PMID- 31814456
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20210819
IS  - 1029-2330 (Electronic)
IS  - 1026-7158 (Linking)
VI  - 28
IP  - 5
DP  - 2020 Jun
TI  - Pyrrole derivatives as potential anti-cancer therapeutics: synthesis, mechanisms 
      of action, safety.
PG  - 547-563
LID - 10.1080/1061186X.2019.1703189 [doi]
AB  - Pyrrole derivatives (PDs) 
      chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1H-pyrrole-2,5-dione 
      (MI-1) and 
      5-amino-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H-pyrrole-3-one 
      (D1) were synthesised as inhibitors of several protein kinases including EGFR and 
      VEGFR. The aim of the study was to reveal the exact mechanisms of PDs' action 
      EGFR and VEGFR are involved in. We observed, that both PDs could bind with EGFR 
      and VEGFR and form stable complexes. PDs entered into electrostatic interactions 
      with polar groups of phospholipid heads in cell membrane, and the power of 
      interaction depended on the nature of PD radical substituents (greater for MI-1 
      and smaller for D1). Partial intercalation of MI-1 into the membrane hydrophobic 
      zone also occurred. PDs concentrations induced apoptosis in malignant cells but 
      normal ones had different sensitivity to those. MI-1 and D1 acted like 
      antioxidants in inflamed colonic tissue, as evidenced by reduce of lipid and 
      protein peroxidation products (by 43-67%) and increase of superoxide dismutase 
      activity (by 40 and 58%) with restoring these values to control ones. MI-1 
      restored reduced haemoglobin and normalised elevated platelets and monocytes in 
      settings of colorectal cancer, whereas D1 normalised only platelets. Thus, MI-1 
      and D1 could be used as competitive inhibitors of EGFR and VEGFR and 
      antioxidants, which might contribute to realisation of their anti-inflammatory, 
      proapoptotic and antitumor activity.
FAU - Kuznietsova, Halyna
AU  - Kuznietsova H
AUID- ORCID: 0000-0002-1296-1007
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Dziubenko, Natalia
AU  - Dziubenko N
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Byelinska, Iryna
AU  - Byelinska I
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Hurmach, Vasyl
AU  - Hurmach V
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Bychko, Andriy
AU  - Bychko A
AD  - Bogomolets National Medical University, Kyiv, Ukraine.
FAU - Lynchak, Oksana
AU  - Lynchak O
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Milokhov, Demyd
AU  - Milokhov D
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Khilya, Olga
AU  - Khilya O
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
FAU - Rybalchenko, Volodymyr
AU  - Rybalchenko V
AD  - Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191218
PL  - England
TA  - J Drug Target
JT  - Journal of drug targeting
JID - 9312476
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antioxidants)
RN  - 0 (Hemoglobins)
RN  - 0 (Pyrroles)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Antioxidants/pharmacology
MH  - Blood Platelets/drug effects/metabolism
MH  - Cell Line, Tumor
MH  - Cell Membrane/drug effects
MH  - ErbB Receptors/metabolism
MH  - Hemoglobins/metabolism
MH  - Humans
MH  - Male
MH  - Monocytes/drug effects/metabolism
MH  - Neoplasms/*drug therapy/metabolism
MH  - Pyrroles/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Vascular Endothelial Growth Factor/metabolism
MH  - Superoxide Dismutase/metabolism
OTO - NOTNLM
OT  - EGFR
OT  - Pyrrole derivatives
OT  - VEGFR
OT  - colon cancer
OT  - colonic inflammation
OT  - haematopoiesis
OT  - lipid membranes
OT  - redox state
EDAT- 2019/12/10 06:00
MHDA- 2021/08/20 06:00
CRDT- 2019/12/10 06:00
PHST- 2019/12/10 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2019/12/10 06:00 [entrez]
AID - 10.1080/1061186X.2019.1703189 [doi]
PST - ppublish
SO  - J Drug Target. 2020 Jun;28(5):547-563. doi: 10.1080/1061186X.2019.1703189. Epub 
      2019 Dec 18.