Publications by authors named "Cody M Orahoske"

5 Publications

  • Page 1 of 1

Pharmacokinetic study of an anti-trypanosome agent with different formulations and administration routes in mice by HPLC-MS/MS.

Biomed Chromatogr 2021 Oct 27;35(10):e5169. Epub 2021 May 27.

Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, Cleveland, OH, USA.

Previously compound 12 showed great anti-trypanosome activity without toxicity in an in vivo study. In the current study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to investigate its pharmacokinetics in mouse plasma. A protein precipitation method was applied to extract the compound, and it was then separated using a Kinetex C column with mobile phase consisting of acetonitrile-0.1% formic acid water (50:50, v/v) at a flow rate of 300 μl/min. The analytes were detected with the multiple reaction monitoring in negative electrospray ionization source for quantitative response of the compounds. Compound 12 was detected at m/z 477.0 → 367.2, while the internal standard compound 14 was detected at m/z 499.2 → 268.2. Inter- and intra-day precision was <5.22 and 2.79% respectively, while the accuracy range was within ±9.65%. The method was successfully applied to evaluate the pharmacokinetics of compound 12 in mouse plasma with two formulations (20% Cremophor EL or sesame oil) and drug administration routes (oral and intraperitoneal injection). We observed a better drug serum concentration with the Cremophor formulation, and the two different drug administration routes did not show significant differences from the drug distribution.
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http://dx.doi.org/10.1002/bmc.5169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434948PMC
October 2021

Small-Molecule HSP27 Inhibitor Abolishes Androgen Receptors in Glioblastoma.

J Med Chem 2021 02 1;64(3):1570-1583. Epub 2021 Feb 1.

Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio 44115, United States.

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC values around 5 nM. The compound also significantly inhibits GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284899PMC
February 2021

Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth.

Bioorg Med Chem 2020 09 25;28(18):115656. Epub 2020 Jul 25.

Rammelkamp Center for Research and Department of Medicine, MetroHealth Campus, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address:

EphA2 receptor kinase could become a novel target for anti-glioblastoma treatment. Doxazosin previously identified acts like the endogenous ligand of EphA2 and induces cell apoptosis. Through lead structure modification a derivative of Doxazosin possessing unique dimeric structure showed an improvement in the activity. In the current study, we expanded the dimeric scaffold by lead optimization to explore the chemical space of the conjoining moieties and a slight variation to the core structure. 27 new derivatives were synthesized and examined with EphA2 overexpressed and wild type glioblastoma cell lines for cell proliferation and EphA2 activation. Three new compounds 3d, 3e, and 7bg showed potent and selective activities against the growth of EphA2 overexpressed glioblastoma cells. Dimer 3d modification replaces the long alkyl chain with a short polyethylene glycol chain. Dimer 7bg has a relatively longer polyethylene glycol chain in comparison to compound 3d and the length is more similar to the lead compound. Whereas dimer 3e has a rigid aromatic linker exploring the chemical space. The diversity of the linkers in the active suggest additional hydrogen binding sites has a positive correlation to the activity. All three dimers showed selective activity in EphA2 overexpressed cells, indicating the activity is correlated to the EphA2 targeting effect.
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http://dx.doi.org/10.1016/j.bmc.2020.115656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446891PMC
September 2020

Lead optimization of selective tubulin inhibitors as anti-trypanosomal agents.

Bioorg Med Chem 2019 04 25;27(8):1517-1528. Epub 2019 Feb 25.

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:

Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited ICs below 5 µM inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.
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http://dx.doi.org/10.1016/j.bmc.2019.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531046PMC
April 2019

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
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