Next Article in Journal
Multiplexed Analysis of Cage and Cage Free Chicken Egg Fatty Acids Using Stable Isotope Labeling and Mass Spectrometry
Previous Article in Journal
Chemical Composition and Biological Activity of Essential Oils of Origanum vulgare L. subsp. vulgare L. under Different Growth Conditions
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols

Laboratory of Microbiocide Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, Poznań 60-780, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2013, 18(12), 14961-14976; https://doi.org/10.3390/molecules181214961
Submission received: 6 November 2013 / Revised: 27 November 2013 / Accepted: 28 November 2013 / Published: 5 December 2013
(This article belongs to the Section Organic Chemistry)

Abstract

:
New quaternary alkylammonium conjugates of steroids were obtained by two step reaction of sterols (ergosterol, cholesterol, dihydrocholesterol) with bromoacetic acid bromide, followed by bimolecular nucleophilic substitution with a long chain tertiary alkylamine. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry and PM5 semiempirical methods. The pharmacotherapeutic potential of synthesized compounds has been estimated on the basis of Prediction of Activity Spectra for Substances (PASS).

1. Introduction

The steroids are modified triterpenoids with the tetracyclic ring system of lanosterol. However, the compounds do not have methyl groups at the C(4) and C(14) position and they have differently modified side chains [1,2] (Figure 1). The compounds of this type are of natural origin and play important biological functions in plant and animal cells. They are also the main sex hormones in mammals (e.g., testosterone and estrogens) and plants (e.g., brassinosteroids). They also regulate metabolism (e.g., glycocholic and taurocholic acid or vitamin D) and are important cardioactive glycosides (e.g., digoxin, gitoxin and scillaren A) [3,4,5,6].
Figure 1. The structure, stereochemistry and numbering of lanosterol.
Figure 1. The structure, stereochemistry and numbering of lanosterol.
Molecules 18 14961 g001
Exceptionally interesting group of steroids are the sterols, e.g., cholesterol, cholestanol, ergosterol and stigmasterol [7,8,9]. Sterols are crystalline compounds which have a secondary hydroxyl group in the C(3) position of the steroid skeleton, one or two double bonds and differently modified side chains. Rings A/B of the steroid skeleton may have trans geometry (the allo series) or cis (the normal series). Sterols have a hydroxy group in the average plane of the ring, and can form a number of β-sterols [10,11].
One of the most important sterol is ergosterol (1, provitamin D2), which performs analogous functions like cholesterol (2). but in the cells of fungi (Figure 2). Ergosterol is vital for fungal survival. It serves two purposes: a bulk membrane function and a vigorous function [1,2]. Furthermore ergosterol is a biological precursor to vitamin D2 [12,13]. Another important compound of this group is cholesterol (and its metabolite cholestanol (3)), which is fundamental component of the cell membranes of animal cells. Cholesterol in the ester form stabilizes and stiffens a protein–lipid membrane. Cholesterol in mammals regulates the cell membrane’s permeability and fluidity, growth rate and membrane-bound enzyme activity.
Figure 2. The structure of ergosterol (1), cholesterol (2) and cholestanol (3).
Figure 2. The structure of ergosterol (1), cholesterol (2) and cholestanol (3).
Molecules 18 14961 g002
Modifications of functional groups in the molecules of sterols such as cholesterol or ergosterol provide compounds with high pharmacological activity. Connecting steroid compound molecules with natural products such as pyrimidines, purines, alkaloids or polyamines allows one to obtain new compounds with high biological activity as well as complexing or gelator agents. All compounds of this type may be classified as steroid conjugates [14].
Quaternary alkylammonium salts are very wide class of compounds which have many applications. Some of them are used as antiseptics and preservation agents [15]. It is proved that the derivatives which contain from 8 to 14 carbon atoms in the alkyl chain group show the greatest biocidal activity [16,17,18]. The mechanism of biocidal activity of quaternary alkylammonium salts is based on adsorption of the alkylammonium cation on the bacterial cell surface, diffusion through the cell wall and then binding and disruption of the cytoplasmatic membrane. Damage of the membrane results in a release of potassium ions and other cytoplasmatic constituents, finally leading to cell death [19,20,21,22,23,24]. A frequently used microbiocide, especially in sublethal concentrations, can result in an increasing resistance of microorganisms. One of the ways to overcome this serious negative side effect is the periodic application of new microbiocides with modified structures.
In recent years the number of applications of quaternary ammonium salts has increased constantly. They are used as biocides [19,20,21,22,23,24] and phase-transfer catalysts, especially in enantioselective reactions [25,26,27,28,29,30,31]. Some quaternary ammonium salts exist as ionic liquids, which can be used as “green solvents” [32,33,34] and electrolytes for liquid batteries [35,36]. Thus, the connection of plant sterols and long-chain amines or polyamines to form quaternary alkylammonium salts appears unusually interesting [37,38,39].
This work reports the synthesis and physicochemical properties of new quaternary alkylammonium conjugates of ergosteryl 3β-bromoacetate (4), cholesteryl 3β-bromoacetate (5) and dihydrocholesteryl 3β-bromoacetate (6) with N,N-dimethyl-N-octylamine (7, 11, 15), N,N-dimethyl-N-decylamine (8, 12, 16), N,N-dimethyl-N-dodecylamine (9, 13, 17), N,N-dimethyl-N-tetradecylamine (10, 14, 18) in acetonitrile. The potential pharmacological activities of the synthesized compounds have been studied using a computer-aided drug discovery approach with the in silico Prediction of Activity Spectra for Substances (PASSs) program. It is based on a robust analysis of the structure–activity relationships in a heterogeneous training set currently including about 60,000 biologically active compounds from different chemical series with about 4,500 types of biological activities. Since only the structural formula of the chemical compound is necessary to obtain a PASS prediction, this approach can be used at the earliest stages of investigation. There are many examples of the successful use of the PASS approach leading to new pharmacological agents [40,41,42,43,44]. The PASS software is useful for the study of biological activity of secondary metabolites. We have selected the types of activities that were predicted for a potential compound with the highest probability (focal activities). If predicted activity (PA) > 0.7, the substance is very likely to exhibit experimental activity and the chance of the substance being the analogue of a known pharmaceutical agent is also high. If 0.5 < PA < 0.7, the substance is unlikely to exhibit the activity in experiment, the probability is less, and the substance is unlike any known pharmaceutical agent.

2. Results and Discussion

The new quaternary alkylammonium conjugates of steroids were obtained by reaction of sterols (ergosterol, cholesterol, dihydrocholesterol) with bromoacetic acid bromide to give intermediates 46. The 3β-bromoacetates of sterols were prepared according to the literature procedures [45]. The structure of ergosteryl 3β-bromoacetate (4) was confirmed by 1H-NMR, 13C-NMR, and FT-IR analysis, as well as ESI-MS. The syntheses of conjugates 718 are shown in Scheme 1.
The structures of all synthesized compounds were determined from their 1H- and 13C-NMR, FT-IR and ESI-MS spectra. Moreover, PM5 calculations were performed on all compounds [46,47,48]. Additionally, analyses of the biological prediction activity spectra for the new esters prepared herein are good examples of in silico studies of chemical compounds.
Scheme 1. Synthesis of quaternary alkylammonium conjugates 718 of sterols 13.
Scheme 1. Synthesis of quaternary alkylammonium conjugates 718 of sterols 13.
Molecules 18 14961 g009
We also selected the types of activity that were predicted for a potential compound with the highest probability (focal activities, Table 1). According to these data the most frequently predicted types of biological activity are: cholesterol antagonist, antihypercholesterolemic, adenomatous polyposis treatment and glyceryl-ether monooxygenase, acylcarnitine hydrolase, alcohol O-acetyltransferase, oxidoreductase, prostaglandin-E2 9-reductase, alkylacetylglycerophosphatase, alkenylglycerophospho- choline hydrolase or dextranase inhibitors, respectively.
Table 1. Probability “to be Active” (PA) values for predicted biological activity of compounds 718.
Table 1. Probability “to be Active” (PA) values for predicted biological activity of compounds 718.
Focal predicted activity (PA > 0.80)Conjugates of
Ergosterol (1)Cholesterol (2)Cholestanol (3)
Cholesterol antagonist0.8800.9040.873
Glyceryl-ether monooxygenase inhibitor0.8890.9180.946
Antihypercholesterolemic0.9070.866-
Acylcarnitine hydrolase inhibitor-0.8730.967
Alcohol O-acetyltransferase inhibitor0.911--
Oxidoreductase inhibitor0.881--
Prostaglandin-E2 9-reductase inhibitor-0.857-
Alkylacetylglycerophosphatase inhibitor--0.916
Alkenylglycerophosphocholine hydrolase inhibitor--0.899
Adenomatous polyposis treatment--0.825
Dextranase inhibitor--0.822
The 1H-NMR spectra of compounds 718 showed characteristic multiplets in the 4.90–4.64 ppm range assigned to the C3α–H protons of the sterol skeleton (Figure 3). Characteristic hydrogen singlets ranging from 0.68–0.65 ppm assigned to CH3–18. The second sets of singlets ranging from 1.02–1.00 ppm and 0.82 ppm were assigned to CH3–19 for 714 and 1518, respectively. The characteristic doublets of CH3–21 are at 1.04 ppm and 0.93–0.90 in the conjugates 710 and 1118, respectively. Overlapping multiplets appear in the 0.91–0.78 ppm range for CH3–26 and CH3–27 of the ergosterol- substituted derivatives. The 1H-NMR spectra of 1118 showed a doublet at 0.86–0.85 ppm for the protons of the C(26) and C(27) methyl groups. For compounds 710 a doublet appears in the 0.93–0.91 ppm range assigned to CH3–28.
Figure 3. .1H-NMR spectra in the 6.2–3.3 ppm region showing the most characteristic signals of conjugates 9 (a), 13 (b) and 17 (c).
Figure 3. .1H-NMR spectra in the 6.2–3.3 ppm region showing the most characteristic signals of conjugates 9 (a), 13 (b) and 17 (c).
Molecules 18 14961 g003
The 1H-NMR spectra of 718 showed a signal in the range 4.90–4.72 ppm for the protons of the COCH2N+ group. The signals for six methyl protons of the N+(CH3)2 and two methylene protons of the N+CH2 occurred as singlets and triplets in the 3.66–3.61 and 3.81–3.76 ppm range, respectively.
The 13C-NMR spectra of compounds 718 show characteristic signals at 12.0–11.2 ppm and 21.2–21.0 ppm (710, 1518) or 18.1 ppm (1114), which are assigned to CH3–18 and CH3–21, respectively. The carbons of the CH3–19 group gave signals in the ranges 16.1-15.8 ppm, 18.2 ppm and 18.6 ppm for 710, 1114 as well as 1518, respectively. Analytical differences in the 13C-NMR spectra of CH3 groups are shown in Figure 4.
Figure 4. Analytical differences of CH3 groups of conjugates 9 (a), 13 (b) and 17 (c) in the corresponding 13C-NMR spectra.
Figure 4. Analytical differences of CH3 groups of conjugates 9 (a), 13 (b) and 17 (c) in the corresponding 13C-NMR spectra.
Molecules 18 14961 g004
Two important signals for C(1')=O and C(3)–O were present at 164.2–164.0 ppm and 76.7–76.0 ppm, respectively. The spectra of all conjugates show two diagnostic signals associated with CH2 atoms in N+–CH2–CO and N+–CH2 groups. The carbon atoms in the first group are located at 64.8–64.5 ppm and the second group 61.5–61.1 ppm, respectively. The carbon atoms of N+(CH3)2 the unit resonate in the 52.1–51.8 ppm range.
The solid-state IR spectra of representative conjugates 9, 13 and 17 are shown in Figure 5. The intense bands in the 1,743–1,740 cm−1 region are due to the carbonyl group ν(C=O) stretching vibrations. Further coupling have little or no effect on the vibration of the carbonyl group. Moreover strong characteristic bands in the 1,248–1,227 cm−1 region are present, which are assigned to the ν(C–O). The ν(C=C) stretching vibration band of compounds 9 and 13 occurs at 1,670 cm1and 1,624 cm−1 respectively, while the band is absent in compound 17. The conjugated C=C bond stretching vibration shifts toward lower frequencies.
Figure 5. FT-IR spectra of conjugates 9 (blue), 13 (red) and 17 (green) in the 3,000–600 cm−1 region.
Figure 5. FT-IR spectra of conjugates 9 (blue), 13 (red) and 17 (green) in the 3,000–600 cm−1 region.
Molecules 18 14961 g005
The ESI-MS spectra were recorded in methanol. In all cases, the molecular ion [M]+ is present, which is associated with the presence of a quaternary ammonium ion. In Figure 6 we present the ESI-MS spectrum of conjugate 13. In the spectrum of this conjugate, the [M]+ molecular ion peak is observed at m/z 641 (100%). Elimination of the steroid skeleton, rearrangement of a hydrogen atom from the cholesteryl part to amine chain and simple cleavage of the C(1')Osp3–C(3)sp3 bond from the molecular ion of 13 gave the fragmenty ion [C12H25–N(CH3)2–CH2–CO2H]+ at m/z 272. The rearrangement of the quaternary alkylammonium chain connected to the amine chain part gave the [C12H25–NH(CH3)–CO–CH2–N(CH3)2]+ fragment ion at m/z 286 (75%). The cleavage of N(sp3)–C(sp3) bond leads to the formation of the [C12H25–N(CH3)2H]+ fragment ion situated at m/z 214.
Figure 6. ESI-MS spectrum of conjugate 13.
Figure 6. ESI-MS spectrum of conjugate 13.
Molecules 18 14961 g006
PM5 semiempirical calculations were performed using the WinMopac 2003 program. The final heat of formation (HOF) for the sterols 13 and conjugates 718 is presented in Table 2. Representative compounds 9, 13 and 17 are shown in Figure 7.
Table 2. Heat of formation (HOF) [kcal/mol] of sterols (13) and conjugates (718).
Table 2. Heat of formation (HOF) [kcal/mol] of sterols (13) and conjugates (718).
CompoundHeat of formation [kcal/mol]ΔHOF [kcal/mol]
1−97.1208-
2−140.1058-
3−162.7945-
7−166.1127−68.9919
8−177.2208−80.1000
9−185.2745−88.1537
10−199.4745−102.3537
11−209.1057−68.9999
12−220.2465−80.1407
13−231.3873−91.2815
14−242.5909−102.4851
15−231.7232−68.9287
16−242.8998−80.1053
17−253.9813−91.1868
18−265.2097−102.4152
ΔHOF = HOFconjugates (718) − HOFsterols (13).
Figure 7. Molecular models of representative compounds (9), (13) and (17) calculated by PM5 method.
Figure 7. Molecular models of representative compounds (9), (13) and (17) calculated by PM5 method.
Molecules 18 14961 g007
The lowest HOF value is observed for cholestanol (3) and its derivatives 1518 where there are no double bonds to stabilize the molecules and hinder their reactivity. In derivatives 45 and 714 where double bonds are present increasing HOF values are observed. Furthermore, it was also observed that the extension of the hydrocarbon chain lowers the HOF values.
Figure 8. Molecular models of conjugates (10) calculated by PM5 method.
Figure 8. Molecular models of conjugates (10) calculated by PM5 method.
Molecules 18 14961 g008
This fact can be explained by the increase in the number of possible conformers. In turn the length of the hydrocarbon chain is not without significance for the antimicrobial activity of the obtained conjugates. The spatial arrangement and interaction of the conjugate 10 is shown in Figure 8. The final heat of formation is −1249.429 kcal/mol and the distances between the quaternary nitrogen and the anion bromide are 4.19 Å. Compensation charges occur only through intermolecular electrostatic interaction. This is a very good confirmation of the conclusion that interactions reduce HOF.

3. Experimental

3.1. General

The NMR spectra were measured with a Spectrometer NMR Varian Mercury 300 (Oxford, UK), operating at 300.07 MHz and 75.4614 MHz for 1H and 13C, respectively. Typical conditions for the proton spectra were: pulse width 32°, acquisition time 5 s, FT size 32 K and digital resolution 0.3 Hz per point, and for the carbon spectra pulse width 60°, FT size 60 K and digital resolution 0.6 Hz per point, the number of scans varied from 1200 to 10,000 per spectrum. The 13C and 1H chemical shifts were measured in CDCl3 relative to an internal standard of TMS. Infrared spectra were recorded in the KBr pellets using a FT-IR Bruker IFS 66 spectrometer (Karlsruhe, Germany). The ESI (electron spray ionization) mass spectra were recorded on a Waters/Micromass (Manchester, UK) ZQ mass spectrometer equipped with a Harvard Apparatus (Saint Laurent, Canada), syringe pump. The sample solutions were prepared in methanol at the concentration of approximately 10−5 M. The standard ESI-MS mass spectra were recorded at the cone voltage 30 V.

3.2. Synthesis: Typical Procedure for the Synthesis of Quaternary Ammonium Conjugates of Sterols

Ergosteryl 3β-bromoacetate (cholesteryl 3β-bromoacetate or dihydrocholesteryl 3β-bromoacetate) (0.20 mmol) was dissolved in CH3CN (3 mL) under reflux. Then the appropriate amine (0.24 mmol) was added and the mixture heated under reflux for 2 h. The precipitate formed was filtered off and crystallized from CH3CN–EtOH (90:1), to give white solids.
3β-Bromoacetate-ergosta-5,7,12-triene (4): white solid (95%), m.p. 168–170 °C. 1H-NMR: δH 6.13 (dd, J1 = 9.8, J2 = 3.0 Hz, 1H, 6–H), 5.36–5.10 (m, 3H, 7–H, 22–H and 23–H), 4.96–4.68 (m, 1H, 3α–H), 3.81 (t, J = 3.0 Hz, 2H, COCH2Br), 1.04 (d, J = 6.6 Hz, 3H, CH3–21), 1.01 (s, 3H, CH3–19), 0.92 (d, J = 6.9 Hz, 3H, CH3–28), 0.91–0.81 (overlapping m, J = 6.7 Hz, 6H, CH3–26 and CH3–27), 0.67 (s, 3H, CH3–18). 13C-NMR: δC 166.80, 147.87, 135.35, 132,13, 128.51, 126.02, 118.05, 75.82, 55.95, 47.98, 44.47, 42.86, 40.73, 39.46, 38.88, 36.53, 34.81, 33.81, 33.08, 27.86, 27.13, 26.34, 24.97, 21.16, 19.98, 19.63, 18.25, 17.64, 15.82, 11.22. FT-IR (KBr) νmax: 3,003, 2,863, 1,778, 1,752, 1,609, 1,540, 1,377, 1,346, 1,278, 1,213, 1,055, 971. ESI-MS (m/z): 555 (40%) [C30H45O2Br+K]+, 539 (80%) [C30H45O2Br+Na]+, 524 (100%) [C30H45O2Br+Li]+, 517 (90%) [C30H45O2Br+H]+.
N,N-dimethyl-(3β-acetate-ergosta-5,7,12-triene)-N-octylammonium bromide (7): white solid (85%), m.p. 203–204 °C. 1H-NMR: δH 6.14 (dd, J1 = 9.8, J2 = 2.8 Hz, 1H, 6–H) 5.35–5.16 (m, 3H, 7–H, 22–H and 23–H ), 4.89–4.74 (m, 3H, COCH2N+ and 3α–H), 3.80 (t, J = 9.0 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 1.04 (d, J = 6.5 Hz, 3H, CH3–21), 1.00 (s, 3H, CH3–19), 0.93 (d, J = 6.9 Hz, 3H, CH3–28), 0.88-0.82 (overlapping m, 9H, CH3–26, CH3–27 and CH3–5'), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.24, 148.21, 135.54, 132.20, 128.16, 123.46, 118.26, 76.72, 64.78, 61.35, 57.15, 52.06, 48.02, 44.87, 43.59, 42.91, 40.91, 38.97, 36.77, 36.52, 35.04, 33.96, 33.17, 31.69, 29.13, 29.06, 27.55, 26.18, 25.17, 22.99, 22.65, 21.90, 21.26, 21.08, 20.05, 19.73, 17.74, 15.91, 14.14, 11.34. FT-IR (KBr) νmax: 2,957, 2,930, 2,868, 1,740, 1,623, 1,489, 1,467, 1,404, 1,371, 1,227, 1,205, 1,138, 1,014, 999. ESI-MS (m/z): 754 (100%) [C40H68NO2Br2], 595 (100%) [C40H68NO2]+, 482 (20%) [C32H51NO2+H]+.
N,N-dimethyl-(3β-acetate-ergosta-5,7,12-triene)-N-decylammonium bromide (8): white solid (95%), m.p. 186–187 °C. 1H-NMR: δH 6.13 (d, J = 6.9 Hz, 1H), 5.28–5.12 (m, 3H, 7–H, 22–H, 23–H ), 4.88–4.74 (m, 3H, COCH2N+ and 3α–H), 3.76 (t, J = 6.0 Hz, 2H, N+CH2), 3.61 (s, 6H, N+(CH3)2), 1.04 (d, J = 6.5 Hz, 3H, CH3–21), 1.01 (s, 3H, CH3–19), 0.91 (d, J = 6,9 Hz, 3H, CH3–28), 0.88–0.78 (overlapping m, 9H, CH3–26, CH3–27 and CH3–5'), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.05, 148.06, 135.43, 131.94, 128.01, 120.80, 116.14, 76.00, 64.61, 61.20, 55.62, 54.46, 51.92, 51.87, 45.91, 42.75, 40.38, 38.90, 37.66, 36.96, 36.29, 33.01, 31.78, 29.35, 29.28, 29.19, 29.05, 28.21, 27.85, 26.04, 22.91, 22.85, 22.60, 21.05, 20.95, 19.90, 19.59, 17.55, 16.07, 14.06, 12.00. FT-IR (KBr) νmax: 2,956, 2,927, 2,853, 1,742, 1,634, 1,458, 1,368, 1,251, 1,206, 1,021, 968. ESI-MS (m/z): 782 (100%) [C42H72NO2Br2], 623 (100%) [C42H72NO2]+, 244 (85%) [C14H30NO2]+.
N,N-dimethyl-(3β-acetate-ergosta-5,7,12-triene)-N-dodecylammonium bromide (9): white solid (95%), m.p. 194–196 °C. 1H-NMR: δH 6.13 (dd, J1 = 9.8, J2 = 2.8 Hz, 1H, 6–H), 5.24–5.13 (m, 3H, 7–H, 22–H, 23–H ), 4.90–4.72 (m, 3H, COCH2N+, 3α–H), 3.80 (t, J = 8.06 Hz, 2H, N+CH2), 3.67 (s, 6H, N+(CH3)2), 1.04 (d, J = 6.6 Hz, 3H, CH3–21), 1.00 (s, 3H, CH3–19), 0.92 (d, J = 6.8 Hz, 3H, CH3–28), 0.91–0.78 (overlapping m, 9H, CH3–26, CH3–27 and CH3–5'), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.06, 148.08, 135.25, 132.10, 128.00, 123.30, 118.11, 76.57, 64.62, 61.17, 55.89, 52.00, 47.87, 44.41, 43.45, 42.81, 39.41, 36.43, 35.52, 34.70, 33.03, 32.19, 31.85, 29.55, 29.40, 29.28, 29.04, 27.80, 27.15, 26.05, 24.93, 22.85, 22.63, 21.11, 19.93, 19.59, 19.36, 17.60, 15.76, 14.08, 11.19. FT-IR (KBr) νmax: 2,957, 2,926, 2,852, 1,741, 1,631, 1,467, 1,398, 1,248, 1,203, 1,012, 969. ESI-MS (m/z): 651 (100%) [C44H76NO3]+, 272 (50%) [C16H34NO2]+.
N,N-dimethyl-(3β-acetate-ergosta-5,7,12-triene)-N-tetradecylammonium bromide (10): white solid (92%), m.p. 198–200 °C. 1H-NMR: δH 6.14 (dd, J1 = 9.7, J2 = 2.8 Hz, 1H, 6–H), 5.36–5.17 (m, 3H, 7–H, 22–H, 23–H ) 4.86-4.79 (m, 3H, COCH2N+, 3α–H), 3.79 (t, J = 8.0 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 1.04 (d, J = 6.6 Hz, 3H, CH3–21), 1.00 (s, 3H, CH3–19), 0.92 (d, J = 12.1 Hz, 3H, CH3–28), 0.90–0.82 (m, 9H, CH3–26, CH3–27 and CH3–5'), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.09, 148.07, 135.26, 132.10, 128.01, 123.30, 118.12, 76.67, 64.67, 61.23, 57.01, 55.90, 51.99, 47.87, 44.42, 43.45, 42.82, 40.76, 39.42, 38.84, 36.45, 35.53, 34.71, 33.04, 32.20, 31.88, 29.61, 29.41, 29.32, 29.28, 29.05, 27.81, 27.17, 26.06, 24.94, 22.87, 22.65, 21.12, 19.94, 19.61, 17.61, 15.76, 14.09, 11.20. FT-IR (KBr) νmax: 2,957, 2,852, 1,743, 1,635, 1,467, 1,371, 1,247, 1,205, 1,017, 973. ESI-MS (m/z): 839 (100%) [C46H80NO2Br2], 679 (100%) [C46H80NO2]+.
N,N-dimethyl-(3β-acetate-cholest-5-ene)-N-octylammonium bromide (11): white solid (99%), m.p. 210–211 °C. 1H-NMR: δH 5.40 (d, J = 4.8 Hz, 1H, 6–H), 4.85 (d, J = 3.6 Hz, 2H, COCH2N+), 4.71–4.65 (m, 1H, 3α–H), 3.80 (t, J = 8.1 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 2.35 (d, J = 6.3 Hz, 2H, 4–CH2), 1.01 (s, 3H, CH3–19), 0.92 (d, J = 6.5 Hz, 3H, CH3–21), 0.88 (t, J = 3.0Hz, 3H, CH3–5'), 0.86 (d, J = 1.3 Hz, 3H, CH3–26), 0.85 (d, J = 1.3 Hz, 3H, CH3–27), 0.68 (s, 3H, CH3–18). 13C-NMR: δC 164.01, 138.67, 123.45, 76.67, 64.60, 61.15, 56.58, 56.03, 51.80, 49.88, 42.22, 39.60, 39.44, 37.74, 36.74, 36.46, 36.10, 35.71, 31.82, 31.71, 31.55, 28.99, 28.92, 28.15, 27.95, 27.51, 26.02, 24.20, 23.75, 22.84, 22.77, 22.51, 20.95, 19.20, 18.65, 14.01, 11.78. FT-IR (KBr) νmax: 2,956, 2,934, 2,868, 1,741, 1,671, 1,488, 1,467, 1,378, 1,228, 1,211, 1,014, 996. ESI-MS (m/z): 744 (100%) [C39H70NO2Br2]-, 584 (100%) [C39H70NO2]+.
N,N-dimethyl-(3β-acetate-cholest-5-ene)-N-decylammonium bromide (12): white solid (82%), m.p. 210–212 °C. 1H-NMR: δH 5.39 (d, J = 4.3 Hz, 1H, 6–H), 4.85 (d, J = 3.6 Hz, 2H, COCH2N+), 4.72–4.64 (m, 1H, 3α–H), 3.80 (t, J = 8.1 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 2.35 (d, J = 6.1 Hz, 2H, 4–CH2), 1.01 (s, 3H, CH3-19), 0.92 (d, J = 6.7 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.86 (d, J = 1.3 Hz, 3H, CH3–26), 0.85 (d, J = 1.3 Hz, 3H, CH3–27), 0.68 (s, 3H, CH3–18). 13C-NMR: δC 164.01, 138.67, 123.45, 76.68, 64.60, 61.15, 56.58, 56.04, 51.83, 49.88, 42.23, 39.60, 39.44, 37.75, 36.74, 36.46, 36.10, 35.71, 31.82, 31.78, 31.72, 29.34, 29.27, 29.19, 29.04, 28.15, 27.95, 27.51, 26.03, 24.20, 23.75, 22.84, 22.77, 22.61, 22.51, 20.95, 19.21, 18.65, 14.07, 11.78. . FT-IR (KBr) νmax: 2,953, 2,853, 1,742, 1,467, 1,379, 1,248, 1,200, 1,139, 1,026, 942. ESI-MS (m/z): 773 (100%) [C41H74NO2Br2], 613 (100%) [C41H74NO2]+.
N,N-dimethyl-(3β-acetate-cholest-5-ene)-N-dodecylammonium bromide (13): white solid (92%), m.p. 213–214 °C. 1H-NMR: δH 5.39 (d, J = 4.4 Hz, 1H, 6–H), 4.86 (brs, 2H, COCH2N+), 4.70–4.67 (m, 1H, 3α–H), 3.80 (t, J = 12.1 Hz, 2H, N+CH2), 3.66 (s, 6H, N+(CH3)2), 2.35 (d, J = 6.9 Hz, 2H, 4–CH2), 1.02 (s, 3H, CH3–19), 0.92 (d, J = 6.7 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.86 (d, J = 1.3 Hz, 3H, CH3–26), 0.85 (d, J = 1.3 Hz, 3H, CH3–27), 0.68 (s, 3H, CH3–18). 13C-NMR: δC 164.05, 138.70, 123.44, 76.57, 64.63, 61.22, 56.61, 56.08, 51.88, 49.93, 42.25, 39.63, 39.45, 37.77, 36.77, 36.48, 36.13, 35.72, 31.85, 31.75, 29.55, 29.40, 29.28, 29.04, 28.15, 27.95, 27.54, 26.05, 24.21, 23.77, 22.86, 22.76, 22.63, 22.50, 20.97, 19.21, 18.66, 14.07, 11.79. FT-IR (KBr) νmax: 2,954, 2,930, 2,851, 1,742, 1,700, 1,671, 1,468, 1,397, 1,378, 1,248, 1,204, 1,015, 943. ESI-MS (m/z): 800 (100%) [C43H78NO2Br2], 641 (100%) [C43H78NO2]+.
N,N-dimethyl-(3β-acetate-cholest-5-ene)-N-tetradecylammonium bromide (14): white solid (92%), m.p. 197–199 °C. 1H-NMR: δH 5.39 (d, J = 4.67 Hz, 1H, 6–H), 4.86 (brs, 2H, COCH2N+), 4.71–4.64 (m, 1H, 3α–H), 3.81 (brs, 2H, N+CH2), 3.66 (s, 6H, N+(CH3)2), 2.36 (d, J = 6.9 Hz, 2H, 4–CH2), 1.01 (s, 3H, CH3–19), 0.93 (d, J = 6.7 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.86 (d, J = 1.3 Hz, 6H, CH3–26 and CH3–27), 0.68 (s, 3H, CH3–18). 13C-NMR: δC 164.04, 138.69, 123.43, 76.57, 64.60, 61.20, 56.60, 56.06, 51.88, 49.91, 42.24, 39.63, 39.44, 37.76, 36.75, 36.47, 36.11, 35.71, 31.87, 31.76, 29.60, 29.40, 29.27, 29.03, 28.15, 27.94, 27.52, 26.03, 24.21, 23.76, 22.84, 22.75, 22.64, 22.50, 20.96, 19.21, 18.65, 14.07, 11.79. FT-IR (KBr) νmax: 2,954, 2,927, 1,743, 1,467, 1,404, 1,379, 1,286, 1,247, 1,202, 1,175, 1,008, 945. ESI-MS (m/z): 828 (100%) [C45H82NO2Br2], 669 (100%) [C45H82NO2]+.
N,N-dimethyl-(3β-acetate-5β-cholestan)-N-octylammonium bromide (15): white solid (95%), m.p. 209–210 °C. 1H-NMR: δH 4.81–4.74 (m, 3H, 3α–H, COCH2N+), 3.78 (t, J = 8.1 Hz, 2H, N+CH2), 3.63 (s, 6H, N+(CH3)2), 0.91 (d, J = 6.6 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.85 (d, J = 1.3 Hz, 6H, CH3–26 and CH3–27), 0.82 (s, 3H, CH3–19), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.04 , 76.57, 64.83, 61.48, 56.33, 56.21, 54.09, 52.26 , 44.62, 42.52, 39.89, 39.45, 36.56, 36.11, 35.73, 35.37, 33.71, 31.87, 31.57, 29.02, 28.93, 28.48, 28.17, 27.95, 27.27, 26.10, 24.13, 23.78, 22.94, 22.76, 22.52, 21.15, 18.62, 14.01, 12.20, 12.01. FT-IR (KBr) νmax: 2,928, 2,851, 1,740, 1,488, 1,468, 1,405, 1,378, 1,228, 1,209, 1,001, 957, 927, 897. ESI-MS (m/z): 746 (100%) [C39H72NO2Br2], 587 (100%) [C39H72NO2]+.
N,N-dimethyl-(3β-acetate-5β-cholestan)-N-decylammonium bromide (16): white solid (93%), m.p. 209–210 °C. 1H-NMR: δH 4.86–4.74 (m, 3H, 3α-H and COCH2N+), 3.79 (t, J = 9.0 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 0.91 (d, J = 6.6 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.85 (d, J = 1.3 Hz, 6H, CH3–26 and CH3–27), 0.82 (s, 3H, CH3–19), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.07, 76.58, 64.64, 61.21 , 56.34, 56.22, 54.09, 51.90, 44.61, 42.53, 39.89, 39.46, 36.56, 36.11, 35.73, 35.36, 33.67, 31.87, 31.78, 29.34, 29.27, 29.19, 29.04, 28.47, 28.17, 27.96, 27.22, 26.04, 24.14, 23.78, 22.85, 22.76, 22.61, 22.51, 21.15, 18.62, 14.06, 12.19, 12.01. FT-IR (KBr) νmax: 2,954, 2,927, 2,853, 1,741, 1,467, 1,398, 1,248, 1,200, 1,147, 1,134, 1,019, 942. ESI-MS (m/z): 774 (100%) [C41H76NO2Br2], 615 (100%) [C41H76NO2]+.
N,N-dimethyl-(3β-acetate-5β-cholestan)-N-dodecylammonium bromide (17): white solid (92%), m.p. 210–212 °C. 1H-NMR: δH 4.82–4.76 (m, 3H, 3α–H, COCH2N+), 3.77 (t, J = 9.0 Hz, 2H, N+CH2), 3.62 (s, 6H, N+(CH3)2), 0.90 (d, J = 6.00 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.85 (d, J = 1.4 Hz, 6H, CH3–26 and CH3–27), 0.82 (s, 3H, CH3–19), 0.65 (s, 3H, CH3–18). 13C-NMR: δC 164.00, 76.56, 64.77, 61.20, 56.32, 56.20, 54.08, 51.90, 44.59, 42.51, 39.87, 39.44, 36.54, 36.09, 35.71, 35.34, 33.65, 31.84, 29.52, 29.37, 29.30, 29.26, 29.23, 29.00, 28.45, 28.15, 27.93, 27.19, 26.00, 24.11, 23.75, 22.78, 22.73, 22.61, 22.48, 21.14, 18.60, 14.05, 12.16, 11.99. FT-IR (KBr) νmax: 2,927, 2,850, 1,741, 1,467, 1,397, 1,379, 1,333, 1,248, 1,199, 1,015, 1,000. ESI-MS (m/z): 802 (100%) [C43H80NO2Br2], 643 (20%) [C43H80NO2]+, 272 (100%) [C16H34NO2]+.
N,N-dimethyl-(3β-acetate-5β-cholestan)-N-tetradecylammonium bromide (18): white solid (91%), m.p. 195–196 °C. 1H-NMR: δH 4.80–4.75 (m, 3H, 3α–H, COCH2N+), 3.80(t, J = 8.1 Hz, 2H, N+CH2), 3.65 (s, 6H, N+(CH3)2), 0.91 (d, J = 6.6 Hz, 3H, CH3–21), 0.88 (t, J = 3.0 Hz, 3H, CH3–5'), 0.85 (d, J = 1.4 Hz, CH3–26 and CH3–27), 0.82 (s, 3H, CH3–19), 0.65 (s, 3H, CH3–18).13C-NMR: δC 164.04, 76.68, 64.54, 61.14, 56.30, 56.18, 54.05, 51.88, 44.58, 44.52, 42.49, 39.85, 39.43, 36.53, 36.08, 35.71, 35.33, 33.64, 31.86, 31.84, 29.64, 29.60, 29.54, 29.39, 29.31, 29.25, 29.01, 28.45, 28.15, 27.93, 27.19, 27.12, 26.4, 26.06, 24.11, 23.75, 22.81, 22.75, 22.63, 22.53, 22.49, 21.13, 18.59, 14.07, 12.17, 11.98. FT-IR (KBr) νmax: 2,954, 2,849, 1,742, 1,468, 1,399, 1,379, 1,333, 1,248, 1,201, 1,018, 959. ESI-MS (m/z): 831 (100%) [C43H80NO2Br2], 671 (100%) [C45H84NO2]+.

4. Conclusions

In summary, twelve new quaternary ammonium conjugates of sterols 718 were prepared by the reactions in acetonitrile of ergosteryl 3β-bromoacetate, cholesteryl 3β-bromoacetate and dihydrocholesteryl 3β-bromoacetate, with N,N-dimethyl-N-octylamine, N,N-dimethyl-N-decylamine, N,N-dimethyl-N-dodecylamine and N,N-dimethyl-N-tetradecylamine. These new compounds were characterized by spectroscopic and molecular structure methods. These conjugates may find applications in molecular recognition and in pharmacology, especially as compounds with a high antimicrobial activity.

Acknowledgments

This work was supported by the funds from Faculty of Chemistry, Adam Mickiewicz University.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dewick, P.M. Steroids. In Medicinal Natural Products A Biosynthetic Approach, 3rd ed.; John Wiley & Sons, Ltd.: Chichester, UK, 2009; pp. 275–277. [Google Scholar]
  2. Nicolaou, K.C.; Montagnon, T. Steroids and the Pill. In Molecules that Changed the World; WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008; pp. 79–90. [Google Scholar]
  3. Kirson, I.; Glotter, E. Recent developments in naturally occurring ergostane-type steroids. A review. J. Nat. Prod. 1981, 44, 633–647. [Google Scholar] [CrossRef]
  4. Gao, H.; Dias, J.R. Selective protection of the various hydroxy groups of cholic acid and derivatives. A review. Org. Prep. Proced. Int. 1999, 32, 145–166. [Google Scholar] [CrossRef]
  5. Fetizon, M.; Kakis, F.J.; Ignatiadou-Ragoussis, V. Steroids derived from bile acids. Novel side-chain degradation scheme. J. Org. Chem. 1973, 38, 4308–4311. [Google Scholar] [CrossRef]
  6. Okamura, W.H.; Midland, M.M.; Hammond, M.W.; Rahman, N.A.; Dormanen, M.C.; Nemere, I.; Norman, A.W.J. Chemistry and conformation of vitamin D molecules. Steroid Biochem. Mol. Biol. 1995, 53, 603–613. [Google Scholar] [CrossRef]
  7. Fieser, L.F.; Fieser, M. Structures of the Bile Acids and of Cholesterol and Sterols. In Steroids; Reinhold Publishing Corporation: New York, NY, USA, 1959; pp. 53–90, pp. 341–364. [Google Scholar]
  8. Templeton, W. The Sterols, Bile Acids and Related Compounds. In An Introduction to the Chemistry of Terpenoids and Steroids; Butterworths: London, UK, 1969; pp. 158–190. [Google Scholar]
  9. Lednicer, D. Steroid Chemistry at a Glance; John Wiley & Sons, Ltd.: Chichester, UK, 2011. [Google Scholar]
  10. Parish, E.J.; Nes, W.D. Biochemistry and Function of Sterols; CRC-Press: Boca Raton, Florida, USA, 1997. [Google Scholar]
  11. Schaller, H. The role of sterols in plant growth and development. Prog. Lipid Res. 2003, 42, 163–175. [Google Scholar] [CrossRef]
  12. Koskinen, A.M.P. Terpens. In Asymmetric Synthesis of Natural Products; John Wiley & Sons, Ltd.: Chichester, UK, 2012; pp. 235–244. [Google Scholar]
  13. Ikan, R. Isoprenoids. In Natural Products a Laboratory Guide, 2nd ed; Academic Press: London, UK, 1991; pp. 154–159. [Google Scholar]
  14. Salunke, D.B.; Hazra, B.G.; Pore, V.S. Steroidal conjugates and their pharmacological applications. Curr. Med. Chem. 2006, 13, 813–847. [Google Scholar] [CrossRef]
  15. Standt, C.; Barbeau, J.; Gagnon, M.; Lafleur, M. Role of the ammonium group in the diffusion of quaternary ammonium compounds in Streptococcus mutans biofilms. J. Antimicrob. Chemother. 2007, 60, 1281–1287. [Google Scholar] [CrossRef]
  16. Dega-Szafran, Z.; Dulewicz, E. Synthesis and characterization of 1-carbalkoxymethyl-4-hydroxy-1-methylpiperidinium chlorides. ARKIVOC 2007, vi, 90–102. [Google Scholar]
  17. Shelton, R.S.; van Campen, M.G.; Tilford, C.H.; Lang, H.C.; Nisonger, L.; Bandelin, F.J.; Rubenkoening, H.L. Quaternary ammonium salts as germicides. I. Non-acylated quaternary ammonium salts derived from aliphatic amines. J. Am. Chem. Soc. 1946; 68, 753–755. [Google Scholar]
  18. Birnie, C.R.; Malamud, D.; Schnaare, R.L. Antimicrobial evaluation of N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides with variations in chain length. Antimicrob. Agents Chemohter. 2000, 44, 2514–2517. [Google Scholar] [CrossRef]
  19. Block, S.S. Disinfection, Sterilization, and Preservation, 5th ed.; Lippincott Williams & Wilkins: Philadelphia, PA ,USA, 2001. [Google Scholar]
  20. Manivannan, G. Disinfection and Decontamination; Principles, Applications and Related Issues; CRC Press Taylor & Francis Group: Boca Raton, FL, USA, 2008. [Google Scholar]
  21. Brycki, B.; Kowalczyk, I.; Koziróg, A. Synthesis, molecular structure, spectral properties and antifungal activity of polymethylene-α,ω-bis(N,N-dimethyl-N-dodecyloammonium bromides. Molecules 2011, 16, 319–335. [Google Scholar] [CrossRef]
  22. Paulus, W. Directory of Microbiocides for the Protection of Materials. A. Handbook; Springer: Dordrecht, The Netherlands, 2005. [Google Scholar]
  23. Fraise, A.P.; Maillard, J.-Y.; Sattar, S.A. Russell, Hugo & Ayliffe’s Principles and Practice of Disinfection, Preservation & Sterilization, 5th ed.; Wiley-Blackwell: Chichester, UK, 2013. [Google Scholar]
  24. Park, E.J.; Kim, M.H.; Kim, D.Y. Enantioselective alkylation of β-keto esters by phase-transfer catalysis using chiral quaternary ammonium salts. J. Org. Chem. 2004, 69, 6897–6899. [Google Scholar] [CrossRef]
  25. Kim, D.Y.; Huh, S.C.; Kim, S.M. Enantioselective Michael reaction of malonates and chalcones by phase-transfer catalysis using chiral quaternary ammonium salt. Tetrahedron Lett. 2001, 42, 6299–6301. [Google Scholar] [CrossRef]
  26. Kim, D.Y.; Park, E.J. Catalytic enantioselective fluorination of β-keto esters by phase-transfer catalysis using chiral quaternary ammonium salts. Org. Lett. 2002, 4, 545–547. [Google Scholar] [CrossRef]
  27. Niess, B.; Jorgensen, K.A. The asymmetric vinylogous Mannich reaction of dicyanoalkylidenes with α-amido sulfones under phase-transfer conditions. Chem. Commun. 2007, 1620–1622. [Google Scholar] [CrossRef]
  28. Orglmeister, E.; Mallat, T.; Baiker, A. Quaternary ammonium derivatives of cinchonidine as new chiral modifiers for platinum. J. Catal. 2005, 233, 333–341. [Google Scholar] [CrossRef]
  29. Breistein, P.; Karlsson, S.; Hendenström, E. Chiral pyrrolidinium salts as organocatalysts in the stereoselective 1,4-conjugate addition of N-methylpyrrole to cyclopent-1-ene carbaldehyde. Tetahedron Asymmetry 2006, 17, 107–111. [Google Scholar] [CrossRef]
  30. Fuijmori, T.; Fujiii, K.; Kanzaki, R.; Chiba, K.; Yamamoto, H.; Umebayashi, Y.; Ishiguro, S. Conformational structure of room temperature ionic liquid N-butyl-N-methyl-pyrrolidinium bis(trifluoromethanesulfonyl) imide—Raman spectroscopic study and DFT calculations. J. Mol. Liq. 2007, 131–132, 216–224. [Google Scholar]
  31. Yoshinawa-Fujita, M.; Johansson, K.; Newman, P.; MacFarlane, D.R.; Forsyth, M. Novel Lewis-base ionic liquids replacing typical anions. Tetrahedron Lett. 2006, 47, 2755–2758. [Google Scholar] [CrossRef]
  32. Henderson, W.A.; Passerini, S. Phase behavior of ionic liquid-lix mixtures: Pyrrolidinium cations and TFSI - anions. Chem. Mater. 2004, 16, 2758–2881. [Google Scholar]
  33. Sun, J.; MacFarlane, D.R.; Forsyth, M. A new family of ionic liquids based on the 1-alkyl-2-methyl pyrrolinium cation. Electrochim. Acta 2003, 48, 1707–1711. [Google Scholar] [CrossRef]
  34. MacFarlane, D.R.; Forsyth, S.A.; Golding, J.; Deacon, G.B. Ionic liquids based on imidazolium, ammonium and pyrrolidinium salts of the dicyanamide anion. Green Chem. 2002, 4, 444–448. [Google Scholar] [CrossRef]
  35. Sakaaebe, H.; Matsumoto, H. N-Methyl-N-propylpiperidinium bis (trifluoromethanesulfonyl) imide (PP13–TFSI) – novel electrolyte base for Li battery. Electrochem. Commun. 2003, 5, 548–594. [Google Scholar]
  36. Tigelaar, D.M.; Meador, M.A. B.; Bennett, W.R. Composite electrolytes for lithium batteries: Ionic liquids in APTES cross-linked polymers. Macromolecules 2007, 40, 4159–4164. [Google Scholar]
  37. Vida, N.; Svobodova, H.; Rarova, L.; Drašar, P.; Šaman, D.; Cvačka, J.; Wimmer, Z. Polyamine conjugates of stigmasterol. Steroids 2012, 77, 1212–1218. [Google Scholar] [CrossRef]
  38. Kim, H.-S.; Khan, S.N.; Jadhav, J.R.; Jeong, J.-W.; Jung, K.; Kwak, J.-H. A concise synthesis and antimicrobial activities of 3-polyamino-23,24-bisnorcholanes as steroid-polyamine conjugates. Bioorg. Med. Chem. Lett. 2011, 21, 3861–3865. [Google Scholar] [CrossRef]
  39. Bavikar, S.N.; Salunke, D.B.; Hazra, B.G.; Pore, V.S.; Dodd, R.H.; Thierr, J.; Shirazi, F.; Deshpande, M.V.; Kadreppa, S.; Chattopadhyay, S. Synthesis of chimeric tetrapeptide-linked cholic acid derivatives: Impending synergistic agents. Bioorg. Med. Chem. Lett. 2008, 18, 5512–5517. [Google Scholar] [CrossRef]
  40. Pharma Expert Predictive Services © 2011–2013, Version 2.0. Available online: http://www.pharmaexpert.ru/PASSOnline/ (accessed on 1 November 2013).
  41. Poroikov, V.V.; Filimonov, D.A.; Borodina, Y.V.; Lagunin, A.A.; Kos, A. Robustness of biological activity spectra predicting by computer program PASS for noncongeneric sets of chemical compounds. J. Chem. Inf. Comput. Sci. 2000, 40, 1349–1355. [Google Scholar] [CrossRef]
  42. Poroikov, V.V.; Filimonov, D.A. How to acquire new biological activities in old compounds by computer prediction. J. Comput. Aided Mol. Des. 2002, 16, 819–824. [Google Scholar] [CrossRef]
  43. Poroikov, V.V.; Filimonov, D.A. Predictive Toxicology; Helma, C., Ed.; Taylor and Francis: Boca Raton, FL, USA, 2005; pp. 459–478. [Google Scholar]
  44. Stepanchikova, A.V.; Lagunin, A.A.; Filimonov, D.A.; Poroikov, V.V. Prediction of biological activity spectra for substances: Evaluation on the diverse sets of drug-like structures. Curr. Med. Chem. 2003, 10, 225–233. [Google Scholar] [CrossRef]
  45. Aher, N.G.; Pore, V.S.; Patil, S.P. Design, synthesis, and micellar properties of bile acid dimers and oligomers linked with a 1,2,3-triazole ring. Tetrahedron 2007, 63, 12927–12934. [Google Scholar] [CrossRef]
  46. CAChe 5.04 UserGuide, Fujitsu: Chiba, Japan, 2003.
  47. Stewart, J.J.P. Optimization of parameters for semiempirical methods. III Extension of PM3 to Be, Mg, Zn, Ga, Ge, As, Se, Cd, In, Sn, Sb, Te, Hg, Tl, Pb, and Bi. J. Comput. Chem. 1991, 12, 320–341. [Google Scholar] [CrossRef]
  48. Stewart, J.J.P. Optimization of parameters for semiempirical methods I. Method. J. Comput. Chem. 1989, 10, 209–220. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds 46 and 718 are available from the authors.

Share and Cite

MDPI and ACS Style

Brycki, B.; Koenig, H.; Kowalczyk, I.; Pospieszny, T. Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols. Molecules 2013, 18, 14961-14976. https://doi.org/10.3390/molecules181214961

AMA Style

Brycki B, Koenig H, Kowalczyk I, Pospieszny T. Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols. Molecules. 2013; 18(12):14961-14976. https://doi.org/10.3390/molecules181214961

Chicago/Turabian Style

Brycki, Bogumił, Hanna Koenig, Iwona Kowalczyk, and Tomasz Pospieszny. 2013. "Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols" Molecules 18, no. 12: 14961-14976. https://doi.org/10.3390/molecules181214961

Article Metrics

Back to TopTop