Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl

Brockett, Adam T.; Xue, Weijian; King, David; Deng, Chun‐Lin; Zhai, Canjia; Shuster, Malcolm D.; Rastogi, Shivangi; Briken, Volker; Roesch, Matthew R.; Isaacs, Lyle

doi:10.1016/j.chempr.2022.11.019

Cited by 30 publications

(25 citation statements)

References 73 publications

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“…While kinetic lability of imine and boronic cages is essential for their syntheses, [12b] it prevents their use in aqueous environments where water typically degrades such structures [25] . At the same time, water is the medium where most biological processes take place and in which organic cavitands with nonpolar inner space act [26] as effective hosts of drugs, [27] fluorescent dyes, [28] or other functional molecules [29] . In an attempt to address this challenge, Warmuth and co‐workers completed [30] post synthetic functionalization of their imine‐based octahedron by reducing imines followed by oxidizing resorcinarenes’ hydroxyl groups into carboxylates.…”

Section: Introductionmentioning

confidence: 99%

Crystalline Nanoparticles of Water‐Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs

Liyana Gunawardana,

Ward,

Wang

et al. 2023

Angew Chem Int Ed

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We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC‐11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw=8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC‐11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.0, the amphiphilic nature prompts its assembly into nanoparticles (d=250 nm, DLS). Cryo‐TEM examination of nanoparticles revealed their crystalline nature with wafer‐like shapes and hexagonally arranged cages. Nanoparticulate CBC‐11 traps anticancer drugs irinotecan and doxorubicin, with each cage binding up to four drug molecules in a non‐cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), the IC50 value of CBC‐11 was above 100 μM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.

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Section: Introductionmentioning

confidence: 99%

Crystalline Nanoparticles of Water‐Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs

Liyana Gunawardana,

Ward,

Wang

et al. 2023

Angew Chem Int Ed

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“…Although they were first reported as recently as 2008, they have already become established as a vital part of the modern supramolecular chemistry toolbox . This is largely due to their rich host–guest chemistry, which has allowed their incorporation into interlocked structures, , use in molecular separation, − and binding and sequestration of biologically important guests. − …”

Section: Introductionmentioning

confidence: 99%

“…In contrast, while P6 s are very promising for a number of applications particularly binding biologically relevant guests − their synthesis is often nontrivial. When large alkoxy substituents such as hexyl or CH 2 –cyclohexyl are incorporated into the macrocycles ( i.e.…”

Section: Introductionmentioning

confidence: 99%

Balancing on a Knife’s Edge: Studies on the Synthesis of Pillar[6]arene Derivatives

2023

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Pillar[6]arenes are established as crucial building blocks in supramolecular chemistry; however, they can be difficult to synthesize, particularly in the absence of large solubilizing substituents. In this work, we explore variability in literature syntheses of pillar[6]arene derivatives and suggest that the outcome is dependent on whether oligomeric intermediates stay in solution long enough for the thermodynamically favorable macrocyclization to occur. We demonstrate that in a previously capricious BF3·OEt2-mediated procedure, ≤5 mol % of a Brønsted acid can slow down the reaction to favor macrocycle formation.

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“…Importantly, one of our primary motivations for developing such deep-cavity macrocycles was the potential to harness stronger hydrophobic effects, [43][44][45] facilitated by their deep, nano-confined cavities, ultimately leading to exceptionally high binding affinities [46,47] in aqueous environments. To explore this potential in aqueous-phase molecular recognition, we herein introduced ten sulfate groups into C[5]A, inspired by Isaacs et al, [12,30] resulting in water-soluble SC[5]A (Scheme 1). The high charge density of the sulfate groups at both ends of SC[5]A can not only provide strong electrostatic attraction for binding positively charged guests but also help to some extent in preventing the collapse of the cavity structure in aqueous solutions.…”

Section: Introductionmentioning

confidence: 99%

Adaptive and Ultrahigh‐Affinity Recognition in Water by Sulfated Conjugated Corral[5]arene

Wang,

Li,

Deng

et al. 2023

Angew Chem Int Ed

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The pursuit of synthetic receptors with high binding affinities has long been a central focus in supramolecular chemistry, driven by their significant practical relevance in various fields. Despite the numerous synthetic receptors that have been developed, most exhibit binding affinities in the micromolar range or lower. Only a few exceptional receptors achieve binding affinities exceeding 109 M−1, and their substrate scopes remain rather limited. In this context, we introduce SC[5]A, a conjugated corral‐shaped macrocycle functionalized with ten sulfate groups. Owing to its deep one‐dimensional confined hydrophobic cavity and multiple sulfate groups, SC[5]A displays an extraordinarily high binding strength of up to 1011 M−1 towards several size‐matched, rod‐shaped organic dications in water. Besides, its conformation exhibits good adaptability, allowing it to encapsulate a wide range of other guests with diverse molecular sizes, shapes, and functionalities, exhibiting relatively strong affinities (Ka=106–108 M−1). Additionally, we've explored the preliminary application of SC[5]A in alleviating blood coagulation induced by hexadimethrine bromide in vitro and in vivo. Therefore, the combination of ultrahigh binding affinities (towards complementary guests) and adaptive recognition capability (towards a wide range of functional guests) of SC[5]A positions it as exceptionally valuable for numerous practical applications.

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Pillar[6]MaxQ: A potent supramolecular host for in vivo sequestration of methamphetamine and fentanyl

Cited by 30 publications

References 73 publications

Crystalline Nanoparticles of Water‐Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs

Crystalline Nanoparticles of Water‐Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs

Balancing on a Knife’s Edge: Studies on the Synthesis of Pillar[6]arene Derivatives

Adaptive and Ultrahigh‐Affinity Recognition in Water by Sulfated Conjugated Corral[5]arene

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