Bioorganic & Medicinal Chemistry Letters
Click chemistry inspired facile synthesis and bioevaluation of novel
triazolyl analogs of Ludartin q
b
b
c
Shabir H. Lone a, Khursheed A. Bhat a, , Rabiya Majeed , Abid Hamid , Mohd A. Khuroo
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a Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar 190005, India
b Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Jammu 180001, India
c Department of Chemistry, University of Kashmir, Srinagar 190006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and modular synthesis involving diastereoselective Michael addition followed by regiose-
lective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-tri-
azoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen
1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for
the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine
B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines
revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the syn-
thesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and
Received 26 October 2013
Revised 30 December 2013
Accepted 8 January 2014
Available online 15 January 2014
Keywords:
Ludartin
Michael-addition
Huisgen 1,3-dipolar cycloaddition
Cytotoxicity
8.5 lM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 lM against
human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer
cell lines, respectively. The present synthesis was designed based on the previous literature reports of
Ludartin as an aromatase inhibitor. Our work provides an initial study on structure–activity relationship
of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular.
Ó 2014 Elsevier Ltd. All rights reserved.
Sesquiterpene lactones (SLs) form one of the largest biogeneti-
cally homogenous group of secondary metabolites known. SLs have
been a subject of vast number of phytochemical/biological studies
in the past four decades, mainly due to the fact that many of them
display various conspicious biological activities.1–3 These biological
activities are attributed to the presence of electrophilic structure
elements in SLs which undergo covalent reaction with functional
biological molecules resulting in their deactivation.1–3 The
alkylation of free sulphur moieties of enzymes and other functional
proteins by SLs is responsible for SL bioactivity.1–3 This is in har-
mony with the pearsons hard-soft acid base principle (HSAB) that
soft nucleophiles and electrophiles react more readily with each
other than with reactants classified as hard electrophiles and
nucleophiles, for example, non-conjugated carbonyl groups and
amino or hydroxyl groups, respectively.4,5
approach has been developed to improve their pharmacokinetic
potential.7 Following the amino prodrug approach effective
structure–activity relationships have been developed for various
guaianolides (Fig. 1A) including, Ludartin8 (1), arglabin9 and other
non-guaianolide sesquiterpene lactones (Fig. 1B) like alantolac-
tone,10 isoalantolactone,10 costunolide,11 parthenolide,12–15
a
-san-
tonin,16 helenalin17 and ambrosin.18 As a result few synthetic
derivatives which include (11R)-13-(dimethyl-amine)-11,
13-dihydroarglabin and (11R)-13-(dimethyl amine)-11,13-dihy-
droparthenolide have reached to clinical trials.6,9
Arglabin along with its dimethylamine analog, (11R)-13-(di-
methylamine)-11,13-dihydroarglabin is an approved anticancer
agent in several countries for treatment of lung, liver, breast and
ovarian cancers. 9 (11R)-13-(dimethylamine)-11,13-dihydro-argla-
bin has less side effects than other chemotherapeutic agents.9
Ludartin (1), position isomer of Arglabin, shows gastric cytopro-
tective effect19 and also inhibits aromatase enzyme which is in-
volved in hormone-dependent breast cancer.20,21 Earlier, we
reported the structure–activity relationship of amino analogs of
Among the sesquiterpene lactones only a few have reached clin-
ical trials which include artemisinin from Artemisia annua L,
thapsigargin from Thapsia garganica and parthenolide from Tanace-
tum parthenum.6 However owing to the relatively non selective
mechanism of action, most of the SLs are not suitable for drug
development. To address this non specificity issue amino prodrug
Ludartin (1) at its highly reactive a-methylene-c
-lactone moiety.8
Some of the amino derivatives of Ludartin (1) were found to be po-
tent and selective cytotoxic agents and the results were in fine
tune with those reported for Arglabin by R. Csuk and coworkers
that the Michael addition at the exocyclic double bond leads to
derivatives with reduced/or equal cytotoxic effect but cell line
q
Institute’s Publication No.: IIIM/1607/2013.
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Corresponding author. Tel.: +91 194 2431253x123; fax: +91 194 24441331.
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.