Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties

Jan Olof G Karlsson; Louis J Ignarro; Ingemar Lundström; Per Jynge; Torsten Almén

doi:10.1016/j.drudis.2014.11.008

Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties

Drug Discov Today. 2015 Apr;20(4):411-21. doi: 10.1016/j.drudis.2014.11.008. Epub 2014 Nov 20.

Authors

Jan Olof G Karlsson¹, Louis J Ignarro², Ingemar Lundström³, Per Jynge⁴, Torsten Almén⁵

Affiliations

¹ Division of Drug Research/Pharmacology, Linköping University, Linköping, Sweden. Electronic address: janolof.karlsson@ktias.com.
² Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, USA.
³ Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
⁴ Division of Drug Research/Pharmacology, Linköping University, Linköping, Sweden.
⁵ Department of Diagnostic Radiology, Lund University, Malmö, Sweden.

PMID: 25463039
DOI: 10.1016/j.drudis.2014.11.008

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn(2+), the SOD mimetic activity depends on Mn(2+) that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn(2+) and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / therapeutic use*
Antioxidants / chemistry
Antioxidants / metabolism
Antioxidants / therapeutic use*
Biological Mimicry*
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / pathology
Edetic Acid / analogs & derivatives*
Edetic Acid / chemistry
Edetic Acid / metabolism
Edetic Acid / therapeutic use
Ethylenediamines / chemistry
Ethylenediamines / metabolism
Ethylenediamines / therapeutic use*
Humans
Manganese / chemistry
Manganese / metabolism*
Molecular Structure
Myocardial Infarction / therapy
Oxidative Stress / drug effects
Percutaneous Coronary Intervention
Pyridoxal Phosphate / analogs & derivatives*
Pyridoxal Phosphate / chemistry
Pyridoxal Phosphate / metabolism
Pyridoxal Phosphate / therapeutic use
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Superoxide Dismutase / metabolism*
Treatment Outcome

Substances

Antineoplastic Agents
Antioxidants
Ethylenediamines
Reactive Oxygen Species
Manganese
Pyridoxal Phosphate
N,N'-dipyridoxylethylenediamine-N,N'-diacetic acid
Edetic Acid
Superoxide Dismutase
N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid