Design, synthesis and cytotoxic evaluation of 4-methylidenepyrazolidin-3-ones

Jakub Modranka; Rafał Jakubowski; Marek Różalski; Urszula Krajewska; Anna Janecka; Katarzyna Gach; Dorota Pomorska; Tomasz Janecki

doi:10.1016/j.ejmech.2015.01.029

Design, synthesis and cytotoxic evaluation of 4-methylidenepyrazolidin-3-ones

Eur J Med Chem. 2015 Mar 6:92:565-74. doi: 10.1016/j.ejmech.2015.01.029. Epub 2015 Jan 14.

Authors

Jakub Modranka¹, Rafał Jakubowski¹, Marek Różalski², Urszula Krajewska², Anna Janecka³, Katarzyna Gach³, Dorota Pomorska³, Tomasz Janecki⁴

Affiliations

¹ Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
² Department of Pharmaceutical Biochemistry, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland.
³ Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215 Łódź, Poland.
⁴ Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland. Electronic address: tomasz.janecki@p.lodz.pl.

PMID: 25602933
DOI: 10.1016/j.ejmech.2015.01.029

Abstract

Three series of new 4-methylidenepyrazolidin-3-ones with various substitution patterns were synthesized and tested for the cytotoxic activity against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer cell line. Several obtained methylidenepyrazolidinones exhibited high cytotoxic activity with IC50 values below 10 μM, mainly against HL-60 leukemia cell line and two of them, 18d,e, displayed IC50 ≤ 5 μM, against all tested cell lines. Structure-activity relationship studies revealed that the presence of phenyl substituents on both ring nitrogen atoms and vinyl or phenyl substituents in position 5 are crucial for high activity. Selected methylidenepyrazolidinones were also tested on normal human umbilical vein endothelial cells (HUVEC) and pyrazolidinone 18a was found to be 5-fold more toxic against HL-60 than normal cells.

Keywords: -lactams; Cytotoxicity; Pyrazolidinones; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
HL-60 Cells
Human Umbilical Vein Endothelial Cells / drug effects
Humans
MCF-7 Cells
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Pyrazoles