Synthesis of two series of pyrazolic analogues of the marine alkaloids granulatimide and isogranulatimide as potent Checkpoint 1 kinase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2010.08.011

Two series of regioisomeric pyrazolic analogues of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the first series was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrazole followed by addition of the intermediates on dibromomaleimide, the so-obtained acyclic adducts being finally photochemically cyclised to the desired analogues. Compounds of the second series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclisation of the adducts.

Full text of DOI:10.1016/j.tetlet.2010.08.011

Tetrahedron Letters 51 (2010) 5640–5642
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Tetrahedron Letters
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Synthesis of two series of pyrazolic analogues of the marine alkaloids
granulatimide and isogranulatimide as potent Checkpoint 1 kinase inhibitors
⇑
Sébastien Deslandes, Stefan Chassaing, Evelyne Delfourne
Laboratoire de Synthèse et Physicochimie de Molecules d’Intérêt Biologique, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cédex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of regioisomeric pyrazolic analogues of the marine alkaloids granulatimide and isogranulati-
mide were prepared. The synthesis of the first series was based on the condensation reaction of diversely
5-substituted 3-bromoindoles with pyrazole followed by addition of the intermediates on dibromomalei-
mide, the so-obtained acyclic adducts being finally photochemically cyclised to the desired analogues.
Compounds of the second series were obtained by reacting different 5-substituted-indole-3-glyoxylates
with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclisation of the adducts.
Ó 2010 Published by Elsevier Ltd.
Received 21 June 2010
Revised 28 July 2010
Accepted 2 August 2010
Available online 25 August 2010
Keywords:
Marine alkaloid
Granulatimide
Isogranulatimide
Pyrazolic analogues
Checkpoint 1 kinase inhibitors
1. Introduction
ered as analogues of the marine metabolites in which the imidaz-
ole ring has been replaced by a pyrazole ring.
In the cell division cycle, G1 and G2 checkpoints are activated in
response to DNA damage and consequently block the cycle pro-
gression to allow time for DNA repair. Interestingly, in more than
50% of cancer cells, the G1 checkpoint is lacking due to mutation
of the p53 protein. Therefore, a combination of DNA damaging
agent with a G2 checkpoint inhibitor should force selectively can-
cer cells into a premature and lethal mitosis, such a combination
being currently envisaged as an original and particularly promising
chemotherapeutic approach.1–3
2. Chemistry
The synthesis of compounds of the first series 3a–d is outlined in
Scheme 1. It was inspired by the route reported by Prudhomme and
co-workers10 to prepare pyrrolic analogues of isogranulatimide.
The two first steps, consisting in the regioselective bromination
in 3-position of indoles 5a–c and the subsequent reaction of the
In this biological context, granulatimide 1 and isogranulatimide
2, natural alkaloids isolated from the ascidian Didemnum granula-
tum, have triggered considerable attention as cell cycle G2 check-
point inhibitors (Fig. 1).4–6 From a mechanistic point of view,
they have been identified as selective inhibitors of the Chk1 kinase,
a key enzyme involved in the G2 checkpoint regulation.7 Since this
pioneering result, intensive structure–activity relationship studies
have been carried out to investigate the structural parameters re-
quired for the biological activity.8,9 In this way, the importance of
the maleimide moiety which establishes the two fundamental
hydrogen bonds with Glu85 and Cys87 in the ATP binding pocket
of the enzyme has been pointed out.
In this Letter, we describe the synthesis of two new classes 3
and 4 of potent Chk1 inhibitors. These compounds can be consid-
⇑
Corresponding author. Tel.: +33 561556293; fax: +33 561556011.
E-mail address: delfourn@chimie.ups-tlse.fr (E. Delfourne).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.08.011

S. Deslandes et al. / Tetrahedron Letters 51 (2010) 5640–5642
5641
Scheme 1. Reagents and conditions: (a) Br2, DMF, 2 h; (b) TFA, CH2Cl2, rt, 4 h (61%, 39%, 55%, respectively for the two steps); (c) SnCl2, toluene, reflux, 24 h (17%, 28%, 11%,
respectively); (d) Pd black, nitrobenzene, 200 °C, 5 h; (e) EtMgBr, THF, rt, 12 h (58%, 36%, 51%, respectively); (f) hm, CH3CN, rt, 5 h (62%, 73%, 76%, respectively); (g) BBr3, CH2Cl2,
rt, 2 h (84%).
resulting bromo-derivatives 6a–c with pyrazole, were realised
according to the conditions previously described by Bocchi and
Palla.11,12 Noteworthy is that the acid-mediated installation of pyr-
azole onto the indole nucleus leading to the three N-indolylpyraz-
oles 7a–c proceeded in modest to good yields through the
formation of a C–N bond and not a C–C bond as previously ob-
served with pyrrole and indole.10 As in the case of the correspond-
ing pyrolo-derivatives, the Michael addition of compounds 7a–c on
maleimide in the presence of tin(II) chloride, furnished the acyclic
intermediates 8a–c in low yields. The cyclisation of 8a–c unexpect-
edly failed under the conditions used in the pyrrolic series (i.e., Pd
black in nitrobenzene at 200 °C), no conversion of the acyclic pre-
cursor being observed even after prolonged time heating. Finally,
the desired compounds 3a–c could be prepared starting from
N-indolylpyrazoles 7a–c, by using an alternative two-step-
sequence which consists in: (i) nucleophilic addition of the
conjugated base of indolylpyrazoles (generated in situ) on N-
TBDMS-dibromomaleimide with concomitant deprotection of the
TBDMS protective group, (ii) photocyclisation of adducts 9a–c to
the desired pyrazolic analogues 3a–c. Ultimately, the hydroxylated
analogue 3d was obtained by demethylation of the methoxy deriv-
ative 3c with BBr3.
The retrosynthetic scheme for accessing regioisomeric com-
pounds 4a–c of the second series was based on the methodology
reported by Faul to prepare bisindolylmaleimides13 and later on
used by Piers et al. to publish an improved synthesis of isogranu-
latimide (Scheme 2).14
The different ethyl N-Boc-5-substituted-3-glyoxylates 11a–c,
readily obtained in two steps from the corresponding indoles
5a–c,15 were reacted in THF and in the presence of tBuOK with N-
Boc-pyrazole-3-acetamide 12, itself prepared from pyrazole-3-acet-
amide.16 The final photochemical cyclisation of the so-obtained-
indolylpyrazolylmaleimides 10a–c to give the N-Boc-protected
pentacyclic derivatives was effected in the same conditions as for
the first series 3a–c (around 6% overall yields for the two steps).
The BOC group was finally cleaved to yield quantitatively com-
pounds 4a–c and the demethylation of 4c under identical conditions
as in the case of 3c allowed the preparation of phenolic analogue 4d.
In conclusion, this work reports on the preparation of the two
novel series of compounds structurally related to granulatimide,
in which a pyrazole heterocycle replaces the native imidazole moi-
ety. The biological evaluation of these compounds both in terms of
their Chk1 inhibition potential and their antiproliferative activities
is currently in progress.
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