Discovery of 4-aryl-2-oxo-2H-chromenes as a new series of apoptosis
inducers using a cell- and caspase-based high-throughput screening assay
, Songchun Jiang
, Hong Zhang
, Shailaja Kasibhatla
, Candace Crogan-Grundy
, Giorgio Attardo
, Real Denis
, Serge Lamothe
, Henriette Gourdeau
, Ben Tseng
, Sui Xiong Cai
Epicept Corporation, Inc. 6650 Nancy Ridge Drive, San Diego, CA 92121, USA
Shire Biochem Inc., 275 Armand-Frappier Blvd., Laval, Que., Canada H7V 4A7
Received 16 July 2008
Revised 26 August 2008
Accepted 2 September 2008
Available online 6 September 2008
As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as
potential anticancer agents, we explored the removal of the chiral center at the 4-position and prepared a
series of 4-aryl-2-oxo-2H-chromenes. It was found that, in general, removal of the chiral center and
replacement of the 2-amino group with a 2-oxo group were tolerated and 4-aryl-2-oxo-2H-chromenes
exhibited SAR similar to 4-aryl-2-amino-4H-chromenes. The 4-aryl-2-oxo-2H-chromenes with a N-
methyl pyrrole fused at the 7,8-positions were highly active with compound 2a having an EC
of 13 nM in T47D cells. It was found that an OMe group was preferred at the 7-positon. 7-NMe
, 7-Cl and 7,8 fused pyrido analogs all had low potency. These 4-aryl-2-oxo-2H-chromenes are a ser-
ies of potent apoptosis inducers with potential advantage over the 4-aryl-2-amino-4H-chromenes series
via elimination of the chiral center at the 4-position.
Ó 2008 Elsevier Ltd. All rights reserved.
Apoptosis, or programmed cell death, is the process for elimi-
nating excessive cells that may threaten tissue homeostasis and or-
gan morphogenesis. Unlike necrotic cell death, apoptosis involves a
series of precisely regulated events, including condensation of the
nucleoplasm and cytoplasm, chromosomal DNA fragmentation,
and the formation of apoptotic bodies, which are rapidly recog-
nized and eliminated by phagocytes.
The mechanism of apoptosis
has been intensively studied over the past decade and two path-
ways have been identiﬁed, both involving a cascade of initiator
and effector caspases.
Caspase-3 is the main executioner of apop-
tosis by cleaving multiple protein substrates in cells, leading to
irreversible cell death.
Defects in the apoptotic machinery is one
of the mainstays of cancers that leads to uncontrollable tumor cell
growth, as well as tumor resistance to chemotherapeutic treat-
Not surprisingly, many of the clinically useful cytotoxic
agents are known to induce apoptosis in cancer cells
efforts are ongoing to identify apoptosis inducers.
We have been
interested in the discovery and development of apoptosis inducers
as potential anticancer agents,
and have therefore developed a
cell-based high throughput-screening technology for apoptosis
inducers using our proprietary ﬂuorescent caspase-3 substrate.
We have reported the discovery and structure–activity relation-
ships (SAR) of 4-aryl-4H-chromenes as a new series of potent
apoptosis inducers using our cell- and caspase-based Anti-cancer
Screening Apoptosis Program (ASAP) HTS assays. These compounds
were found to be tubulin inhibitors binding at or near the bind-
ing site of colchicine, with vascular disrupting activity and high
in-vivo activity in several anticancer animal models.
our screening hit 2-amino-3-cyano-7-dimethylamino-4-(3-meth-
oxy-4,5-methylenedioxy-phenyl)-4H-chromene (1a) (Chart 1), we
have identiﬁed 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cy-
ano-7-dimethylamino-4H-chromene (1b) as a lead compound.
Additional SAR studies showed that cyclization of the 7,8-posi-
tions into a ring structure led to potent compounds, such as
Introduction of a methyl group at the 7-po-
sition of the pyrrolo ring led to highly potent compounds such as
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +1 858 202 4006; fax: +1 858 202 4000.
E-mail address: email@example.com (S.X. Cai).
Bioorganic & Medicinal Chemistry Letters 18 (2008) 5571–5575
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl