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Arzneimittelforschung 2005; 55(2): 114-122
DOI: 10.1055/s-0031-1296832
Antibiotika · Chemotherapeutika · Virustatika · Zytostatika
Editio Cantor Verlag Aulendorf (Germany)

Anti-Proliferative and Anti-Leukemic Activity of DDE46 (Compound WHI-07), a Novel Bromomethoxylated Arylphos-phate Derivative of Zidovudine, and Related Compounds

Studies using human acute lymphoblastic leukemia cells and the Zebrafish model
Alexey O. Benyumov
a   Departments of Embryology, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
h   Departments of Paradigm Pharmaceuticals, St. Paul, MN, USA
,
Taracad K. Venkatachalam
b   Departments of Chemistry, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
h   Departments of Paradigm Pharmaceuticals, St. Paul, MN, USA
,
Olga O. Grigoriants
c   Departments of Enzyme Kinetics, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
,
Alexei O. Vassilev
d   Departments of Biochemistry, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
h   Departments of Paradigm Pharmaceuticals, St. Paul, MN, USA
,
Heather E. Tibbles
d   Departments of Biochemistry, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
h   Departments of Paradigm Pharmaceuticals, St. Paul, MN, USA
,
Suzanne Downs
a   Departments of Embryology, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
,
Darin Dumez
b   Departments of Chemistry, Roseville, MN, USA
f   Departments of Drug Discovery Program, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
,
Fatih M. Uckun
e   Departments of Immunology, Roseville, MN, USA
f   Departments of Drug Discovery Program, Roseville, MN, USA
g   Departments of Parker Hughes Institute, Roseville, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
23 December 2011 (online)

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Summary

The anti-proliferative effects of a novel bromomethoxylated arylphosphate derivative of zidovudine (compound DDE46, CAS 213982-96-8) were first examined in a zebra fish embryo model. DDE46 blocked the cell division at the 2-cell stage of the embryonic development followed by total cell fusion. DDE46 also inhibited the proliferation of the leukemic cell lines NALM-6 and MOLT-3. DDE46 enhanced the activity of the pro-apoptotic enzymes Caspase-3, Caspase-6, Caspase-8, and Caspase-9 leading to the apoptotic death of the leukemic cell line Jurkat. These results justify the further development of this agent as a new anti-leukemic drug candidate.

Zusammenfassung

Antiproliferative und antileukämische Wirkung von DDE46 (Verbindung WHI-07), einem neuartigen brommethoxylierten Arylphosphat-Derivat von Zidovudin, sowie verwandter Verbindungen / Studien an Leukämiezellen sowie am Zebrafisch-Modell

Die antiproliferative Wirkung eines neuartigen brommethoxylierten Arylphosphat-Derivates von Zidovudin (Substanz DDE46, CAS 213982-96-8) wurden erstmals am Zebrafischembryo-Modell untersucht. DDE46 verhinderte the Zellteilung und verursachte eine totale Zellfusion. DDE46 inhibierte die Proliferation der leukämischen Zell-Linien NALM-6 und MOLT-3. Es erhöhte die Wirkung der pro-apoptotischen Enzyme Caspase-3, Caspase-6, Caspase-8, und Caspase-9 und verursachte dabei den apoptotischen Tod der leukämischen Zell-Linie Jurkat. Diese Ergebnisse rechtfertigen die weitere Entwicklung dieser Substanz als neuen antileukämischen Wirkstoff.

Key words

CAS 213982-96-8 - DDE46, antileukemic activity, apoptosis, Zebrafish model - Zidovudine, bromomethoxylated arylphosphate derivative