6]]AS binds to rocuronium bromide more strongly than previously known compounds (Motor 2, which is also known AS calabeads 2).

The crystal structure P [6] AS is also determined. FIGS. 10 and 13 show the crystal structure of P [6] AS.

Table 1. Crystal data and structure of P [ 2 ] ]ASare refined.

Crystal C _45.44 H ₂₄ Na ₁₂ O _65.65 S ₁₂ Is of empirical formula

TABLE 2.P [ 2 ] 2]Fractional atomic coordinate and equivalent isotropic displacement parameter of AS

Ueq is defined as 1/3 of the trace of the orthogonalized UIJ tensor.

Table 3. P2]Anisotropic displacement parameter of AS

The anisotropy displacement factor index takes the form: -2 pi ² [h ² a* ² U ₁₁ +2hka*b*U ₁₂ +…]。

Table 4. Bond length of P [ 2 ]. AS.

¹ 1+Y-X，1-X，+Z； ² 1-Y，+X-Y，+Z； ³ 1-Y+X，1-Y，1/2-Z； ⁴ +X，+X-Y，1/2+Z； ⁵ 2-X，1-Y，1-Z； ⁶ 1-X，1-Y，1-Z； ⁷ 2-X，1-X+Y，1/2-Z； ⁸ 1+Y-X，+Y，1/2+Z； ⁹ 1-Y，1+X-Y，+Z； ¹⁰ +Y，+X，1/2-Z； ¹¹ -X，-Y，1-Z； ¹² -Y+X，+X，1-Z； ¹³ +Y，-X+Y，1-Z

Table 5. Bond angle of P [ 2 ] ]AS.

¹ 1+Y-X，1-X，+Z； ² 1-Y，+X-Y，+Z； ³ 1-Y+X，1-Y，1/2-Z； ⁴ +X，+X-Y，1/2+Z； ⁵ 2-X，1-Y，1-Z； ⁶ 1-X，1-Y，1-Z； ⁷ 2-X，1-X+Y，1/2-Z； ⁸ 1+Y-X，+Y，1/2+Z； ⁹ 1-Y，1+X-Y，+Z； ¹⁰ +Y，+X，1/2-Z； ¹¹ +X，+X-Y，-1/2+Z； ¹² 1+Y-X，+Y，-1/2+Z； ¹³ -Y+X，1-Y，1/2-Z； ¹⁴ -X，-Y，1-Z； ¹⁵ -Y+X，+X，1-Z； ¹⁶ +Y，-X+Y，1-Z； ¹⁷ +Y-X，1-X，+Z

Table 6. Torsion angle of P [ 2 ]. AS.

¹ 1-Y，+X-Y，+Z； ² 2-X，1-Y，1-Z； ³ 2-X，1-X+Y，1/2-Z； ⁴ +Y，+X，1/2-Z； ⁵ +X，+X-Y，-1/2+Z； ⁶ 1+Y-X，+Y，-1/2+Z； ⁷ -Y+X，1-Y，1/2-Z； ⁸ 1-X，1-Y，1-Z； ⁹ 1+Y-X，1-X，+Z； ¹⁰ 1+Y-X，+Y，1/2+Z； ¹¹ 1-Y，1+X-Y，+Z； ¹² 1+X，1+Y，+Z； ¹³ -Y+X，+X，1-Z； ¹⁴ -X，-Y，1-Z； ¹⁵ +Y，-X+Y，1-Z； ¹⁶ +Y-X，1-X，+Z； ¹⁷ +Y-X，-X，+Z； ¹⁸ -Y，+X-Y，+Z

TABLE 7.P [ 2 ]]Hydrogen atom coordinates and isotropic displacement parameters of AS

Atom(s)	Z	y	z	U(eq)
					H3	1.002(2)	0.569(2)	0.2874(14)	0.039(9)
H4	0.937(2)	0.703(2)	0.1741(14)	0.026(7)
					H6	0.691(2)	0.532(2)	0.3338(14)	0.032(8)
H7	0.590(2)	0.588(2)	0.2112(14)	0.035(8)

Table 8. Atomic occupancy of P [ 2 ]. AS.

Atom(s)	Occupancy rate	Atom(s)	Occupancy rate	Atom(s)	Occupancy rate
						Na3	0.6667	O1	0.887(5)	O2	0.887(5)
O3	0.887(5)	S1	0.887(5)	O4	0.887(5)
						O1A	0.113(5)	O2A	0.113(5)	O3A	0.113(5)
S1A	0.113(5)	O4A	0.113(5)	O5	0.58(3)
						S2	0.58(3)	O6	0.58(3)	O7	0.58(3)
O8	0.58(3)	O5A	0.42(3)	S2A	0.42(3)
						O6A	0.42(3)	O7A	0.42(3)	O8A	0.42(3)
O1B	0.85	C2B	0.285(13)	O3B	0.308(7)
						C4B	0.15	O1C	0.808(11)	O2C	0.317(10)
O3C	0.306(10)	O1D	0.353(9)	C2D	0.412(17)

And (5) carrying out experiments. Selection of the appropriate P6]AS single crystals were grown and measured on a Bruker Smart Apex2 diffractometer. The crystal corresponds to C _45.44 H ₂₄ Na ₁₂ O _65.65 S ₁₂ . During data collection, the crystals were maintained at 150 (2) K. With the multi-scan method, the integrated intensity is correct for absorption (correct) using the SADABS software. The resulting minimum and maximum transmission were 0.634 and 0.959, respectively. The structure was solved using the ShelXT-2014 (Sheldrick, 2015 a) program and refined using the ShelXL-2015 (Sheldrick, 2015 c) program and least squares minimization using the ShelX software package. The number of constraints used =387.

And (5) determining a crystal structure. C _45.44 H ₂₄ Na ₁₂ O _65.65 S ₁₂ (M =2280.86 g/mol) crystal data: trigonal system, space group P-3c1 (No. 165),

Z＝2，T＝150(2)K，μ(MoKα)＝0.519mm ^-1 ，D _calc ＝1.881g/cm ³ 23483 reflections (4 DEG 2 theta 53.178 DEG) and 2810 unique (R) _int ＝0.0602，R _sig = 0.0410) (for all calculations). Final R ₁ Is 0.0448 (I)>2 σ (I)) and wR ₂ And 0.1097 (all data).

And (6) refining details. H atoms (except those in disordered (disordered) solvents) are located from the differential fourier map and are free to refine (including Uiso). Water and ethanol solvents were severely disordered and modeled with partially occupied O and C atoms.

Example 2

This example provides the synthesis, X-ray crystal structure, and molecular recognition properties of the column [ n ] arene derivative P [6] AS (which is occasionally referred to herein as column [6] MaxQ), as well as analogs P [5] AS and P [7] AS for guests 11-28. This example demonstrates the ultra-tight binding affinity of P [5] as and P [6] as for quaternary (di) ammonium ions, which supports their use for imaging and delivery applications in non-covalent bioconjugation in vitro and in vivo, as well as in vivo chelators.

In more detail, those skilled in the art will recognize that advances in the construction of supramolecular systems for biological (e.g., imaging and drug delivery) and chemical (e.g., sensing, catalysis, separation) applications depend heavily on the availability of libraries of building blocks that can be easily integrated into more complex and more functional systems. Molecular containers, whether prepared by covalent bond formation reactions or by self-assembly processes, occupy a central region of the field. Some of the most popular molecular containers include cyclodextrins, calipers [ n ]]Aromatic hydrocarbon, crown ether, cyclic aromatic hydrocarbon, coordination cage, molecular clamp, tweezers and cucurbit [ n ]]Urea (CB [ n ]]) And H-bonded capsules. In this group, CB [ n ]]The family (FIG. 11 a) has proven to be particularly useful because they form tight CBn in a selective and stimuli-responsive manner]Guest complexes, which allow them to be used to create sensing ensembles,Supramolecular polymers, molecular machinery, for bioconjugation, as non-covalent locking systems, and for drug solubilization and delivery. In view of acyclic CB [ n ]]For high binding affinity of their best guests, acyclic CB [ n ] was developed](e.g., M2, FIG. 11 a) as an in vivo chelator for neuromuscular blockers and drugs of abuse. Recently, column [ n ]]Arenes (FIG. 11b, e.g. WP [5]]And WP [6]]) The synthesis and molecular recognition properties in both organic and aqueous solutions have been extensively studied and are well reviewed with respect to their chemical and biological applications. Column [ n ]]Aromatic hydrocarbons represent the best point for studies on molecular recognition in water, as they typically exhibit a K in the μ M range _d Value, and ratio CB [ n ]]It is easier to functionalize. Thus, this embodiment provides a pair of columns [ n ]]Aromatic sulfate (also known as colum [ n ]]MaxQ), column [ n ]]The aromatic sulfate has extremely high binding affinity (K) to quaternary diammonium ions in aqueous solution _d In the pM range) which makes them particularly well suited as in vivo chelators.

Considering column-based [ n ]]The creation of new ultra-tight binding hosts by aromatics led us to think about CB [ n ]]The relevant structural features of (1) (fig. 11 a). CB [ n ]]Has been traced to their high electrostatic negative ureido C = O entry and the number and energy of water molecules within the bulk cavity released upon bonding (e.g., non-classical hydrophobic effects). Due to their double CH ₂ -linker, CB [ n ]]Without free rotors, self-complexation cannot occur and is therefore a highly pre-organized body. The present disclosure relates to the use of rational molecular design on columns [ n ]]These structural features are replicated in the aromatic family. Although anionic water soluble pillaraarenes are known (e.g., WP [5]]And WP [6]]) But they contain a CH between the aromatic ring and the anionic functional group (e.g. carboxylate, sulfonate, phosphonate) ₂ -a linker. The present disclosure includes removing CH ₂ Linker and changing to highly acidic sulfate functional groups to provide a higher negative charge density around the opening of the cavity. At the same time, the addition of two sulfate groups per phenylene group is contemplated to electrostatically minimize the possibility of known phenylene groups tilting into their own cavities.

FIG. 11 shows P [5]]AS–P[7]And (6) synthesizing the AS. Preparation of parent hydroxylated pillararene (P5) according to literature procedure]A-P[7]A) In that respect Subsequently, P [5]]A–P[7]A is each reacted with pyridine SO in pyridine at 90 DEG C ₃ Reaction to give P5 in yields of 70%, 66% and 46%, respectively]AS–P[7]And (6) the AS. To get a deep understanding of CH ₂ The function of a linker by reacting P5]Reaction of A with propane sultone and NaOH in acetone produced P [5] in low yield (8%)]ACS was used as a control compound. Finally, a known body WP [5] is prepared by methods known in the art]And WP [6]]As an additional comparator. All the new compounds are obtained by ¹ H and ¹³ c NMR, IR and high resolution electrospray ionization mass spectrometry were well characterized. It is known that columns [6] are due to rotation around the phenylene unit]Aromatic hydrocarbons can exist in five different conformational forms. FIG. 12a shows that at D ₂ For P6 in O at room temperature]AS recorded ¹ H NMR, which consists of two relatively sharp single peaks. This indicates P [6]]AS is either locked to the depicted C ₆ In a symmetric structure, either the phenylene units rotate rapidly on the chemical shift timescale. Based on the subject/object experiments, OSO can be inferred ₃ ^- The radicals passing through P6]The rotation of the ring of the AS column arene is fast.

Two most effective bodies (P5)]AS：100mM；P[6]And AS:20mM; see below)) is obtained by dissolving the host in water ¹ H NMR resonance relative to a known concentration of sodium 3- (trimethylsilyl) propionate-2, 3-d as an internal standard ₄ Is measured by integrating the methyl resonance of (a). Before starting to study the host-guest properties of new hosts, we have conducted ¹ H NMR spectroscopy monitored dilution experiments to quantify their intermolecular self-association. By using a standard 2-fold self-association model, P5 is recorded]AS and P [6]]AS for calculating K _s Concentration of value (P5)]AS：20–0.1mM；P[6]AS:20-0.1 mM). These K _s The values ensure that the host remains monomeric at the mM concentrations used in the NMR and ITC experiments described below in this example. Obtain P6]AS and P [5]]Crystals of both ACS, and their structures as resolved by X-ray diffraction measurements (A)FIG. 13, CCDC 1996177 and CCDC 1996179). FIG. 13d shows P5 in the crystal]Structure of one molecule of ACS. As is commonly seen in the pillared arene crystal structure, the phenylene rings are oriented approximately perpendicular to the average plane of the macrocycle, and the substituents serve to deepen the cavity. The S.S distance between the sulfonate attached to a single phenylene ring is

Within the range of (1). FIG. 13a shows P6 in the crystal]Structure of a single molecule of AS. And P5]Different ACS, P6]AS adopts an unusual conformation in which alternating phenylene units in a geometry reminiscent of cyclotriveratrylene (cyclovertrylene) are slightly inclined into the cavities on opposite sides of the macrocycle. The inclination of the phenylene group from the vertical was measured to be 35 to 38 degrees. Interestingly, OSO ₃ ^- The groups are not located on the average plane of the phenylene units, but are shown alternately above and below this plane. This tilting and alternating results in 12 OSOs ₃ ^- The radicals being arranged approximately on a side of

And has a height of

At the corners and edges of the triangular anti-prism. Thus, P [6]]AS in a small volume (P6)]CPK molecular volume of AS

) Having a relatively high charge density of-12 therein. Na (Na) ⁺ Observed P6 of counterion pair]The effect of the conformation of AS is not clear. P6]The molecules of AS are packed in a hexagonal array on the xy-plane, AS shown in fig. 13 b; OSO ₃ ^- Subunit is through coordination of Na ⁺ The ions are widely bridged. These hexagonally packed P6]AS sheets are stacked in alignment with each other along the z-axis such that P6]The AS cell defines a tube (fig. 13 c). P5]Stacking of ACS was also shown to bridge Na ⁺ A stack of sheets in which a network of ions is held together.

FIG. 12a shows P [6] alone]Two singlet sums P6 of AS]A single set of sharp resonances for the AS 25 complex (fig. 12 c). The significant high field shift observed for the resonance of object 25 confirms its inclusion in P6]In the cavity of the AS. In the sequence 1]At the AS:25 ratio, the shift of the resonance of guest 25 back towards free 25 indicates that guest exchange occurs rapidly on the chemical shift timescale. Similar studies were performed for different combinations of subjects and objects from fig. 2-4, and in many cases the situation was more complex. For example, in many cases, the aryl H-atom (H) is, after mixing with one equivalent of the guest _a ) Broadens or splits into many different sharp resonances. Of course, it is well known that columns [ n ]]Aromatic hydrocarbons have several different less symmetrical conformations (n = 5. For the body P [6]]AS and P [7]]AS, a high field shift of the guest resonance was observed after binding, indicating a cavity binding of the hydrophobic part of the guest. For P [5]]As, the narrower guests (e.g., 21 and 23) bind within the cavity AS indicated by the high field change in chemical shift, but the wider guests (e.g., 12 and 25) show NMe ₃ ⁺ High field displacement of groups other than their hydrophobic part, which indicates near the inlet ⁺ NMe ₃ And (4) combining. ITC measurements (see below) indicate that 12 and 25 are measured at a host to guest stoichiometry to P [5] of 1]And (5) combining the AS.

Initially, by ¹ H NMR spectroscopy investigated the molecular recognition properties of the new host for guests 11-28 (FIG. 2). Compounds 11-28 were chosen because they have different numbers of charged groups (one or two), length of hydrophobic residues, width of hydrophobic residues, and degree of ammonium ion substitution (1 °,2 °,3 °,4 °) for evaluation of the preference of new subjects. FIG. 12 shows the data for P [6]]AS, 25 and P [6]]AS and 25 of a mixture of 1 ¹ H NMR spectrum, which is a particularly well resolved example. Next, the strength of the binding interaction between the various hosts and guests was quantified. In view of ¹ Complexity of H NMR spectra and observed tight binding (see below)) We used Isothermal Titration Calorimetry (ITC). For most complexes, we performed a direct titration of the host in the cell with the guest in the syringe. Thermodynamic parameters determined by these direct ITC titrations are shown in fig. 5-7, and representative experimental data is shown in fig. 69-83. Direct titration is not applicable to K therein _a Value exceeding 4X 10 ⁷ M ^-1 In a relatively compact host-guest complex, even in [ host ]]The c-value also exceeds the recommended range when operating at 10 μ M. In these cases, a competitive ITC experiment was used in which a mixture of host and excess weaker binding guest in a pool was titrated with the stronger binding guest in a syringe. In these ITC competition experiments, the weaker Δ H and K of the host-guest complex _a Values were determined independently and used as input for competitive ITC titration. FIG. 14a shows the use of a stronger binding guest 20 in a syringe versus P6 in the well]The mixture of AS and weakly bound guest 17 is titrated. Fitting the data (FIG. 14 b) to a competitive binding model allows extraction of P [6]]Thermodynamic parameter (K) of AS 20 _a ＝(1.20±0.06)×10 ¹¹ M ^-1 ；ΔH＝-17.1±0.033kcal mol ^-1 ). Fig. 5-7 report the results of competitive ITC titration for the more compact host-guest complexes.

The extensive data sets presented in FIGS. 5-7 allow for the comparison of new subjects with previously known WP [5]]And WP [6]]The binding preferences of the phase are discussed more fully. All complexes were driven by favorable Δ H values, indicating that these complexes benefit from non-classical hydrophobic effects as intended. First, note P [5]]ACS and its (CH) ₂ ) ₃ Binding ratio of linker to alkanediammonium ions 16-20 to WP [5]]Observed weak 10 ¹ –10 ² This may be the result of the moieties blocking the bulk cavity or with anionic SO ₃ ^- Longer linkers for the groups reduce the consequences of electrostatic interactions. In addition, based on the degree of methylation of the diammonium ion (e.g., 1 °:17,2 °:18 °:3 °:19]ACS and WP [5]]Very little selectivity in binding was shown. In contrast, P [5]]AS is the ratio WP [5] to diammonium ion]More excellent hosts (e.g. 17;18:390 times; 19:7300 times; 20:88000 times). P5 with increasing degree of methylation of N atom of guest]AS showed increased binding affinity. Thus, such bodies are called columns [ n ]]MaxQ to predict their generally superior binding affinity and selectivity for quaternary ammonium ions. P5]Comparison of binding affinities of AS for quaternary diammonium ions of different lengths (e.g., 15, 16, 20) showed that the binding of C4-diammonium ion was 317-458 times weaker than that of C5-and C6-analogues, probably due to N.N. ^- O ₃ S···SO ₃ ^- Better matching of distances and increased hydrophobicity of C6-hydrophobic residues. Of great interest is P [5]]AS for Single season guest 13 (4.41X 10) ⁸ M ^-1 ) And biquaternary guest 20 (9.90X 10) ¹¹ M ^-1 ) The comparison of affinities reveals the importance of electrostatic interactions in the recognition process. All of these narrow objects form 1]AS guest complex. In contrast, the ITC results revealed that broader objects (e.g., 12, 25, 27, cis, roc, vec, pan) could not interact with P [5]]As forms a clathrate complex, but forms a 1]AS guest complex. P5]ITC titration of guests by AS with this subset is well suited for 1 _a Value has M ^-1 Units, and involves each of two independent binding events. P5]AS for Me ₄ N ⁺ K of _a Value (P5)]AS·26；K _a ＝3.11×10 ⁴ M ^-1 ) Revealing the observed P5 of each quaternary ammonium ion head group pair]AS makes a significant contribution to the ultra-high affinity of (di) quaternary ammonium ions (e.g. 20).

FIGS. 5-7 show binding constants (K) for various hosts and guests 11-28 _a ，M ^-1 ) And thermodynamic parameters (. DELTA.H, kcal mol) ^-1 ) The neuromuscular blocking agent is shown in figure 4 and the drug of abuse is shown in figures 3 and 68. Conditions are as follows: h ₂ O，20mM NaH ₂ PO ₄ Buffer, pH7.4, 298K. -not measured. n.b. = no heat change detected by ITC. ^a By using [ main body ]]Measured by direct ITC titration of ≧ 10 μ M. ^b Measured by competitive ITC titration with 13. ^c Measured by competitive ITC titration with 14. ^d Measured by competitive ITC titration with 16. ^e Measured by competitive ITC titration with 17. ^f Measured by competitive ITC titration with 21. ^g Measured by competitive ITC titration with 24. ^h Measured by competitive ITC titration with 27. ⁱ Measured by competitive ITC titration with 28. ^j 1. ^k 2.

The correlation comparison can be at the subject WP [6]]And P6]AS, which showed a host-guest complexation of 1. For example, P6 in addition to including 1 ammonium ions 24 and 27]AS is an excellent host for 20 out of 23 subjects studied. And P5]AS is similar, P [6]]AS is based on guest length (e.g., 14 versus 28 versus 17 versus 15 versus 16 versus 20) and on the degree of methylation of the diammonium ion (e.g., 17 versus 20 k _a ＝1.43×10 ⁹ Relative to 1.20X 10 ¹¹ M ^-1 ) Is highly selective. Of interest is P [6]]AS for Me ₄ N ⁺ (26，K _a ＝2.32×10 ⁶ M ^-1 ) Has a binding affinity of P [5]]75 times AS strong AS AS, indicating P6]AS should be considered a potent host for quaternary ammonium ions. In fact, P6]K of AS for object group _d Values lie in the range of single digit. Mu.M to 1pM, which gives P [6]]AS and CB [ n ]]And listed as one of the highest affinity synthetic host-guest systems in water, although the balance between the composite driving forces (e.g., electrostatic versus hydrophobic effect) is significantly different. Finally, FIGS. 5-7 show P [7]]Binding affinity of AS to a set of guests (11-28). In this case, the reaction with a water-soluble column aromatic hydrocarbon analog (WP [7 ]) cannot be carried out]) Because it is not available. In any case, FIGS. 5-7 show in detail that P7 is present in addition to the primary ammonium ion 24]AS is the ratio P [6] to the object group]AS is a significantly less potent receptor. Although for P [7]]The reason for the relatively poor performance of the AS is not determined, but without intending to be bound by any particular theory, it is speculated that the reason may be with CB n]Those causes of the subject family are similar, where static electricity isThe size of the negative inlet and the energetics and number of bound water in the body cavity play an important role.

In view of the proven P5]AS and P [6]]The preference of AS for quaternary diammonium ions, the guest group was expanded to include the clinically important neuromuscular blockers roc, vec, pan and cis AS well AS acetylcholine (ACh). Macrocyclic receptors (e.g., by Merck in Bridion) ^TM The commercial gamma-cyclodextrin derivative Sugammadex (Sugammadex), acyclic CB [ n [ [ n ]]Type-acceptors M2 and WP [6]]) Have previously been used as in vivo chelators for NMBA. Thus, P [5] is measured]AS–P[7]AS、WP[5]And WP [6]]Binding affinity for NMBA (figure 7). Most notably, discovery with WP [6]]Or sugammadex, P6]Binding of AS to roc, vec and pan was tighter 10 ⁴ -10 ⁵ Doubling while maintaining a very good discrimination level for acetylcholine (10) ³ –10 ⁴ Double), acetylcholine is also present in the neuromuscular junction. In fact, P6]The affinity of AS for roc, vec and pan was previously reported for the subject M2 (K) _a ：M2·roc＝3.4×10 ⁹ M ^-1 ；M2·vec＝1.6×10 ⁹ M ^-1 ；M2·pan＝5.3×10 ⁸ M ^-1 ) Is/are as follows>100-fold higher, this subject M2 has been demonstrated to successfully reverse the biological effects of roc, vec and cis in vivo in rats. To further confirm P6]Excellent binding affinity of AS for roc relative to M2, by ¹ Head-to-head testing for H NMR spectroscopic monitoring. FIGS. 15a-e show P6 for uncomplexed]AS, M2 and roc and P6]AS roc complex and M2 roc complex ¹ H NMR. For the M2. Roc complex, for the enantiomerically pure complex, H is present _a* And H _b* Splitting into a total of 8 resonances and a low field offset. For both complexes, axial steroid Me-groups (H) are present _p And H _q ) This allows monitoring the composition of a mixture of the two competing host-guest complexes. FIG. 15f shows P6 when 1 equivalent is used]Recorded when AS treated solutions of M2. Roc (0.5 mM) ¹ H NMR spectrum. Loss of resonance of M2 roc and P6]The appearance of resonance of AS roc further verifies P6]Excellent affinity of AS in the context of neuromuscular blockers. Previously, due to the lower binding affinity (K) of the M2. Cis complex _a ＝4.8×10 ⁶ M ^-1 ) As a result, only at higher doses of M2 (. Gtoreq.40 mg kg ^-1 ) The reversal of the in vivo effect of cis was achieved in rats. Found by experiment that P7]AS and cis formation (P7]AS) ₂ Cis complexes in which the benzylisoquinolinium end groups are each interrupted by P [7]]And (5) compounding the AS main body. (P7)]AS) ₂ The ITC data of cis can be fitted to where N _{Site of the body} K and =2 _a ＝1.52×10 ⁷

M

^-1 1 of (1). Thus, P [7]]AS has the potential to convert to in vivo reversal agents for cis.

In general, this example describes P [5]]AS-P[7]Synthesis of AS, P [5]]ACS and P [6]]The X-ray crystal structure of AS and their molecular recognition properties for (di) ammonium ions in aqueous solution. P [ n ]]AS accumulates 2n negative charges into a small volume near the entrance of the acceptor, which increases the electrostatic contribution to the binding self-energy. Found P5]AS and P [6]]Binding affinity of AS for (bis) quaternary ammonium ion than WP [5]]And WP [6]]Is significantly higher. Thus, the suggested family name is column [ n ]]MaxQ。P[6]The picomolar affinity of AS for roc and vec greatly exceeds that of acyclic CB [ n ]]Receptor type M2 and the receptor class B in clinical practice ^TM Sugammadex (r) is used under the trade name sugammadex (r). From P5]AS and P [6]]Ultra-tight bonding AS demonstrated (e.g. picomolar K) _d ) Make them react with CB [ n ]]Are juxtaposed together as some of the most efficient synthetic receptors in water. P5]AS and P [6]]The ultra-tight binding of AS suggests that sulfated pillararomatics and their functionalized derivatives can be used AS non-covalent linkers for bioconjugation, for (bio) chemical separations, for theranostics and for sequestration and repair in chemical and biological systems.

Determination of K between various hosts and cationic guests using Isothermal Titration Calorimetry (ITC) _a . All ITC experiments were performed in a 200 μ L working volume of the sample cell of the PEAQ ITC instrument. An injection syringe of 40 μ L capacity was used. In each case, the host and guest solutions were prepared at 20mM NaH ₂ PO ₄ Buffer (pH 7.4). The sample cell was filled to capacity (200 μ L) with host solution and to guest solution (first)One injection =0.4 μ L followed by 18 injections =2 μ L). The binding data were fitted using either the 1.

Example 3

This example provides the in vivo effect of P [6] AS in a relevant mouse model for reversing methamphetamine-induced excitatory autonomic activity (hypercomphenotion). This example also provides results from in vivo toxicology studies of P [5] AS and P [6] AS.

P[5]AS and P [6]]Cytotoxicity data of AS. To test the cytotoxicity and cell survival of the above compounds, we used two different assays: MTS (CellTiter 96 AQueous) for measuring cell metabolism

) AK (AK) determined and measured for cell death by release of the cytoplasmic adenylate kinase into the supernatant

Kit) was measured. Both assays were performed using two different cell lines. HEK293 and Hep G2 cells are frequently used for drug toxicity studies. HEK293 (human kidney cell line) was used to evaluate the effect of drugs on the renal system, while Hep G2 (human liver cell line) was used to assess the response of liver cells in which the drug was metabolized. MTS and AK assays for both cell lines were performed after 24h incubation with compounds at concentrations of 0.01mM, 0.03mM, 0.1mM, 0.3mM and 1 mM. Eight technical replicates were assigned to untreated cells and four technical replicates were assigned to cells treated with each compound and staurosporine (apoptosis inducing agent).

The absorbance and relative luminescence data collected were normalized to percent cell survival (MTS) and percent cell death (AK) using equations 1 and 2:

1) Cell survival% = (Abs samples/mean Abs UT) × 100

2) % cell death = (RLU sample/mean RLU distilled water) × 100

Toxicity studies on the liver cell line HepG2 using the MTS and AK assays showed that P [5] AS exhibited low cytotoxicity up to a concentration of 1mM and high cell tolerance up to a concentration of 0.3mM (FIGS. 63A, B). P [6] AS showed low cytotoxicity up to 1mM concentration and high cell tolerance up to 0.1mM concentration in human HepG2 cells (FIGS. 63C, D).

Similar toxicity studies performed on human kidney (HEK 293) cells showed that P [5] AS exhibited low cytotoxicity up to a concentration of 1mM and high cellular tolerance up to a concentration of 0.1mM (FIGS. 64A, B). P [6] AS showed low cytotoxicity up to 1mM concentration and high cellular tolerance up to 0.03mM concentration (FIGS. 64C-D).

Maximum tolerated dose study (MTD) in vivo. Animal studies (IACUC # R-JAN-17-25) were conducted in the University of Maryland microbiological Building (University of Maryland, microbiology construction) under the supervision of doctor Volker Briken. A total of 20 female Swiss Webster were used in this study. Three different concentrations of P [6] AS (11.31mM, 7.54mM, 3.77mM) were used. A PBS control group was also included. Each concentration group and control group contained 5 mice. Mice received compounds in 0.150ml PBS via tail vein injection with 48 hours interval between injections. Mice were monitored for body weight and health for 2 weeks after the last injection. And (4) behavior summary: the 11.31mM dose group showed dose-dependent side effects in the form of immobility (freeze up) and some dyspnea. The 11.31mM dose group returned to baseline behavior (behavior observed with PBS control) at ≈ 2-3 hours post-injection. The lowest dose group, 3.77mM, showed no side effects and behavior overall comparable to the PBS control group.

MTD study was performed on P [6] AS. Female Swiss Webster mice (n =5 per group) were given different concentrations of P [6] as or Phosphate Buffered Saline (PBS) via the tail vein on days 0 and 2 (indicated by a). Normalized mean body weight change for each study group is indicated. Error bars represent SEM.

In vivo reversal of methamphetamine-induced excitatory autonomic activity by P [6] AS

An animal. Eight male Swiss Webster (CFW) mice were obtained from Charles River Laboratories, and these mice weighed-30 g at arrival. Mice were housed individually in temperature and humidity controlled rooms on a 12h light/dark schedule with lights on 6. During the duration of these two experiments, the mice were fed food and water ad libitum. All behavioral tests were performed between 6 am and 2 pm of the EST at 00 am, and all experimental procedures were approved by the university of maryland animal care and use committee and met the guidelines set by the american National Research Council (National Research Council).

And (4) performing surgical procedures. Mice were anesthetized by Intraperitoneal (IP) injection of ketamine (100 mg/kg)/xylazine (10 mg/kg) (n = 8) and implanted with a jugular vein catheter with a head mounted port. All surgical procedures were performed using sterile techniques, with body temperature monitored and maintained throughout the surgery. The catheter was placed in the right jugular vein with the port leading subcutaneously out the top of the skull. The port (5MM Up pedestal, p1 Technologies) was fixed to the skull with a combination of super glue (Loctite) and dental cement. Immediately after surgery, mice received Rimadyl (5 mg/kg) injections and 0.4mL of warmed sterile saline. Mice were treated with rimadal (5 mg/kg) for two days post-operatively and given at least 5 days for recovery prior to recovery training. The catheter was flushed daily with 0.1mL of sterile saline solution containing gentamicin (0.33 mg/mL) and 0.1mL of sterile saline solution containing heparin (20 IU/mL) to reduce clotting and maintain catheter patency. Catheter patency was assessed daily starting the first day after surgery until the end of the test. Any mice whose catheters showed significant reflux over most of the days were excluded from the analysis.

And (5) testing the behavior. Mice were trained according to the standard self-plastication task described previously. All behavioral procedures were performed in a Med Associates test room equipped with a food cup, a retractable rod, and 4 floor IR beams. The time stamp is generated when the head enters the food cup, the lever deflects downward, or the floor beam breaks, and is recorded by the action computer.

Mice were provided a one-day potty training regimen which involved randomly delivering thirty 20mg sucrose pellets (Bioserv) on a schedule of variable intervals 30 ± 15 to habituate the mice to the kit and pellet delivery. To minimize the effects of novelty-induced feeding depression, mice were provided with five to six 20mg sucrose pellets in their respective cages for 2-3 days before training was initiated.

After the diet training, the mice began the Pavlovian training phase, which consisted of having the lever (CS) present for 8 seconds continuously, followed immediately by delivering the sucrose pellets and retracting the lever. The CSs are presented at random intervals of 90 ± 30 s. Each Pavlovian phase included 30 trials. Pavlovian training lasted 4 days prior to surgery. After surgery and recovery, mice were subjected to Pavlovian training for an additional 8 days while being exposed to various treatments.

And (4) designing an experiment. The efficacy of P [6] AS was evaluated using a semi-offset design, in which all mice received every possible experimental treatment. The purpose of the experiment was: (1) verification that methamphetamine binding by P [6] AS is not impaired in vivo, (2) verification that P [6] AS does not alter locomotor activity, and (3) verification that P [6] AS sequesters methamphetamine in vivo. On the first day, mice received a treatment-free rejuvenation phase (refreshsession) regardless of the experiment. In the next six stages, the mice received one of six possible treatments: 0.01M PBS (0.2 mL, infused), P [6] AS only (4 mM, 0.178mL, infused), methamphetamine only (0.5 mg/kg;0.022mL, infused), a premixed solution of P [6] AS and methamphetamine (premix;. 7. Mice received only one infusion per day. The dose of methamphetamine was chosen based on previously published values for reliable excitatory autonomic activity observed in mice. This is to select the minimum dose that reliably induces excitatory autonomic activity.

After completing the first six phases, the mice completed two additional days of behavioral testing. On day 7, half of the mice (n = 4) received P [6] AS followed by methamphetamine (0.178mL P [6] AS,0.022mL Meth, infused) administered 5 minutes later, followed by methamphetamine infusion administered on day 8 of the test, followed by P [6] AS (0.022mL Meth,0.178mL P [6] AS, infused) administered 5 minutes later. The other half of the mice (n = 4) received exactly the same but in reverse order treatment on

day

7 and 8.

For each experiment, a total autonomic activity count (i.e., the total number of beam breaks) was obtained for each mouse throughout each training session. For each experiment, autonomic activity counts were then analyzed during treatment using one-way repeated measures ANOVA (paired post-hoc t-test corrected with tukey) in Graphpad Prism (version 9.0.0).

After a 5 minute delay between treatment with methamphetamine and P [6] AS administration, an in vivo reversal of the methamphetamine-induced excitatory autonomic activity effect was observed. On

days

7 and 8, mice (n = 8) received methamphetamine followed by infusion of 0.01M PBS (REV-C; 0.022mL meth,0.2mL PBS infusion) administered 5 minutes later, or methamphetamine followed by P [6] AS administered in a counteracting fashion 5 minutes later (REV-5, 0.022mL meth,0.178mL P [6] AS, infused). Administration of P [6] as reduced excitatory autonomic activity 5 minutes after methamphetamine exposure (paired t-test, t (7) =2.757, P = 0.0282). Bars represent average autonomic activity counts. Error bars represent standard error of the mean (SEM). Dots represent counts for each mouse (n = 8).

It will be appreciated from the foregoing that this example provides an analysis of the efficacy of P [6] AS in chelating methamphetamine in vivo. Eight male Swiss Webster (CFW) mice were trained according to the previously described Pavlovian autoplastic task, and autonomic activity values were obtained and analyzed accordingly. To establish methamphetamine-induced excitatory locomotor activity and examine the efficacy of P [6] as, mice were treated first with a single infusion of PBS (0.01M), P [6] as alone, methamphetamine alone, a pre-mixed solution of P [6] as and methamphetamine, P [6] as followed by methamphetamine administration 30s later, or methamphetamine followed by P [6] as administration 30s later (in a counteracting fashion). Fig. 66 depicts the results of this experiment by plotting the autonomic activity counts as a function of treatment. Mixed effects analysis revealed a significant major effect of treatment (F (5,35) =7.116, p = 0.0001), with Tukey-corrected postmortem comparisons showing a significant increase in autonomic activity counts with methamphetamine treatment over all other treatments (p's < 0.05). Crucially, there was no difference in autonomic activity for comparison between reversals (i.e. meth first, followed by P6 as after 30 seconds), indicating that P6 as itself had no negative effect on autonomic activity behaviour and that successive administration of P6 as reduced methamphetamine induced excitatory autonomic activity to control levels.

Although the results of this first analysis indicate the potential efficacy of P [6] as in chelating methamphetamine and inducing behavioral changes, it is likely that the 30 second interval between methamphetamine administration and P [6] as administration in reversal conditions is too short to be behaviorally relevant. To address this issue, subsequent experiments were performed in which mice (n = 8) were administered methamphetamine followed by 0.01M PBS (REV-C) after 5 minutes or methamphetamine followed by P [6] as (REV-5) after 5 minutes in a counteracting manner before completing the self-plastication task on

days

7 and 8 of the test. FIG. 67 plots autonomic activity counts as a function of REV-C or REV-5 treatment. A significant reduction in autonomic activity was observed under REV-5 conditions relative to REV-C (paired t-test, t (7) =2.757, p = 0.0282). Although not directly comparable from an experimental design point of view, it is important that on days 1-6, the level of autonomic activity under REV-5 conditions closely approximates the level observed under control conditions, while the autonomic activity count under REV-C conditions appears to approximate the level observed when treated with methamphetamine alone. Taken together, these findings indicate that P [6] AS is able to sequester methamphetamine and reverse methamphetamine-induced excitatory locomotor activity in vivo with little to no effect on the locomotor activity behavior of the animal itself.

Example 4

The following examples illustrate ITC data for various drugs in conjunction with the subject of the present disclosure.

TABLE 10K of MDMA, methoxylin and heroin _a 。

^a Measured by ITC competitive titration of host (0.1 mM) and 1, 3-propanediammonium chloride (0.15 mM) in a pool with guest (1 mM) in a syringe. ^b Measured directly by ITC titration of the subject (10 μ M) in the cell with the guest (100 μ M) in the syringe. ^c Measured directly by ITC titration of the subject (0.1 mM) in the well with guest (1 mM) in syringe.

FIGS. 69-71 show ITC data for P [6] AS and MDMA, methoxyephedrine, and heroin.

Although the present disclosure has been described with respect to one or more particular embodiments, it is to be understood that other embodiments of the present disclosure may be made without departing from the scope of the present disclosure.

Claims

1. A compound having the structure:

wherein

Ar is an aryl group, wherein the aryl group is attached to an adjacent methylene group with para substitution;

each R is independently selected from: -OS (O) ₂ O ^– M ⁺ 、-OS(O) ₂ OH, a non-sulfate anionic group, a carboxylic acid/carboxylate group, a phosphonic acid/phosphonate group, a phosphate group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aliphatic group, an O-alkyl group, -H, a substituted or unsubstituted alkyl group, a halogen, an amide group, a cyano group, a substituted or unsubstitutedA substituted sulfur-containing aliphatic group, a nitro group, an amino group, a substituted or unsubstituted nitrogen-containing aliphatic group, a substituted or unsubstituted polyethylene glycol group, a polyether group, an O-aryl group, an ester group, a carbamate group, an imine group, an aldehyde group, -SO ₃ H group, -SO ₃ Na group, -OSO ₂ F group, -OSO ₂ CF ₃ Group, -OSO ₂ OR '"group, wherein R'" is a substituted OR unsubstituted aryl group OR a substituted OR unsubstituted alkyl group and combinations thereof, wherein M ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS),

x is 0, 1,2 or 3; and y is independently at each occurrence 0, 1,2,3, or 4, provided that at least one y is 1 and at least one R group is-OS (O) ₂ O ^– M ⁺ Wherein M is ⁺ Is Na ⁺ 、K ⁺ 、Ca ²⁺ 、Mg ²⁺ 、Zn ²⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ Or a cationic form of ethylenediamine, piperazine or TRIS (hydroxymethyl) aminomethane (TRIS), or-OS (O) ₂ OH，

Or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer or mixture thereof.

2. The compound of claim 1, wherein the aryl group is independently selected at each occurrence from a phenyl group, a fused ring group, a biaryl group, and a terphenyl group.

3. The compound of claim 1, wherein the cyclic core of the compound comprises one or more phenyl groups of one or more of the aryl groupsHas at least 1 independently selected from-OS (O) ₂ O ^– M ⁺ and-OS (O) ₂ R group of OH.

4. The compound of claim 3, wherein the compound has the structure:

5. the compound of claim 1, wherein all of said aryl groups contain independently-OS (O) ² O ^– M ⁺ or-OS (O) ₂ R group of OH.

6. The compound of claim 1, wherein at least one aryl group is not comprised of is-OS (O) ₂ O ^– M ⁺ or-OS (O) ₂ R group of OH.

7. The compound of claim 1, wherein the compound has the structure:

8. the compound of claim 7, wherein 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently-OS (O) ₂ O ^– M ⁺ Radical or-OS (O) ₂ An OH group.

9. The compound of claim 7, wherein the cyclic core of the compound comprises at least 1 phenyl group per phenyl group independently selected from-OS (O) ₂ O ^– M ⁺ and-OS (O) ₂ R group of OH.

10. The compound of claim 7, wherein at least one phenyl group does not comprise a group that is-OS (O) ₂ O ^– M ⁺ or-OS (O) ₂ R group of OH.

11. The compound of claim 1, wherein M ⁺ Is Na ⁺ 、K ⁺ 、H ₄ N ⁺ 、Et ₃ NH ⁺ 、Me ₄ N ⁺ 、(HOCH ₂ CH ₂ ) ₃ NH ⁺ 。

12. The compound of claim 11, wherein M ⁺ Is Na ⁺ 。

13. A composition comprising one or more compounds of claim 1.

14. The composition of claim 13, further comprising a pharmaceutical carrier.

15. The composition of claim 13, wherein the one or more compounds are disposed on at least a portion of a solid substrate.

16. The composition of claim 15, wherein the solid substrate comprises silica, polymer beads, polymer resins, metal nanoparticles, metals, or combinations thereof.

17. The composition of claim 13, wherein at least a portion or all of the one or more compounds have one or more pharmaceutically active agents disposed in a cavity of the one or more compounds.

18. A method for sequestering one or more neuromuscular blocking agents, one or more anesthetics, one or more medicants, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof, comprising:

contacting the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or combinations thereof with one or more compounds of claim 1,

wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more medicants, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are sequestered by the one or more compounds.

19. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in an aqueous sample, in a solid sample, in a gaseous sample, or on a solid surface.

20. The method of claim 19, wherein the aqueous sample is a wastewater sample, an industrial water sample, or a municipal water sample.

21. The method of claim 18, wherein a complex is formed from the one or more compounds and the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof.

22. The method of claim 18, wherein the complex is removed from the aqueous sample, the solid sample, or the gas sample.

23. The method of claim 18, wherein the one or more neuromuscular blocking agents, the one or more anesthetics, the one or more pharmaceutical agents, the one or more pesticides, the one or more dyes, the one or more malodorous compounds, the one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in and/or on an individual, and the contacting comprises administering the one or more compounds.

24. The method of claim 23, wherein the individual is a human or non-human mammal.

25. A method for reversing drug-induced neuromuscular blockade and/or anesthesia and/or the effect of one or more agents in an individual comprising administering to the individual in need of reversing neuromuscular blockade and/or reversing anesthesia and/or reversing the effect of one or more agents one or more compounds according to claim 1.

26. The method of claim 25, wherein the subject is in need of reversal of drug-induced neuromuscular blockade.

27. The method of claim 25, wherein the subject is in need of reversal of anesthesia.

28. The method of claim 25, wherein the subject is in need of reversal of drug-induced neuromuscular blockade and anesthesia.

29. The method of claim 25, wherein the subject is in need of reversal of the effect of one or more agents.

30. The method of claim 29, wherein the one or more agents are selected from the group consisting of one or more drugs of abuse, one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites, and combinations thereof.

31. The method of claim 25, wherein the individual in need thereof is a human.

32. The method of claim 25, wherein the individual in need thereof is a non-human mammal.

33. A method for the prevention and/or treatment of a disorder in an individual, comprising administering to an individual in need of said prevention and/or said treatment one or more compounds according to claim 1 and one or more agents, wherein said one or more compounds and said one or more agents are present as a complex, wherein said treatment and/or said prevention of a disorder in said individual is performed after said administration.

34. The method of claim 33, wherein one or more of the one or more pharmaceutical agents has a solubility of less than 100 μ Μ in an aqueous solvent.