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Dive into the research topics where Ben Zhang is active.

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Featured researches published by Ben Zhang.


Nature Chemistry | 2012

Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

Da Ma; Gaya Hettiarachchi; Duc Thang Nguyên; Ben Zhang; James B. Wittenberg; Peter Y. Zavalij; Volker Briken; Lyle Isaacs

The solubility characteristics of 40–70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container–drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery. Acyclic cucurbituril-type molecular containers have been found to increase the solubility of insoluble pharmaceutical agents in water by up to 2,750-fold. In vitro and in vivo toxicology studies suggest that the containers are well tolerated, and paclitaxel solubilized in this manner efficiently kills HeLa and SK-OV-3 cancer cells.


Angewandte Chemie | 2012

Acyclic Cucurbit[n]uril‐Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo

Da Ma; Ben Zhang; Ulrike Hoffmann; Martina Grosse Sundrup; Matthias Eikermann; Lyle Isaacs

Be my guest: two acyclic cucurbit[n]uril-type receptors that carry SO(3) (-) -groups bind tightly to several commonly used neuromuscular blocking agents, such as rocuronium, in aqueous solution as revealed by direct and competitive UV/Vis binding assays. One of these containers functions as a potent reversal agent for rocuronium-induced neuromuscular block in rats.


Journal of the American Chemical Society | 2012

Supramolecular sensor for cancer-associated nitrosamines.

Tsuyoshi Minami; Nina A. Esipenko; Ben Zhang; Maria E. Kozelkova; Lyle Isaacs; Ryuhei Nishiyabu; Yuji Kubo; Pavel Anzenbacher

A supramolecular assay based on two fluorescent cucurbit[n]uril probes enables the recognition and quantification of nitrosamines, including cancer-associated nitrosamines, compounds that are difficult to recognize. The cross-reactive sensor leverages weak interactions and competition among the probe, metal, and guest, yielding high information density in the signal output (variance) and enabling the recognition of structurally similar guests.


Journal of the American Chemical Society | 2013

Multianalyte Sensing of Addictive Over-the-Counter (OTC) Drugs

Tsuyoshi Minami; Nina A. Esipenko; Ali Akdeniz; Ben Zhang; Lyle Isaacs; Pavel Anzenbacher

A supramolecular sensor array composed of two fluorescent cucurbit[n]uril-type receptors (probe 1 and probe 2) displaying complementary selectivities was tested for its ability to detect and quantify drug-related amines. The fluorimetric titration of the individual probes showed highly variable and cross-reactive analyte-dependent changes in fluorescence. An excellent ability to recognize a variety of analytes was demonstrated in qualitative as well as quantitative assays. Importantly, a successful quantitative analysis of several analytes of interest was achieved in mixtures and in human urine. The throughput and sensitivity surpass those of the current state-of-the-art methods that usually require analyte solid-phase extraction (SPE). These results open up the opportunity for new applications of cucurbit[n]uril-type receptors in sensing and pave the way for the development of simple high-throughput assays for various drugs in the near future.


Journal of Medicinal Chemistry | 2014

Acyclic cucurbit[n]uril-type molecular containers: influence of aromatic walls on their function as solubilizing excipients for insoluble drugs.

Ben Zhang; Lyle Isaacs

We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a–1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M–1). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a–1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a–1e, lower concentrations of 1a–1e are required to achieve identical [drug].


Anesthesiology | 2013

Calabadion: A new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents.

Ulrike Hoffmann; Martina Grosse-Sundrup; Katharina Eikermann-Haerter; Sebastina Zaremba; Cenk Ayata; Ben Zhang; Da Ma; Lyle Isaacs; Matthias Eikermann

Introduction:To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n]uril family of molecular containers, reverses benzylisoquinoline and steroidal neuromuscular-blocking agent effects. Methods:A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at 30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012 mg/kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a 1H NMR assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure. Results:After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were accelerated from 12.3 ± 1.1 and 16.2 ± 3.3 min with placebo to 4.6 ± 1.8 min with neostigmine/glycopyrrolate to 15 ± 8 and 84 ± 33 s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio of 0.9 were accelerated from 8.7 ± 2.8 and 9.9 ± 1.7 min with placebo to 2.8 ± 0.8 and 7.6 ± 2.1 min with neostigmine/glycopyrrolate to 47 ± 13 and 87 ± 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered calabadion 1 appeared in the urine within 1 h. Conclusion:Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-blocking agents.


Journal of Virology | 2014

New Small-Molecule Inhibitors Effectively Blocking Picornavirus Replication

Lauren A. Ford Siltz; Ekaterina G. Viktorova; Ben Zhang; Diana Kouiavskaia; Eugenia Dragunsky; Konstantin Chumakov; Lyle Isaacs; George A. Belov

ABSTRACT Few drugs targeting picornaviruses are available, making the discovery of antivirals a high priority. Here, we identified and characterized three compounds from a library of kinase inhibitors that block replication of poliovirus, coxsackievirus B3, and encephalomyocarditis virus. Using an in vitro translation-replication system, we showed that these drugs inhibit different stages of the poliovirus life cycle. A4(1) inhibited both the formation and functioning of the replication complexes, while E5(1) and E7(2) were most effective during the formation but not the functioning step. Neither of the compounds significantly inhibited VPg uridylylation. Poliovirus resistant to E7(2) had a G5318A mutation in the 3A protein. This mutation was previously found to confer resistance to enviroxime-like compounds, which target a phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ)-dependent step in viral replication. Analysis of host protein recruitment showed that E7(2) reduced the amount of GBF1 on the replication complexes; however, the level of PI4KIIIβ remained intact. E7(2) as well as another enviroxime-like compound, GW5074, interfered with viral polyprotein processing affecting both 3C- and 2A-dependent cleavages, and the resistant G5318A mutation partially rescued this defect. Moreover, E7(2) induced abnormal recruitment to membranes of the viral proteins; thus, enviroxime-like compounds likely severely compromise the interaction of the viral polyprotein with membranes. A4(1) demonstrated partial protection from paralysis in a murine model of poliomyelitis. Multiple attempts to isolate resistant mutants in the presence of A4(1) or E5(1) were unsuccessful, showing that effective broad-spectrum antivirals could be developed on the basis of these compounds. IMPORTANCE Diverse picornaviruses can trigger multiple human maladies, yet currently, only hepatitis A virus and poliovirus can be controlled with vaccination. The development of antipicornavirus therapeutics is also facing significant difficulties because these viruses readily generate resistance to compounds targeting either viral or cellular factors. Here, we describe three novel compounds that effectively block replication of distantly related picornaviruses with minimal toxicity to cells. The compounds prevent viral RNA replication after the synthesis of the uridylylated VPg primer. Importantly, two of the inhibitors are strongly refractory to the emergence of resistant mutants, making them promising candidates for further broad-spectrum therapeutic development. Evaluation of one of the compounds in an in vivo model of poliomyelitis demonstrated partial protection from the onset of paralysis.


Anesthesiology | 2015

Comparative Effectiveness of Calabadion and Sugammadex to Reverse Non-depolarizing Neuromuscular-blocking Agents.

Friederike Haerter; Jeroen C. P. Simons; Urs Foerster; Ingrid Moreno Duarte; Daniel Diaz-Gil; Shweta Ganapati; Katharina Eikermann-Haerter; Cenk Ayata; Ben Zhang; Manfred Blobner; Lyle Isaacs; Matthias Eikermann

Background:The authors evaluated the comparative effectiveness of calabadion 2 to reverse non-depolarizing neuromuscular-blocking agents (NMBAs) by binding and inactivation. Methods:The dose–response relationship of drugs to reverse vecuronium-, rocuronium-, and cisatracurium-induced neuromuscular block (NMB) was evaluated in vitro (competition binding assays and urine analysis), ex vivo (n = 34; phrenic nerve hemidiaphragm preparation), and in vivo (n = 108; quadriceps femoris muscle of the rat). Cumulative dose–response curves of calabadions, neostigmine, or sugammadex were created ex vivo at a steady-state deep NMB. In living rats, the authors studied the dose–response relationship of the test drugs to reverse deep block under physiologic conditions, and they measured the amount of calabadion 2 excreted in the urine. Results:In vitro experiments showed that calabadion 2 binds rocuronium with 89 times the affinity of sugammadex (Ka = 3.4 × 109 M−1 and Ka = 3.8 × 107 M−1). The results of urine analysis (proton nuclear magnetic resonance), competition binding assays, and ex vivo study obtained in the absence of metabolic deactivation are in accordance with an 1:1 binding ratio of sugammadex and calabadion 2 toward rocuronium. In living rats, calabadion 2 dose-dependently and rapidly reversed all NMBAs tested. The molar potency of calabadion 2 to reverse vecuronium and rocuronium was higher compared with that of sugammadex. Calabadion 2 was eliminated renally and did not affect blood pressure or heart rate. Conclusions:Calabadion 2 reverses NMB induced by benzylisoquinolines and steroidal NMBAs in rats more effectively, i.e., faster than sugammadex. Calabadion 2 is eliminated in the urine and well tolerated in rats.


Molecular Pharmaceutics | 2016

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors

Gaya Hettiarachchi; Soumen K. Samanta; Shane Falcinelli; Ben Zhang; Damien Moncelet; Lyle Isaacs; Volker Briken

Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.


Journal of the American Chemical Society | 2017

Supramolecular Sensors for Opiates and Their Metabolites

Elena G. Shcherbakova; Ben Zhang; Samer Gozem; Tsuyoshi Minami; Peter Y. Zavalij; Mariia Pushina; Lyle Isaacs; Pavel Anzenbacher

The present study highlights a sensing approach for opiates using acyclic cucurbituril (aCBs) sensors comprising four glycouril units terminated on both ends with naphthalene fluorophore walls. The connectivity between the glycourils and naphthalene rings largely defines the opening size of the cucurbituril cavity and its diameter. The large hydrophobic binding cavity is flexible and is able to adapt to guests of various size and topology. The recognition event between the aCBs and guests results in modification of the fluorescence of the terminal walls, a fluorescence response that can be used to sense the drugs of abuse morphine, heroin, and oxycodone as well as their metabolites. Molecular dynamics is employed to understand the nature of the binding interactions. A simple three sensor cross-reactive array enables the determination of drugs and their metabolites in water with high fidelity and low error. Quantitative experiments performed in urine using a new three-way calibration model allows for determination of drugs and their metabolites using one sensor from a single fluorescence reading.

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Pavel Anzenbacher

Bowling Green State University

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Nina A. Esipenko

Bowling Green State University

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