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
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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