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Bioorganic & Medicinal Chemistry Letters
Targeting Tyrosine Kinase: Development of Acridone – Pyrrole –Oxindole
Hybrids against Human Breast Cancer
Manpreet Kaur, Palwinder Singh
Department of Chemistry, UGC sponsored centre for advanced studies, Guru Nanak Dev University, Amritsar-143005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Based on the molecular modelling studies, a rational modification of the lead molecule was
made to develop highly potent compounds showing anti-cancer activity against human breast
cancer cell lines MCF 7, MD-MB-468 and T-47D. The most potent compounds have Log P and
total polar surface area 4.4 – 5.4 and 59.8 Å, respectively and they also exhibited promising
ADME profile.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole
Oxindole
Acridone
Molecular modeling
Tyrosine kinase
Anticancer
The physiological alterations causing an imbalance in cellular
signals controlling cell proliferation, morphogenesis, migration
and apoptosis are the primary factors resulting in the emanation
of the cancer diseases.1 These cellular signals are regulated by
tyrosine kinases (TKs) through the catalytic phosphorylation of
specific tyrosine residues, consequently, recognition of signalling
proteins is made and transfer of information across the plasma
membrane takes place.2 Activated by the ligand induced receptor
dimerization, epidermal growth factor receptor kinase (EGFR), a
transmembrane PTK and insulin growth factor receptor (IGFR)
play a key role in the formation of many types of solid tumors,
lung, breast, kidney and bladder cancers.3 Due to the mutations or
chromosomal dislocation or after genomic amplification many
TKs become potent oncogenes resulting in enhanced or
continuous signals causing numerous cancers.4 Hence receptor
tyrosine kinase is one of the potential cellular targets for the
development of anticancer drugs.5
Chart 1. Based on the structural features of known drugs and lead molecule
1, compounds 2 – 4 were designed.
Based on the understanding of signalling mechanism of many
tyrosine kinases as well as their crystallographic structures, the
inhibition of these enzymes has been adopted as one of the
strategic approaches to combat cancer. The potentially interested
TK inhibitors compete with ATP for binding to the ATP binding
site of the enzyme- its catalytic pocket.6 In the previous report,
the catalytic pocket of TK was analyzed and the role of
hydrophobic interactions in enzyme – ligand binding was
emphasized for the identification of compound 1 as anti-cancer
agent.7 Here, compound 1 was further modified by introducing a
bigger hydrophobic moiety acridone and also varying the
compounds 2–4 (Chart 1).
The molecular docking of compounds 2–4 in the active site of
TK showed that the acridone part of the molecule is buried in the
hydrophobic pocket of the enzyme and its orientation is effected
by the heterocycle moiety present on the pyrrole ring. In the case
of compound 2b, the acridone moiety was pushed outside the
hydrophobic pocket of the enzyme (Figure 1A) whereas the
indolinone fragment of compound 4b was not able to enter the
active site pocket (Figure 1C). Apparently, in comparison to
compounds 2b and 4b, compound 3b fitted better in the active
site pocket of the enzyme (Figure 1B). The oxindole moiety of
heterocycle moiety attached to the pyrrole ring for the design of
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Corresponding author. Tel.: +91-183-225-9902 x 3278; fax: 91-183-225-8819; e-mail: palwinder_singh_2000@yahoo.com