New pemetrexed-peptide conjugates

Synthesis, characterization and in vitro cytostatic effect on non-small cell lung carcinoma (NCI-H358) and human leukemia (HL-60) cells

Zsanett Miklán, Erika Orbán, Z. Bánóczi, F. Hudecz

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Pemetrexed (Pem) is a novel antimetabolite type of anticancer drug that demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung carcinoma and malignant pleural mesothelioma. It inhibits enzymes involved in the folate pathway, for which the presence of its free carboxylic groups is necessary. The heteroaromatic ring system of Pem has a modifiable amino group, which opens a possibility to apply a new strategy to conjugate Pem to carrier molecules. Considering this as well as the necessity of untouched carboxylic groups of Pem in the new conjugates, we developed a new synthesis strategy. Here, we describe the synthesis and the characterization of new Pem-peptide conjugates in which cell-penetrating octaarginine or/and lung-targeting H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 peptide is attached to the drug by thioether bond. The conjugates characterized by RP-HPLC and MS exhibited cytostatic effect in vitro on non-small cell lung carcinoma as well as on human leukemia cell lines. The IC 50 values of the conjugates were similar, but the conjugates with H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 sequence were slightly more effective. Our data show that the in vitro cytostatic effect of the free Pem was essentially maintained after conjugation with cell-penetrating or cell-targeting peptides. Thus, the conjugation strategy reported could lead to the development of a new generation of active Pem conjugates.

Original languageEnglish
Pages (from-to)805-811
Number of pages7
JournalJournal of Peptide Science
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 2011

Fingerprint

Pemetrexed
HL-60 Cells
Cytostatic Agents
Non-Small Cell Lung Carcinoma
Leukemia
Cells
isoleucyl-glutamyl-leucyl-leucyl-glutaminyl-alanyl-arginine
Peptides
Antimetabolites
Sulfides
In Vitro Techniques
Folic Acid
Pharmaceutical Preparations
Tumors
High Pressure Liquid Chromatography
Cell Line

Keywords

  • Human leukemia
  • IELLQAR lung-targeting peptide
  • In vitro cytostatic effect of conjugates
  • Non-small cell lung carcinoma
  • Pemetrexed
  • Synthesis of pemetrexed-oligoarginine conjugates

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

@article{84ba0b06a8164dfbbf1db2e3df65de9f,
title = "New pemetrexed-peptide conjugates: Synthesis, characterization and in vitro cytostatic effect on non-small cell lung carcinoma (NCI-H358) and human leukemia (HL-60) cells",
abstract = "Pemetrexed (Pem) is a novel antimetabolite type of anticancer drug that demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung carcinoma and malignant pleural mesothelioma. It inhibits enzymes involved in the folate pathway, for which the presence of its free carboxylic groups is necessary. The heteroaromatic ring system of Pem has a modifiable amino group, which opens a possibility to apply a new strategy to conjugate Pem to carrier molecules. Considering this as well as the necessity of untouched carboxylic groups of Pem in the new conjugates, we developed a new synthesis strategy. Here, we describe the synthesis and the characterization of new Pem-peptide conjugates in which cell-penetrating octaarginine or/and lung-targeting H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 peptide is attached to the drug by thioether bond. The conjugates characterized by RP-HPLC and MS exhibited cytostatic effect in vitro on non-small cell lung carcinoma as well as on human leukemia cell lines. The IC 50 values of the conjugates were similar, but the conjugates with H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 sequence were slightly more effective. Our data show that the in vitro cytostatic effect of the free Pem was essentially maintained after conjugation with cell-penetrating or cell-targeting peptides. Thus, the conjugation strategy reported could lead to the development of a new generation of active Pem conjugates.",
keywords = "Human leukemia, IELLQAR lung-targeting peptide, In vitro cytostatic effect of conjugates, Non-small cell lung carcinoma, Pemetrexed, Synthesis of pemetrexed-oligoarginine conjugates",
author = "Zsanett Mikl{\'a}n and Erika Orb{\'a}n and Z. B{\'a}n{\'o}czi and F. Hudecz",
year = "2011",
month = "12",
doi = "10.1002/psc.1407",
language = "English",
volume = "17",
pages = "805--811",
journal = "Journal of Peptide Science",
issn = "1075-2617",
publisher = "John Wiley and Sons Ltd",
number = "12",

}

TY - JOUR

T1 - New pemetrexed-peptide conjugates

T2 - Synthesis, characterization and in vitro cytostatic effect on non-small cell lung carcinoma (NCI-H358) and human leukemia (HL-60) cells

AU - Miklán, Zsanett

AU - Orbán, Erika

AU - Bánóczi, Z.

AU - Hudecz, F.

PY - 2011/12

Y1 - 2011/12

N2 - Pemetrexed (Pem) is a novel antimetabolite type of anticancer drug that demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung carcinoma and malignant pleural mesothelioma. It inhibits enzymes involved in the folate pathway, for which the presence of its free carboxylic groups is necessary. The heteroaromatic ring system of Pem has a modifiable amino group, which opens a possibility to apply a new strategy to conjugate Pem to carrier molecules. Considering this as well as the necessity of untouched carboxylic groups of Pem in the new conjugates, we developed a new synthesis strategy. Here, we describe the synthesis and the characterization of new Pem-peptide conjugates in which cell-penetrating octaarginine or/and lung-targeting H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 peptide is attached to the drug by thioether bond. The conjugates characterized by RP-HPLC and MS exhibited cytostatic effect in vitro on non-small cell lung carcinoma as well as on human leukemia cell lines. The IC 50 values of the conjugates were similar, but the conjugates with H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 sequence were slightly more effective. Our data show that the in vitro cytostatic effect of the free Pem was essentially maintained after conjugation with cell-penetrating or cell-targeting peptides. Thus, the conjugation strategy reported could lead to the development of a new generation of active Pem conjugates.

AB - Pemetrexed (Pem) is a novel antimetabolite type of anticancer drug that demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung carcinoma and malignant pleural mesothelioma. It inhibits enzymes involved in the folate pathway, for which the presence of its free carboxylic groups is necessary. The heteroaromatic ring system of Pem has a modifiable amino group, which opens a possibility to apply a new strategy to conjugate Pem to carrier molecules. Considering this as well as the necessity of untouched carboxylic groups of Pem in the new conjugates, we developed a new synthesis strategy. Here, we describe the synthesis and the characterization of new Pem-peptide conjugates in which cell-penetrating octaarginine or/and lung-targeting H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 peptide is attached to the drug by thioether bond. The conjugates characterized by RP-HPLC and MS exhibited cytostatic effect in vitro on non-small cell lung carcinoma as well as on human leukemia cell lines. The IC 50 values of the conjugates were similar, but the conjugates with H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH 2 sequence were slightly more effective. Our data show that the in vitro cytostatic effect of the free Pem was essentially maintained after conjugation with cell-penetrating or cell-targeting peptides. Thus, the conjugation strategy reported could lead to the development of a new generation of active Pem conjugates.

KW - Human leukemia

KW - IELLQAR lung-targeting peptide

KW - In vitro cytostatic effect of conjugates

KW - Non-small cell lung carcinoma

KW - Pemetrexed

KW - Synthesis of pemetrexed-oligoarginine conjugates

UR - http://www.scopus.com/inward/record.url?scp=81155155496&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81155155496&partnerID=8YFLogxK

U2 - 10.1002/psc.1407

DO - 10.1002/psc.1407

M3 - Article

VL - 17

SP - 805

EP - 811

JO - Journal of Peptide Science

JF - Journal of Peptide Science

SN - 1075-2617

IS - 12

ER -