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Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549.

Abstract Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-κB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer.
PMID
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Authors

Mayor MeshTerms
Keywords

1,2,3-triazole

Purine

non-small cell lung cancer A549

p38 MAPK

purinomimetic

Journal Title journal of enzyme inhibition and medicinal chemistry
Publication Year Start




PMID- 29271659
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20180105
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 33
IP  - 1
DP  - 2018 Dec
TI  - Small molecule purine and pseudopurine derivatives: synthesis, cytostatic
      evaluations and investigation of growth inhibitory effect in non-small cell lung 
      cancer A549.
PG  - 271-285
LID - 10.1080/14756366.2017.1414807 [doi]
AB  - Novel halogenated purines and pseudopurines with diverse aryl-substituted
      1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted
      1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong 
      albeit unselective activity on pancreatic adenocarcinoma cells
      CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed
      selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 
      1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most
      pronounced and highly selective inhibitory effect in nM range on non-small cell
      lung cancer A549. This compound revealed to target molecular processes at the
      extracellular side and inside the plasma membrane regulated by GPLD1 and growth
      factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation
      and induction of apoptosis mediated by p38 MAP kinase and NF-kappaB,
      respectively. Further optimisation of this compound as to reduce its toxicity in 
      normal cells may lead to the development of novel agent effective against lung
      cancer.
FAU - Bistrovic, Andrea
AU  - Bistrovic A
AD  - a Department of Organic Chemistry, Faculty of Chemical Engineering and Technology
      , University of Zagreb , Zagreb , Croatia.
FAU - Grbcic, Petra
AU  - Grbcic P
AD  - b Department of Biotechnology, Center for High-Throughput Technologies ,
      University of Rijeka , Rijeka , Croatia.
FAU - Harej, Anja
AU  - Harej A
AD  - b Department of Biotechnology, Center for High-Throughput Technologies ,
      University of Rijeka , Rijeka , Croatia.
FAU - Sedic, Mirela
AU  - Sedic M
AD  - b Department of Biotechnology, Center for High-Throughput Technologies ,
      University of Rijeka , Rijeka , Croatia.
FAU - Kraljevic-Pavelic, Sandra
AU  - Kraljevic-Pavelic S
AD  - b Department of Biotechnology, Center for High-Throughput Technologies ,
      University of Rijeka , Rijeka , Croatia.
FAU - Kostrun, Sanja
AU  - Kostrun S
AD  - c Chemistry Department , Fidelta Ltd. , Zagreb , Croatia.
FAU - Plavec, Janez
AU  - Plavec J
AD  - d Slovenian NMR Centre , National Institute of Chemistry , Ljubljana , Slovenia.
AD  - e En-FIST Centre of Excellence , Ljubljana , Slovenia.
AD  - f Faculty of Chemistry and Chemical Technology , University of Ljubljana ,
      Ljubljana , Slovenia.
FAU - Makuc, Damjan
AU  - Makuc D
AD  - d Slovenian NMR Centre , National Institute of Chemistry , Ljubljana , Slovenia.
AD  - e En-FIST Centre of Excellence , Ljubljana , Slovenia.
FAU - Raic-Malic, Silvana
AU  - Raic-Malic S
AD  - a Department of Organic Chemistry, Faculty of Chemical Engineering and Technology
      , University of Zagreb , Zagreb , Croatia.
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cytostatic Agents)
RN  - 0 (Purines)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Triazoles)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Cytostatic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/pathology
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Purines/chemical synthesis/chemistry/*pharmacology
MH  - Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - Triazoles/chemistry/pharmacology
OTO - NOTNLM
OT  - 1,2,3-triazole
OT  - Purine
OT  - non-small cell lung cancer A549
OT  - p38 MAPK
OT  - purinomimetic
EDAT- 2017/12/23 06:00
MHDA- 2018/01/06 06:00
CRDT- 2017/12/23 06:00
PHST- 2017/12/23 06:00 [entrez]
PHST- 2017/12/23 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
AID - 10.1080/14756366.2017.1414807 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2018 Dec;33(1):271-285. doi:
      10.1080/14756366.2017.1414807.