Aryl maleimides as apoptosis inducers on L5178-Y murine leukemia cells (in silico, in vitro and ex vivo Study)

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

© 2016 Bentham Science Publishers. Thiol reagents were shown to act as potent inhibitors of L5178-Y murine leukemia cell proliferation. A series of aryl maleimides (AMI) was synthesized and evaluated theoretically for global and local reactivity, showing their selectivity for thiol groups, due to a reaction of the vinyl moiety (a soft acid) with thiols (a soft base). Two AMI that are benzoic acid derivatives (1f and 1h) were tested with an in vitro and ex vivo model to evaluate their reactivity with thiols and their activity in L5178-Y cells. The in vitro reactions clearly showed a selective Michael type 1,4-addition reaction between thiols (glutathione and N-acetylcysteine, which are nucleophiles) and the AMI (1f and 1h, which are electrophiles). In cell cultures, the compounds induced a decreasing cellular viability and an apoptotic effect of up to 59.8% at 48 h. The ex vivo experimental model showed an important reduction of thiol levels in cells treated with 1h. Decreased cellular viability and increased apoptosis were confirmed by flow cytometry, DNA fragmentation and microscopy analysis (cytological studies). The increase in apoptosis on L5178-Y cells probably occurred, at least in part, by a decrease in glutathione levels and an increase in free radicals concentration. The decreased glutathione levels seem to make cancer cells more susceptible to death by apoptosis, and should certainly make them more vulnerable to a less aggressive treatment.
Original languageAmerican English
Pages (from-to)1615-1621
Number of pages1452
JournalAnti-Cancer Agents in Medicinal Chemistry
DOIs
StatePublished - 1 Dec 2016

Fingerprint

Maleimides
Sulfhydryl Compounds
Computer Simulation
Leukemia
Apoptosis
Glutathione
Sulfhydryl Reagents
Benzoic Acid
Acetylcysteine
DNA Fragmentation
Free Radicals
Microscopy
Flow Cytometry
Theoretical Models
Cell Culture Techniques
Cell Proliferation
In Vitro Techniques
Acids
Neoplasms

Cite this

@article{7af6f71f6eb2493e969f2eb74194f8d4,
title = "Aryl maleimides as apoptosis inducers on L5178-Y murine leukemia cells (in silico, in vitro and ex vivo Study)",
abstract = "{\circledC} 2016 Bentham Science Publishers. Thiol reagents were shown to act as potent inhibitors of L5178-Y murine leukemia cell proliferation. A series of aryl maleimides (AMI) was synthesized and evaluated theoretically for global and local reactivity, showing their selectivity for thiol groups, due to a reaction of the vinyl moiety (a soft acid) with thiols (a soft base). Two AMI that are benzoic acid derivatives (1f and 1h) were tested with an in vitro and ex vivo model to evaluate their reactivity with thiols and their activity in L5178-Y cells. The in vitro reactions clearly showed a selective Michael type 1,4-addition reaction between thiols (glutathione and N-acetylcysteine, which are nucleophiles) and the AMI (1f and 1h, which are electrophiles). In cell cultures, the compounds induced a decreasing cellular viability and an apoptotic effect of up to 59.8{\%} at 48 h. The ex vivo experimental model showed an important reduction of thiol levels in cells treated with 1h. Decreased cellular viability and increased apoptosis were confirmed by flow cytometry, DNA fragmentation and microscopy analysis (cytological studies). The increase in apoptosis on L5178-Y cells probably occurred, at least in part, by a decrease in glutathione levels and an increase in free radicals concentration. The decreased glutathione levels seem to make cancer cells more susceptible to death by apoptosis, and should certainly make them more vulnerable to a less aggressive treatment.",
author = "Erik Andrade-Jorge and Marycarmen God{\'i}nez-Victoria and S{\'a}nchez-Torres, {Luvia Enid} and Fabila-Castillo, {Luis Humberto} and Trujillo-Ferrara, {Jos{\'e} G.}",
year = "2016",
month = "12",
day = "1",
doi = "10.2174/1871520615666160504094417",
language = "American English",
pages = "1615--1621",
journal = "Anti-Cancer Agents in Medicinal Chemistry",
issn = "1871-5206",
publisher = "Bentham Science Publishers B.V.",

}

TY - JOUR

T1 - Aryl maleimides as apoptosis inducers on L5178-Y murine leukemia cells (in silico, in vitro and ex vivo Study)

AU - Andrade-Jorge, Erik

AU - Godínez-Victoria, Marycarmen

AU - Sánchez-Torres, Luvia Enid

AU - Fabila-Castillo, Luis Humberto

AU - Trujillo-Ferrara, José G.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - © 2016 Bentham Science Publishers. Thiol reagents were shown to act as potent inhibitors of L5178-Y murine leukemia cell proliferation. A series of aryl maleimides (AMI) was synthesized and evaluated theoretically for global and local reactivity, showing their selectivity for thiol groups, due to a reaction of the vinyl moiety (a soft acid) with thiols (a soft base). Two AMI that are benzoic acid derivatives (1f and 1h) were tested with an in vitro and ex vivo model to evaluate their reactivity with thiols and their activity in L5178-Y cells. The in vitro reactions clearly showed a selective Michael type 1,4-addition reaction between thiols (glutathione and N-acetylcysteine, which are nucleophiles) and the AMI (1f and 1h, which are electrophiles). In cell cultures, the compounds induced a decreasing cellular viability and an apoptotic effect of up to 59.8% at 48 h. The ex vivo experimental model showed an important reduction of thiol levels in cells treated with 1h. Decreased cellular viability and increased apoptosis were confirmed by flow cytometry, DNA fragmentation and microscopy analysis (cytological studies). The increase in apoptosis on L5178-Y cells probably occurred, at least in part, by a decrease in glutathione levels and an increase in free radicals concentration. The decreased glutathione levels seem to make cancer cells more susceptible to death by apoptosis, and should certainly make them more vulnerable to a less aggressive treatment.

AB - © 2016 Bentham Science Publishers. Thiol reagents were shown to act as potent inhibitors of L5178-Y murine leukemia cell proliferation. A series of aryl maleimides (AMI) was synthesized and evaluated theoretically for global and local reactivity, showing their selectivity for thiol groups, due to a reaction of the vinyl moiety (a soft acid) with thiols (a soft base). Two AMI that are benzoic acid derivatives (1f and 1h) were tested with an in vitro and ex vivo model to evaluate their reactivity with thiols and their activity in L5178-Y cells. The in vitro reactions clearly showed a selective Michael type 1,4-addition reaction between thiols (glutathione and N-acetylcysteine, which are nucleophiles) and the AMI (1f and 1h, which are electrophiles). In cell cultures, the compounds induced a decreasing cellular viability and an apoptotic effect of up to 59.8% at 48 h. The ex vivo experimental model showed an important reduction of thiol levels in cells treated with 1h. Decreased cellular viability and increased apoptosis were confirmed by flow cytometry, DNA fragmentation and microscopy analysis (cytological studies). The increase in apoptosis on L5178-Y cells probably occurred, at least in part, by a decrease in glutathione levels and an increase in free radicals concentration. The decreased glutathione levels seem to make cancer cells more susceptible to death by apoptosis, and should certainly make them more vulnerable to a less aggressive treatment.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84995932355&origin=inward

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84995932355&origin=inward

U2 - 10.2174/1871520615666160504094417

DO - 10.2174/1871520615666160504094417

M3 - Article

SP - 1615

EP - 1621

JO - Anti-Cancer Agents in Medicinal Chemistry

JF - Anti-Cancer Agents in Medicinal Chemistry

SN - 1871-5206

ER -