Benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indole-2-substituted acetates: One-pot-preparation, anti-tumor activity, docking toward DNA and 3D QSAR analysis

doi:10.1016/j.bmc.2010.01.038

Bioorganic & Medicinal Chemistry

Volume 18, Issue 5, 1 March 2010, Pages 1910-1917

https://doi.org/10.1016/j.bmc.2010.01.038 Get rights and content

Abstract

To discover the anti-tumoral indoles a series of benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indole-2-substituted acetates (2a–n) are prepared via one-pot-preparation. The IC₅₀ values of 2a–n in vitro against human lung carcinoma, prostate cancer, nasopharyngeal carcinoma, vincristine-resistant KB subline and human breast carcinoma cells range from 40 nM to 60 μM. On Sarcoma 180 (S180) tumor-bearing mouse model four of them (2e,g,h,i) significantly inhibited the tumor growth. At the dose of 0.1 mg/kg the efficacy of the most potent 2h was equal to that of 1.0 mg/kg of doxorubicin. In contrast to doxorubicin, at 1.0 mg/kg of dose 2e,g,h,i did not induce the treated S180 mice to have organ atrophy and body emaciation. The healthy mice receiving 10, 100 and 500 mg/kg of 2e,g,h,i gave no any neurotoxic response. Even up to the dose of 500 mg/kg the healthy mice occurred no death. The interaction of 2a–n with DNA was confirmed by the fluorescence quenching experiments and automated flexible ligand docking. By 3D QSAR analysis the IC₅₀ values of 2a–n against prostate cancer cells were correlated with the structures and conformations of their side chains. To increase the data related to their physical-chemical properties the experimental Log P values were also provided.

Graphical abstract

Introduction

Despite a better understanding of the disease, the advent of modern technology and rationally targeted drugs, the incidence and cure rate of cancer have not improved. In the past decades continuous efforts have been made for discovering of new anti-tumor compounds and a number of substances have been reported. Among the discovered substances β-carboline derivatives have been particularly known possessing diverse action mechanism. β-Carboline derivatives may induce DNA damage,¹ intercalate toward DNA,² bind minor groove,3, 4 inhibit DNA synthesis⁵ or repair DNA.⁶ β-Carboline derivatives are also capable of inducing crossing-over and mitotic gene conversion⁷, modulating the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway⁸, as well as target Ras and their signaling pathways.⁹ β-Carboline derivatives may also inhibit indoleamine 2,3-dioxygenase,¹⁰ topoisomerase11, 12, 13 and cyclin-dependent kinases.13, 14 Among these action mechanisms intercalation has particular importance in the clinical oncology and some β-carboline derivatives are routinely used.15, 16

Structurally, β-carboline derivatives with DNA intercalation activities are characterized by a polycyclic aromatic planar pharmacophore capable of stacking between DNA pairs.17, 18 However, DNA intercalation of substituted β-carbolines may result in serious neurotoxicity.¹⁹ Discovering of non-neurotoxic β-carbolines has attracted a lot of interests.20, 21 As part of our ongoing efforts, recently a series of β-carboline-3- carbonylamino acid benzyl ester conjugates were evaluated as potent anticancer agents and substituted benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indole-2-acetates were considered P glucose protein (Pgp) inhibitors possessing reversing resistance activity.²² Afterwards they were found having low neurotoxicity. In this context, in the present paper the in vitro anti-proliferation, in vivo anti-tumor activity, neurotoxicity, organ damage, acute toxicity, 3D QSAR analysis, experimental Log P values and intercalating mechanism of β-carboline derivatives, benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indole-2-substituted acetates, were investigated.

Section snippets

Chemistry

The synthetic route was depicted in Scheme 1. In this one-pot-three-step procedure 3S-N-Boc-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid was firstly prepared from the coupling of β-carboline-3-carboxylic acid and Boc-N₃. The coupling product was then amidated with l-amino acid benzylester to gave 3S-N-Boc-1,2,3,4-tetrahydro-β-carboline-3-carbonyl-L-amino acid benzylester, which was unprotected to remove the Boc group, and treated with acetone and triethylamine to form benzyl

Conclusions

In a previous paper 2a–n were prepared by following a 4-step-route in 22–33% total yields. In this paper 2a–n were prepared by following a one-pot-preparation in 36–48% total yields. Thus the preparation of 2a–n was improved. In vitro some of the present compounds were capable of inhibiting the proliferation of cancer cell lines at a nanomolar concentration. In the toxicology evaluation the healthy mice receiving up to a dose of 500 mg/kg of some of the present compounds neither gave neurotoxic

General

The protected amino acids with l-configuration were purchased from Sigma Chemical Co. All the coupling and deprotective reactions were carried out under anhydrous conditions. Chromatography was performed on Qingdao silica gel H. The purities of the intermediates and the products were tested on TLC (Merck silica gel plates of type 60 F₂₅₄, 0.25 mm layer thickness) and HPLC (Waters, C₁₈ column 4.6 × 150 mm), respectively. HPLC purities of 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H

Acknowledgements

This work was finished in Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, supported by the National Natural Scientific Foundation of China (30801426, 30901843) Special Project (2008ZX09401-002) of China and PHR (IHLB, KZ200810025010) and PHR (IHLB, KZ200810025010 & KZ200910025004).

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Benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H-imidazo[3′,4′:1,2]pyridin[3,4-b]indole-2-substituted acetates: One-pot-preparation, anti-tumor activity, docking toward DNA and 3D QSAR analysis

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

General

Acknowledgements

Exp. Toxicol. Pathol.

Chem. Biol.

Int. J. Mass Spectrom.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Mutat. Res.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Int. Congress Series

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem.