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One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.
PMID
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Authors

Mayor MeshTerms
Keywords

EGFR

Triple-negative breast cancer

anti-proliferative activity

apoptosis

spirooxindoles

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




PMID- 29281924
OWN - NLM
STAT- MEDLINE
DCOM- 20180105
LR  - 20180105
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 33
IP  - 1
DP  - 2018 Dec
TI  - One-pot three-component synthesis of novel spirooxindoles with potential
      cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.
PG  - 309-318
LID - 10.1080/14756366.2017.1417276 [doi]
AB  - Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with
      limited treatment options due to its heterogeneity and the lack of well-defined
      molecular targets. In our endeavour towards the development of novel anti-TNBC
      agents, herein we report a one-pot three-component synthesis of novel
      spirooxindoles 6a-p, and evaluation of their potential anti-proliferative
      activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as
      the most potent analogues with IC50 = 6.70, 6.40 and 6.70 microM, respectively.
      Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the
      up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting
      caspase-3 levels. Additionally, 6e displayed significant increase in the percent 
      of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore,
      spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 
      120 and 150 nM, respectively). Collectively, these data demonstrated that 6e
      might be a potential lead compound for the development of effective anti-TNBC
      agents.
FAU - Eldehna, Wagdy M
AU  - Eldehna WM
AD  - a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Kafrelsheikh
      University , Kafr El-Sheikh , Egypt.
FAU - El-Naggar, Dina H
AU  - El-Naggar DH
AD  - b Department of Applied Organic Chemistry , National Research Center , Giza ,
      Egypt.
FAU - Hamed, Ahmed R
AU  - Hamed AR
AD  - c Department of Phytochemistry , National Research Center , Giza , Egypt.
AD  - d Biology Unit, Central Laboratory of the Pharmaceutical & Drug Industries
      Research Division , National Research Center , Giza , Egypt.
FAU - Ibrahim, Hany S
AU  - Ibrahim HS
AD  - e Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Egyptian Russian 
      University , Badr City, Cairo , Egypt.
FAU - Ghabbour, Hazem A
AU  - Ghabbour HA
AD  - f Department of Medicinal Chemistry, Faculty of Pharmacy , Mansoura University , 
      Mansoura , Egypt.
AD  - g Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud
      University , Riyadh , Saudi Arabia.
FAU - Abdel-Aziz, Hatem A
AU  - Abdel-Aziz HA
AD  - b Department of Applied Organic Chemistry , National Research Center , Giza ,
      Egypt.
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 (Indoles)
RN  - 0 (Spiro Compounds)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Indoles/chemical synthesis/chemistry/*pharmacology
MH  - Molecular Structure
MH  - Spiro Compounds/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - Triple Negative Breast Neoplasms/*drug therapy/pathology
OTO - NOTNLM
OT  - EGFR
OT  - Triple-negative breast cancer
OT  - anti-proliferative activity
OT  - apoptosis
OT  - spirooxindoles
EDAT- 2017/12/29 06:00
MHDA- 2018/01/06 06:00
CRDT- 2017/12/29 06:00
PHST- 2017/12/29 06:00 [entrez]
PHST- 2017/12/29 06:00 [pubmed]
PHST- 2018/01/06 06:00 [medline]
AID - 10.1080/14756366.2017.1417276 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2018 Dec;33(1):309-318. doi:
      10.1080/14756366.2017.1417276.