Evidence map›Paper›PMID 36603398›Full record

ArticleBioorganic & medicinal chemistry2023

Synthesis and biological evaluation of tert-butyl ester and ethyl ester prodrugs of L-γ-methyleneglutamic acid amides for cancer.

Md Imdadul H Khan, Fakhri Mahdi, Patrice Penfornis, Nicholas S Akins, Md Imran Hossain, Seong Jong Kim, Suresh P Sulochana, Amna T Adam, Tristan D Tran, Chalet Tan and 3 more

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In one paragraph

Article in Bioorganic & medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.5field-weighted citation impact, top 41% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 5 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Md Imdadul H KhanDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Fakhri MahdiDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Patrice PenfornisCancer Center & Research Institute, Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Nicholas S AkinsDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Md Imran HossainDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Seong Jong KimNatural Products Utilization Research Unit, United States Department of Agriculture, Agricultural Research Service, University, MS 38677, USA.
Suresh P SulochanaCenter of Biomedical Research Excellence (COBRE) CDMPK Core, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Amna T AdamDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Tristan D TranDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Chalet TanDepartment of Pharmaceutics and Drug Delivery and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Pier Paolo ClaudioDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA; Cancer Center & Research Institute, Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA; National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Jason J ParisDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Hoang V LeDepartment of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. Electronic address: hle@olemiss.edu.
University of Mississippi · USUniversity of Mississippi Medical Center · USAgricultural Research Service · US

Funding

Pilot Project ProgramP30GM122733 · NIGMS · UNIVERSITY OF MISSISSIPPI · PI MAJUMDAR, SOUMYAJIT · 2018 to 2022
$5.3M
Opiate abuse and sex steroids influence neuroAIDS pathologyR00DA039791 · NIDA · UNIVERSITY OF MISSISSIPPI · PI PARIS, JASON RICHARD · 2017 to 2019
$734k
NIDA NIH HHS R00 DA039791NIGMS NIH HHS P30 GM122733
6 · The paper itself

Abstract

In cancer cells, glutaminolysis is the primary source of biosynthetic precursors. Recent efforts to develop amino acid analogues to inhibit glutamine metabolism in cancer have been extensive. Our lab recently discovered many L-γ-methyleneglutamic acid amides that were shown to be as efficacious as tamoxifen or olaparib in inhibiting the cell growth of MCF-7, SK-BR-3, and MDA-MB-231 breast cancer cells after 24 or 72 h of treatment. None of these compounds inhibited the cell growth of nonmalignant MCF-10A breast cells. These L-γ-methyleneglutamic acid amides hold promise as novel therapeutics for the treatment of multiple subtypes of breast cancer. Herein, we report our synthesis and evaluation of two series of tert-butyl ester and ethyl ester prodrugs of these L-γ-methyleneglutamic acid amides and the cyclic metabolite and its tert-butyl esters and ethyl esters on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the nonmalignant MCF-10A breast cell line. These esters were found to suppress the growth of the breast cancer cells, but they were less potent compared to the L-γ-methyleneglutamic acid amides. Pharmacokinetic (PK) studies were carried out on the lead L-γ-methyleneglutamic acid amide to establish tissue-specific distribution and other PK parameters. Notably, this lead compound showed moderate exposure to the brain with a half-life of 0.74 h and good tissue distribution, such as in the kidney and liver. Therefore, the L-γ-methyleneglutamic acid amides were then tested on glioblastoma cell lines BNC3 and BNC6 and head and neck cancer cell lines HN30 and HN31. They were found to effectively suppress the growth of these cancer cell lines after 24 or 72 h of treatment in a concentration-dependent manner. These results suggest broad applications of the L-γ-methyleneglutamic acid amides in anticancer therapy.

Indexed as

Breast NeoplasmsProdrugsAmidesAmino AcidsCell Line, TumorEstersFemaleHumansAmidesAmino AcidsEstersProdrugsBreast cancerGlioblastomaGlutaminolysisHead and neck cancerL-γ-Methyleneglutamic acid amides

Identifiers

PMID36603398
PMCPMC9879311
OpenAlexW4312058708

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.