Synthesis and anticancer activity of new pyrrolocarbazoles and pyrrolo-β-carbolines

doi:10.1016/j.bmc.2004.12.045

Bioorganic & Medicinal Chemistry

Volume 13, Issue 6, 15 March 2005, Pages 2263-2283

https://doi.org/10.1016/j.bmc.2004.12.045 Get rights and content

Abstract

‘Bended’ 1, 3 or ‘linear’ 2 pyrrolidino-fused (aza)carbazoles were prepared and screened towards a few cancer-related targets. Whereas ‘bended’ derivatives 1 and 3 proved to be weakly toxic, several members of the ‘linear’ family strongly interact with DNA, especially derivative 28a.

Graphical abstract

Introduction

2,5-Pyrrolidinedione (succinimide) or 2-pyrrolidone appended polycyclic (hetero)aromatics are of interest in at least two families of anticancer drugs: (i) inhibitors of kinases implicated in cell signaling like the PKC inhibitor staurosporine1(a), 1(b) or/and in cell-cycle control like the CDK or CHK inhibitors granulatimide2(a), 2(b) or UCN-01³ (connections between checkpoint kinases, cyclin-dependent kinases, p53 and chemosensitization have been recently reviewed⁴); (ii) inhibitors of topoisomerase I like rebeccamycin.⁵ Synthetic analogues of these products have been developed in the field of topoisomerase I⁶ inhibitors, CDK7(a), 7(b) or CHK⁸ inhibitors. Recent reviews cover the staurosporine-like kinase or phosphatase inhibitors,⁹ the structure of kinase/inhibitor complexes10(a), 10(b) and the potential use of pharmacological inhibitors of CDKs¹¹ and GSK-3.12(a), 12(b) Such pyrrolidine(di)ones could be useful in pathologies other than cancer such as diabetes and neurodegenerative diseases (for example, GSK-3β inhibitors13(a), 13(b), 13(c)), viral¹⁴ or fungal¹⁵ pathologies.

The succinimide part interacts with the ATP binding pocket via an hydrogen-bonds network. The nature and the substitution pattern of the fused heterocycle provide some selectivity towards specific enzymes. For anti-topoisomerase agents, the requirement for a five membered lactam or imide is less obvious¹⁶ but it contributes both to the conformational rigidity and to the DNA binding ability of the inhibitor.

The substitution of the heterocycle alkylamino chain(s) increases the affinity for DNA, generally by filling up the DNA minor groove.¹⁷

The location of the merging bond between the heterocycle and the pyrrole ring, as well as the bioisosteric replacement of a carbon atom by nitrogen, allow other structural variations, which could improve biological activity.

Section snippets

Chemistry

In this work, we describe our chemical approach towards ‘bended’ (1) or ‘linear’ (2) 2-pyrrolidone or 2,5-pyrrolidinedione derivatives fused to carbazole as well as ‘bended’ 2-azacarbazoles (β-carbolines) 3: indeed oxygenated derivatives of 3 have been shown to present interesting anti-topoisomerase I activities18(a), 18(b) (Scheme 1). Their in vitro pharmacological activities are reported.

Cytotoxicity and cell-cycle effects

L1210 murine leukemia cells were used to estimate the cytotoxic potential of the compounds. IC₅₀ values are collated in Table 1, Table 2.³⁶ Some of the molecules showed submicromolar activities, such as 20b and 28a for example. This latter compound, which is the most cytotoxic molecule in the series, proved to be a potent DNA binder (see below). In parallel, the effect of the most cytotoxic compounds on the cycle of L1210 cells was investigated (Table 1, Table 2). In general, these compounds

Conclusion

Nearly all the derivatives we synthesized showed a micromolar range activity on L1210 cells. It could be noticed that the N-substitution of the pyrrolocarbazoles by the SEM group (vs NH compounds) did not modify the activity. In the camptothecin family, it has already been observed that appendage with a lipophilic trialkylsilyl chain are not detrimental to the anticancer activity.⁴¹ Some of the molecules tested induce a strong accumulation of L1210 cells in the G1 or G2+M phases of the cell

Materials and methods

Melting points were determined with a Reichert Thermovar hot-stage apparatus and are uncorrected. IR spectra (film or KBr) were measured with a Bomem FTIR instrument. UV spectra were measured in MeOH, using a UNICAM 8700 UV–vis spectrophotometer. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were acquired on a Bruker AC 300 spectrometer in CDCl₃ with TMS as internal standard, or in DMSO-d₆ and chemical shifts were expressed in ppm (δ). Mass spectra were recorded with a VG Autospec apparatus. All

Acknowledgements

We acknowledge the Groupe Servier and the Centre National de la Recherche Scientifique (C.N.R.S.) for financial support and grants for M.L. and M.B. This research was also supported by the Ministère de la Recherche/INSERM/CNRS ‘Molécules et Cibles Thérapeutiques’ Programme (L. Meijer). C.B. and A.L. thank the Ligue Nationale Française contre le Cancer (comité du Nord) and the Institut de Recherches sur le Cancer de Lille (IRCL) for a financial support.

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^†: Present address: GEVSM, UMR CNRS 7565, Faculté de Pharmacie, 5 Rue Albert Lebrun, 54001 Nancy, France

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Synthesis and anticancer activity of new pyrrolocarbazoles and pyrrolo-β-carbolines

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Cytotoxicity and cell-cycle effects

Conclusion

Materials and methods

Acknowledgements

Bioorg. Med. Chem. Lett.

Chem. Rev.

Science

Bioorg. Med. Chem.

Arch. Pharm. Pharm. Med. Chem.

Tetrahedron

J. Org. Chem.

Tetrahedron

J. Chem. Soc., Chem. Commun.

Tetrahedron Lett.

J. Org. Chem.

Tetrahedron

Tetrahedron Lett.

Bioorg. Med. Chem.

J. Org. Chem.

Eur. J. Org. Chem.

Methods Enzymol.

J. Biomol. Struct. Dyn.

Bull. Soc. Chim. Fr.

Biochemistry

Biochemistry

J. Biol. Chem.

Protein Expres. Purif.

J. Med. Chem.

J. Med. Chem.

J. Org. Chem.

Cancer Res.

Nature Rev.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Curr. Med. Chem.