Apoptosis plays a very crucial role in the maintenance of tissue
homeostasis by regulating cell death. The
fragmentation of chromosomal DNA into nucleosomal units, producing small DNA
fragments or DNA ladder, is considered as a prominent biochemical hallmark of
apoptotic cell death. The molecular
characterization of this process identifies a specific DNase called Caspase
activated DNase (CAD) or DNA fragmentation factor (DFF-40) that cleaves cellular DNA in a
caspase-dependent manner that kills the cells in an appropriate way. Our lab
used this phenomenon and synthesized series of novel molecules to identify an
active molecule capable of inducing apoptosis by activating CAD.
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Published in the
journal Bioorganic chemistry: doi:10.1016/j.bioorg.2016.02.001
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strictly prohibited.
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This laboratory (MBL) in collaboration with Department of
Chemistry, Yuvaraja’s College, University of Mysore, made an attempt to synthesize
the compounds which would activate CAD by dissociating the inhibitor of CAD
(ICAD) from CAD which is normally heterodimerised with ICAD. A series of benzophenone tagged pyridine
analogues were synthesized. Our group has reported a number of novel benzophenone conjugated
analogues as potent inhibitors targeting angiogenesis. Pyridine, one of the
most prevalent heterocyclic compounds in nature, which is present in the
coenzyme vitamin B6 family and in numerous alkaloids, was conjugated
with benzophenone. Among the synthesized series the lab has identified two
novel active molecules, 8b and 8e. Compounds 8b with fluoro group and 8e with chloro substituent at the benzoyl ring of benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant
activity. Further investigations suggested that compounds 8b and 8e have the
potency to activate caspase activated DNase (endonuclease) which is responsible
for DNA fragmentation, a primary hallmark of apoptosis and thereby inhibits the
Dalton’s lymphoma ascites tumour growth.
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| Dr.B.T. Prabhakar and Mr. Prabhu Thirusangu |
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| Mr.H.G. Shamanth Neralagundi |
This research work was published in the journal Bioorganic
chemistry (Published by Elsevier). This
work is funded by Government of Karnataka, Vision
Group on Science and Technology, Bangalore [VGST/CISEE/2012-13/282], Lady Tata Memorial Trust, Mumbai, UGC
(F.No.41-507/2012(SR), SERB-DST (SR/FT/LS-25/2011) and VGST (VGST/ GRD231/
CISEE/2013-14), DBT (6242-P37/RGCB/PMD/DBT/PBKR/2015). [Note: This is inclusive of the
grants/funds of both the collaborators]. Shaukath Ara Khanum, Mohammed Al-Ghorbani, Gurupadaswamy H.D, and Girish V were involved in design
and synthesis of molecules. Prabhakar B.T and Prabhu Thirusangu were
involved in the project design, experimental plan and writing of the biological
section of this manuscript. Shamanth Neralagundi HG assisted the
experimental section of the biology work.
ABSTRACT
A series of benzophenones
possessing pyridine nucleus 8a-l
were synthesized by multistep reaction sequence and evaluated for antiproliferative activity against DLA
cells by in vitro and in vivo studies. The results suggested
that, compounds 8b with fluoro group and 8e with chloro
substituent at the benzoyl ring of
benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant
activity. Further investigation in mouse model suggests that compounds 8b and 8e have the potency to activate caspase activated DNase
(endonuclease) which is responsible for DNA fragmentation, a primary hallmark
of apoptosis and thereby inhibits the Dalton’s lymphoma ascites tumour growth.
Keywords: Benzophenone-pyridine; DLA; CAD; Endonuclease
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