The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

doi:10.1016/j.ejmech.2008.03.015

European Journal of Medicinal Chemistry

Volume 44, Issue 1, January 2009, Pages 54-62

https://doi.org/10.1016/j.ejmech.2008.03.015 Get rights and content

Abstract

This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a–c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC₅₀ values in the two series of compounds are presented based on molecular modeling, log P values and respiration in rat liver mitochondria.

Graphical abstract

The incorporation of a dimethylene bridge between the C2 and C6 atoms of series 3 led to series 2 with reduced cytotoxic potencies. This disparity in cytotoxic potencies was attributed inter alia to differences in topography, log P values and effect on respiration in mitochondria.

Introduction

The major interest in these laboratories is the development of antineoplastic agents which are structurally divergent from contemporary anticancer drugs. These novel compounds are principally conjugated unsaturated ketones which are known to react with thiols [1] but have low or nonexistent affinities for amino and hydroxy groups [2], [3]. Since thiols, in contrast to amino or hydroxy groups, are not found in nucleic acids, α,β-unsaturated ketones may be bereft of the carcinogenic and mutagenic properties displayed by various anticancer drugs [4]. There are a number of critical biochemical processes which involve thiols and the importance of compounds which interact with multiple molecular targets has been emphasized recently [5], [6].

The 1,5-diaryl-3-oxo-1,4-pentadienyl group has been mounted on a variety of cyclic scaffolds leading to the discovery of a number of potent cytotoxins [7], [8]. This group is considered to react at a primary binding site. However, the magnitude of the bioactivity observed will be influenced by the presence of other structural units in the molecule which align at an auxiliary site. These possibilities are illustrated in Fig. 1A. In order to probe as to the nature of the groups in the vicinity of the pharmacophore which affect cytotoxic potencies, various compounds possessing the general structure 1 were prepared (Fig. 1B). Several studies revealed that compounds in which R² is an acyl group have increased cytotoxic potencies compared to the analogs when R² is a hydrogen atom [9], [10]. In fact a number of N-acyl compounds have submicromolar IC₅₀ values and displayed selective toxicity to neoplasms than normal cells [11]. Thus by expanding the size of the molecules, there is the possibility of additional binding of the ligand at a receptor which results in the lowering of the IC₅₀ values. The hypothesis formulated in this study is that by increasing the size of the heterocyclic scaffold, cytotoxic potencies will be elevated compared to the analogs lacking this additional structural unit. In the present case, a dimethylene bridge was placed between carbon atoms 2 and 6 of the piperidine ring to give series 2 with a view to comparing cytotoxic potencies with the analogs 3 which lack this structural feature.

Previous studies revealed that the lack of coplanarity of rings A and B with the adjacent unsaturated linkages in 1 was caused, inter alia, by nonbonded interactions between one of the ortho protons of each aryl ring with the equatorial hydrogen atoms at C2 and C6 [12]. The decision was made, therefore, to replace the axial and not equatorial protons on the C2 and C6 atoms by substituents. In this way, changes in the cytotoxic potencies between 1 and various analogs could be attributed to the topographical, physicochemical and chemical properties of the groups at C2 and C6 per se and the interpretation of the results would not be complicated by changes in the torsion angles θ₁ and θ₂. X-ray crystallography revealed that the displacement of the C2 and C6 axial hydrogen atoms of various piperidines by a dimethylene bridge afforded 8-azabicyclo[3.2.1]octanes [13], [14]. Hence the aim of the present investigation was to prepare a small cluster of prototypic molecules related to 1 which bear C2 and C6 substituents, namely series 2, and to compare their cytotoxic properties with the analogs having both axial protons intact on the C2 and C6 atoms viz series 3. In particular, the information gained from this study may contribute to an understanding of those structural features which lead to marked cytotoxic properties.

Section snippets

Chemistry

The compounds in series 2 and 3 were prepared by the synthetic chemical route presented in Scheme 1. X-ray crystallography was undertaken on 2e and an ORTEP diagram [15] of this compound is displayed in Fig. 4. Molecular models of 2a–e and 3a–e were built and the torsion angles θ₁ and θ₂ are recorded in Table 1.

Bioevaluations

All of the compounds in series 2 and 3 were evaluated against human Molt 4/C8 and CEM T-lymphocytes and murine L1210 lymphoid leukemia cells. These results are portrayed in Table 1. In addition, these compounds were assayed for inhibitory effects towards human HSC-2, HSC-3 and HSC-4 oral squamous cell carcinomas and human HL-60 promyelocytic leukemia cells. Three normal human cell lines were also used, namely HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament fibroblasts.

Results and discussion

¹H NMR spectroscopy revealed that the compounds in series 2 and 3 are isomerically pure. X-ray crystallography of 8-methyl-2,4-bis(3-thienylmethylene)-8-azabicyclo[3.2.1]octan-3-one [17] as well as 2e revealed that the olefinic double bonds adopted the E configuration. In addition, the same stereochemistry was noted with various 3,5-bis(benzylidene)-1-methyl-4-piperidones [18], [19]. Hence the assumption was made that all of the compounds in series 2 and 3 are the E,E isomers.

All of the

Conclusions

This study has revealed clearly that in general replacement of the 2a and 6a protons in series 3 by a dimethylene bridge leading to 2a–e is accompanied by a reduction in cytotoxic potencies. Thus development of the cytotoxic 3,5-bis(benzylidene)-4-piperidones in which two protons are present on the carbon atoms attached to the basic centre appears to be a prudent decision. However, limited molecular modifications whereby groups of varying sizes are placed on the 2 and 6 carbon atoms of series 3

Chemistry

Melting points which are uncorrected were determined using a Gallenkamp instrument. ¹H NMR spectra were recorded using a Bruker AMX 500 FT machine while elemental analyses (C, H, N) were obtained using an Elementer analyzer and were within 0.4% of the calculated values. 4-Piperidones 3a,c,d were crystallized with 0.25, 0.75 and 0.25 mol of water of crystallization, respectively. X-ray crystallography was undertaken using a Nonius instrument.

Acknowledgments

The authors thank the following agencies and individuals who enabled this study to be undertaken. The Canadian Institutes of Health Research provided operating grants to J.R. Dimmock and B. Bandy. The Molt 4/C8, CEM and L1210 assays were undertaken by Mrs. Lizette van Berckelaer and funded by the Flemish Fonds voor Wetenschappelijk Onderzoek (FWO). A Grant-in-Aid was provided by the Ministry of Education, Science, Sports and Culture of Japan to H. Sakagami (No. 19592156). The Canadian

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Original articleThe cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Bioevaluations

Results and discussion

Conclusions

Chemistry

Acknowledgments

Anal. Biochem.

J. Pharm. Sci.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

J. Pharm. Sci.

J. Pharm. Sci.

Biochem. Biophys. Acta

Biochem. Biophys. Acta

J. Biol. Chem.

Methods Enzymol.

Mini Rev. Med. Chem.

Chem. Ind.

Nature

Drug Des. Deliv.

Acta Crystallogr.

Acta Crystallogr.

J. Appl. Crystallogr.

Pharm. Assoc. Sci. Ed.

Original article
The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones