Ionic liquids with methotrexate moieties as a potential anticancer prodrug: Synthesis, characterization and solubility evaluation

Rahman Md Moshikur, Md Raihan Chowdhury, Rie Wakabayashi, Yoshiro Tahara, Muhammad Moniruzzaman, Masahiro Goto

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1 H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.

Original languageEnglish
Pages (from-to)226-233
Number of pages8
JournalJournal of Molecular Liquids
Volume278
DOIs
Publication statusPublished - Mar 15 2019

Fingerprint

Ionic Liquids
Prodrugs
Ionic liquids
Methotrexate
solubility
Solubility
evaluation
synthesis
liquids
ingredients
Drug products
Pharmaceutical Preparations
body fluids
Body fluids
Salts
salts
esters
Esters
drugs
Sodium

All Science Journal Classification (ASJC) codes

  • Electronic, Optical and Magnetic Materials
  • Atomic and Molecular Physics, and Optics
  • Condensed Matter Physics
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Materials Chemistry

Cite this

Ionic liquids with methotrexate moieties as a potential anticancer prodrug : Synthesis, characterization and solubility evaluation. / Moshikur, Rahman Md; Chowdhury, Md Raihan; Wakabayashi, Rie; Tahara, Yoshiro; Moniruzzaman, Muhammad; Goto, Masahiro.

In: Journal of Molecular Liquids, Vol. 278, 15.03.2019, p. 226-233.

Research output: Contribution to journalArticle

@article{4eee2f5dcfc24bc88d6a68ddbbd2e0fa,
title = "Ionic liquids with methotrexate moieties as a potential anticancer prodrug: Synthesis, characterization and solubility evaluation",
abstract = "The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1 H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.",
author = "Moshikur, {Rahman Md} and Chowdhury, {Md Raihan} and Rie Wakabayashi and Yoshiro Tahara and Muhammad Moniruzzaman and Masahiro Goto",
year = "2019",
month = "3",
day = "15",
doi = "10.1016/j.molliq.2019.01.063",
language = "English",
volume = "278",
pages = "226--233",
journal = "Journal of Molecular Liquids",
issn = "0167-7322",
publisher = "Elsevier",

}

TY - JOUR

T1 - Ionic liquids with methotrexate moieties as a potential anticancer prodrug

T2 - Synthesis, characterization and solubility evaluation

AU - Moshikur, Rahman Md

AU - Chowdhury, Md Raihan

AU - Wakabayashi, Rie

AU - Tahara, Yoshiro

AU - Moniruzzaman, Muhammad

AU - Goto, Masahiro

PY - 2019/3/15

Y1 - 2019/3/15

N2 - The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1 H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.

AB - The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1 H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.

UR - http://www.scopus.com/inward/record.url?scp=85060078342&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060078342&partnerID=8YFLogxK

U2 - 10.1016/j.molliq.2019.01.063

DO - 10.1016/j.molliq.2019.01.063

M3 - Article

AN - SCOPUS:85060078342

VL - 278

SP - 226

EP - 233

JO - Journal of Molecular Liquids

JF - Journal of Molecular Liquids

SN - 0167-7322

ER -