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Article

Synthesis of Both Ionic Species of Ammonium Dithiocarbamate Derived Cholic Acid Moieties

Department of Chemistry, FI-40014 University of Jyväskylä, Finland
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(8), 6306-6312; https://doi.org/10.3390/molecules16086306
Received: 1 July 2011 / Revised: 18 July 2011 / Accepted: 25 July 2011 / Published: 26 July 2011
(This article belongs to the Special Issue Steroids)

Abstract

:
The reaction of 3-aminopropylamide of cholic acid with CS2 produced a bile acid derivative of dithiocarbamic acid which further formed an ammonium salt with another molecule of 3-aminopropylamide of cholic acid. The cationic 3-ammonium propylamide of cholic acid did not react further with CS2 and the formed salt was stable in the reaction mixture, even when excess CS2 was used. When the reaction was carried out in the presence of aqueous sodium hydroxide, only the bile acid derivative of sodium dithiocarbamate was formed. The dithiocarbamate derivatives were characterized by 1H- and 13C-NMR spectroscopy and ESI-TOF mass spectrometry.

Graphical Abstract

1. Introduction

It is known that amines react with CS2 forming dithiocarbamates [1,2,3,4,5,6]. Recently, Yavari et al. [7] have reported new synthetic strategies to prepare dithiocarbamates due to their large application potential. Dithiocarbamates exhibit numerous biological activities [9,10,11,12] and they are used in agriculture [12,13,14] and as linkers in solid-phase organic synthesis [15,16,17]. Further, dithiocarbamates are also widely used in medicinal chemistry and they have found application in cancer therapy [18,19]. As a biologically important expansion of the topic, we now present the synthesis and characterization of cholic acid-derived ammonium dithiocarbamates. This straightforward synthetic method offers an effective route to bile acid derivatives with increased water solubility, which is an essential property in the design of physiologically active receptors [20,21] and drug carriers [22]. The synthetic route and numbering of 2 are shown in Scheme 1.

2. Results and Discussion

2.1. Chemistry

As the first step, N-(3-aminopropyl)-3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-amide (1) was prepared by a reaction of methyl cholate (methyl 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oate) with 1,3-diaminopropane (7 days at r.t.) [23]. Then compound 1 was allowed to react with CS2 in methanol to form the desired product, N-(3-aminopropyl)-3-α,7-α,12-α-trihydroxy-5-β-cholan-24-oyl ditihiocarbamate of N-(3-ammoniumpropyl)-3-α,7-α,12-α-trihydroxy-5-β-cholan-24-oic acid amide (2).
Scheme 1. Synthesis and numbering of 2.
Scheme 1. Synthesis and numbering of 2.
Molecules 16 06306 g001

2.2. Spectroscopy

The structural characterization of 2 is based on one-dimensional 1H-, 13C-, and 13C DEPT-135 data, as well as two-dimensional PFG DQF 1H-1H COSY [24,25,26], PFG 1H-13C HMQC [27,28], PFG 1H-13C HMBC [29] NMR studies and mass spectra, as well as elemental analysis. The 1H- and 13C-NMR spectra of the sodium dithiocarbamate derivative of cholic acid 3-aminopropylamide was also used to distinguish the assignments of anionic and cationic parts.1H-NMR spectral assignments of non-steroidal parts and some of the steroidal part are presented in Figure 2, where the signals marked in blue coming from the cationic part and those marked in red from the anionic part, respectively. Their unambiguous assignments are based on the comparison of the 1H-NMR spectra of 1 with the cholic acid-derived sodium dithiocarbamate prepared in the presence of aqueous sodium hydroxide and PFG DQF 1H,1H COSY correlations. The signals originating from protons 3, 7, 12, Me-18, Me-19, Me-21 and 23 of the bile acid moieties in both ionic species overlap. For the assignment of the 13C-NMR spectrum (Figure 3 and Table 1) the reference data [30] and heteronuclear chemical shift correlation measurements PFG 1H,13C HMQC and HMBC were used. Unfortunately the ammonium dithiocarbamate moiety of 2 was not thermally stable and it degraded in one week, whereas the sodium salt remained unchanged for several months when stored at room temperature.
Figure 2. 1H-NMR spectrum of 2 in CD3OD at 303 K and its partial assignment.
Figure 2. 1H-NMR spectrum of 2 in CD3OD at 303 K and its partial assignment.
Molecules 16 06306 g002
Figure 3. 13C-NMR spectrum of 2 in CD3OD at 303 K.
Figure 3. 13C-NMR spectrum of 2 in CD3OD at 303 K.
Molecules 16 06306 g003
Table 1. 13C NMR chemical shifts (±0.1 ppm) of 2 from int. TMS in CD3OD at 303 K.
Table 1. 13C NMR chemical shifts (±0.1 ppm) of 2 from int. TMS in CD3OD at 303 K.
Carbonδ (ppm)Carbonδ (ppm)
1,1’36.615,15’24.4
2,2’31.316,16’28.8
3,3’73.017,17’48.2,48.1
4,4’40.618,18’13.2
5,5’43.319,19’23.4
6,6’37.020,20’37.2
7,7’69.121,21’18.0
8,8’41.122,22’33.5,33.4
9,9’28.023,23’34.5,34.2
10,10’36.024,24’176.8,177.6
11,11’29.925,25’37.8,37.2
12,12’74.026,26’29.9,29.1
13,13’47.627,27’45.9,38.6
14,14’43.128214.7

3. Experimental

3.1. General

All reagents and solvents of analytical grade were purchased from Sigma-Aldrich and were used without further purification. 1H- and 13C-NMR experiments were run on a Bruker Avance DRX 500 FT NMR spectrometer equipped with a 5 mm diameter inverse detection probehead and z-gradient accessory. 1H chemical shifts were referenced to the center peak of the CD2HOD quintet δ(1H) = 3.31 ppm and 13C chemical shifts to the center peak of the CD3OD heptet δ(13C) = 49.15 ppm from the internal TMS. Mass spectra were run with a QSTAR Elite MS/MS mass spectrometer system. Elemental analyses were performed on a Perkin Elmer 2400, series II, CHNS/O analyzer.

3.2. Synthesis of N-(3-aminopropyl)-3-α,7-α,12-α-trihydroxy-5-β-cholan-24-oyl ditihiocarbamate of N-(3-ammoniumpropyl)-3-α,7-α,12-α-trihydroxy-5-β-cholan-24-oic acid amide (2)

3-Aminopropylamide of cholic acid (1) (100 mg, 0.22 mmol) and CS2 (30 μL, 0.50 mmol) were dissolved in methanol (10 mL) and stirred overnight at room temperature. After that the solvent and an excess CS2 was removed in vacuo. Yield 100%. 1H-NMR (methanol-d4): δ (ppm) = 0.71 (Me-18, 6H, s), 0.92 (Me-19, 6H, s), 1.06 (Me-21, 6H, d), 1.07-2.06 (44H), 2.08-2.20 (2H), 2.21-2.33 (6H), 3.01 (2H, t), 3,22 (2H, t), 3.31 (2H, t), 3.37 (2H, m), 3.63 (2H, t), 3.80 (2H, d), 3.95 (2H, s), 4.83 (12H). MS (ESI-TOF): m/z = 1006 [M+H]+, 1028 [M+Na]+, 465 [M-C28H47N2O4S2]+, 539 [M-C27H49N2O4]. M.W. (C55H96N4O8S2) = 1005.50. Elemental analysis: calcd (%) for C55H96N4O8S2 5 H2O: C, 60.30; H, 9.75; N, 5.11. Found C, 60.38; H, 9.42; N, 5.02.

4. Conclusions

We have demonstrated the straightforward synthesis of the cholic acid derived ammonium dithiocarbamate in both ionic species in 100% yield. We are planning to extend this approach starting from other ω-aminoalkylamides of other bile acids. The sodium salts of their dithiocarbamates are very promising starting materials in the preparation of dithiocarbamate gold(III) complexes, which have been shown to possess cytotoxic properties. They are being evaluated as potential antitumor agents as an alternative to cisplatin [18,31,32,33].

Acknowledgements

We are grateful to special laboratory technician Reijo Kauppinen for his help in running the NMR spectra, to special laboratory technician Mirja Lahtiperä for mass spectral determinations and to laboratory technician Elina Hautakangas for elemental analysis. Emer. Matti Nurmia and Wendie Nurmia are thanked for the revision of the English language.

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MDPI and ACS Style

Koivukorpi, J.; Kolehmainen, E. Synthesis of Both Ionic Species of Ammonium Dithiocarbamate Derived Cholic Acid Moieties. Molecules 2011, 16, 6306-6312. https://doi.org/10.3390/molecules16086306

AMA Style

Koivukorpi J, Kolehmainen E. Synthesis of Both Ionic Species of Ammonium Dithiocarbamate Derived Cholic Acid Moieties. Molecules. 2011; 16(8):6306-6312. https://doi.org/10.3390/molecules16086306

Chicago/Turabian Style

Koivukorpi, Juha, and Erkki Kolehmainen. 2011. "Synthesis of Both Ionic Species of Ammonium Dithiocarbamate Derived Cholic Acid Moieties" Molecules 16, no. 8: 6306-6312. https://doi.org/10.3390/molecules16086306

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