Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line

Samir M El-Moghazy; Riham F George; Essam Eldin A Osman; Ahmed A Elbatrawy; Miroslava Kissova; Ambra Colombo; Emmanuele Crespan; Giovanni Maga

doi:10.1016/j.ejmech.2016.07.034

Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line

Eur J Med Chem. 2016 Nov 10:123:1-13. doi: 10.1016/j.ejmech.2016.07.034. Epub 2016 Jul 19.

Authors

Samir M El-Moghazy¹, Riham F George², Essam Eldin A Osman¹, Ahmed A Elbatrawy³, Miroslava Kissova⁴, Ambra Colombo⁴, Emmanuele Crespan⁴, Giovanni Maga⁴

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-kasr Elaini Street, Cairo 11562, Egypt.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-kasr Elaini Street, Cairo 11562, Egypt. Electronic address: rihamfgeorge@yahoo.com.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University, Beni Suef 62511, Egypt.
⁴ Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy.

PMID: 27474918
DOI: 10.1016/j.ejmech.2016.07.034

Abstract

Some novel 6-substituted pyrazolo[3,4-d]pyrimidines 4, 5, 6a-d, 7a-c, 8 and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines 9a-c, 10a-c, 11, 12a,b, 13a-c and 14 were synthesized and characterized by spectral and elemental analyses. They were screened for their biological activity in vitro against Abl and Src kinases. Compounds 7a and 7b revealed the highest activity against both wild and mutant Abl kinases as well as the Src kinase and the leukemia K-562 cell line. They can be considered as new hits for further structural optimization to obtain better activity.

Keywords: Abl inhibition; K-562 cell line; Molecular modeling; Pyrazolo[3,4-d]pyrimidines; Src inhibition.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Humans
K562 Cells
Leukemia / drug therapy
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
Proto-Oncogene Proteins c-abl / genetics
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Structure-Activity Relationship
src-Family Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
pyrazolo(3,4-d)pyrimidine
Proto-Oncogene Proteins c-abl
src-Family Kinases