Publications by authors named "Morgan M Ashcraft"

3 Publications

  • Page 1 of 1

Reactive Oxygen Species-Triggered Dissociation of a Polyrotaxane-Based Nanochelator for Enhanced Clearance of Systemic and Hepatic Iron.

ACS Nano 2021 01 30;15(1):419-433. Epub 2020 Dec 30.

Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States.

Chronic blood transfusions are used to alleviate anemic symptoms in thalassemia and sickle cell anemia patients but can eventually result in iron overload (IO) and subsequently lead to severe oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat transfusional IO, but the use of the iron chelator is hindered by nonspecific toxicity and poor pharmacokinetic (PK) properties in humans, resulting in the need to administer the drug long-term infusion regimens that can often lead to poor patient compliance. Herein, a nanochelator system that uses the characteristic IO physiological environment to dissociate was prepared through the incorporation of DFO and reactive oxygen species (ROS)-sensitive thioketal groups into an α-cyclodextrin-based polyrotaxane platform (rPR-DFO). ROS-induced dissociation of this nanochelator (. 10 nm) into constructs averaging 2 nm in diameter significantly increased urine and fecal elimination of excess iron . In addition to significantly improved PK properties, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in single high dose or multiple dose acute toxicity studies. The overall features of rPR-DFO as a promising system for iron chelation therapy can be attributed to a combination of the nanochelator's improved PK, favorable distribution to the liver, and ROS-induced dissociation properties into constructs <6 nm for faster renal elimination. This ROS-responsive nanochelator design may serve as a promising alternative for safely prolonging the circulation of DFO and more rapidly eliminating iron chelates from the body in iron chelation therapy regimens requiring repeated dosing of nanochelators.
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http://dx.doi.org/10.1021/acsnano.0c01083DOI Listing
January 2021

Synthesis and biological evaluation of anti-cancer agents that selectively inhibit Her2 over-expressed breast cancer cell growth via down-regulation of Her2 protein.

Bioorg Med Chem Lett 2018 02 12;28(4):727-731. Epub 2018 Jan 12.

Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA. Electronic address:

Compound JCC76 selectively inhibited the proliferation of human epidermal growth factor 2 (Her2) over-expressed breast cancer cells. In the current study, a ligand based structural optimization was performed to generate new analogs, and we identified derivatives 16 and 17 that showed improved activity and selectivity against Her2 positive breast cancer cells. A structure activity relationship (SAR) was summarized. Compounds 16 and 17 were also examined by western blot assay to check their effect on Her2 protein. The results reveal that the compounds could decrease the Her2 protein, which explains their selectivity to Her2 over-expressed breast cancer cells. Furthermore, the compounds inhibited the chaperone activity of small chaperone protein that could stabilize Her2 protein.
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http://dx.doi.org/10.1016/j.bmcl.2018.01.016DOI Listing
February 2018

Copalic acid analogs down-regulate androgen receptor and inhibit small chaperone protein.

Bioorg Med Chem Lett 2017 06 13;27(11):2292-2295. Epub 2017 Apr 13.

Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA. Electronic address:

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well.
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http://dx.doi.org/10.1016/j.bmcl.2017.04.046DOI Listing
June 2017