Molecular design, synthesis and physical properties of novel Cytisine-derivatives – Experimental and theoretical study

Journal of Molecular Structure 1034 (2013) 173–182

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Molecular design, synthesis and physical properties of novel Cytisine-derivatives – Experimental and theoretical study Bojidarka Ivanova ⇑, Michael Spiteller Lehrstuhl für Analytische Chemie, Institut für Umweltforschung, Fakultät für Chemie, Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, North Rheine-Westphalia, Germany

h i g h l i g h t s " Cytisine alkaloids. " Mass spectrometry. " Quantum chemistry. " Raman spectroscopy. "

a7-Sub-unit agonists.

a r t i c l e

i n f o

Article history: Received 22 June 2012 Received in revised form 15 August 2012 Accepted 15 August 2012 Available online 3 September 2012 Keywords: Quinolozidine alkaloids Cytisine Mass spectrometry Quantum chemistry Raman spectroscopy Schizophrenia

a b s t r a c t The paper presented a comprehensive theoretical and experimental study on the molecular drugs-design, synthesis, isolation, physical spectroscopic and mass spectrometric elucidation of novel functionalization derivatives of Cytisine (Cyt), using nucleosidic residues. Since these alkaloids have established biochemical profile, related the binding affinity of the nicotinic acetylcholine receptors (nAChRs), particularly a7 sub-type, the presented correlation between the molecular structure and properties allowed to evaluated the highlights of the biochemical hypothesises related the Schizophrenia. The anticancer activity of a7 subtype agonists and the crucial role of the nucleoside-based medications in the cancer therapy provided opportunity for further study on the biochemical relationship between Schizophrenia and few kinds of cancers, which has been hypothesized recently. The physical electronic absorptions (EAs), circular dichroic (CD) and Raman spectroscopic (RS) properties as well as mass spectrometric (MS) data, obtained using electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) methods under the positive single (MS) and tandem (MS/MS) modes of operation are discussed. Taking into account reports on a fatal intoxication of Cyt, the presented data would be of interest in the field of forensic chemistry, through development of highly selective and sensitive analytical protocols. Quantum chemical method is used to predict the physical properties of the isolated alkaloids, their affinity to the receptor loop and gas-phase stabilized species, observed mass spectrometrically. Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction Cytisine (Cyt) and its derivatives, belonging to the quinolizidine type of natural products (NPs) or to the family of Lupin-alkaloids, comprised a wide range of primarily, bi-, tri-, and tetracyclic molecules, representing an increasingly important group of chemicals, exhibiting a diverse array of biological activity [1]. They are promising molecular templates for semi-synthetic drugs-design, which are of interest as medications for the treatment the wide variety of conditions such as disorders, nicotine and alcohol dependences, ⇑ Corresponding author. Tel.: +49 231 755 4089; fax: +49 231 755 40 84. E-mail addresses: [email protected], [email protected] (B. Ivanova). 0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2012.08.025

depression and neurogenerative diseases [1]. Related our on-going studies on the naturally occurred anticancer agents [2] and potential psychoactive drugs for controlled/treatment the disorders/illnesses on the central nervous system (CNS) as well as elaboration of highly selective and simultaneously precise protocols for analysis [3], the Cyt derivatives are of great interest, since several findings suggested their promising biological activity for treatment the Schizophrenia [1], associated with agonism the a7 and a4b2 subtype units of nAChRs, predominating in the CNS [1d]. Since natural products (NPs) have a chiefly place in the history of medicinal chemistry, as well as their established clinical profile, the possibilities for modulation of their biological activity represented challenge in searching of the new potential drugs. Resent structurally oriented discoveries on the bio-macromolecular

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R1

R1

N

O

O

O

HO

N N

HO OH

N N

NH

N

N

HO

HO R1 = –H, –OH, –Cl, –COOH, –NH2

OH O

N H

N

N NH

Scheme 1. Chemical diagram of the studied natural products.

receptors, related CNS disorders allowed to elucidate comprehensively the biochemical mechanisms of drugs–receptor interactions [4], in particular, those related the Schizophrenia [5]. Of significant importance are the theoretical data and experimental evidences about the role the different molecular fragments involving the amino acid residues to given receptor loops [4], which allowed to evaluate the highlights of the hypothesized biochemical mechanisms, having main impact. The efforts in this field provided great possibility for implementation in the clinical practice of more effective medications for treatment the CNS’ diseases. Since only few NPs were found place in the modern medicine, the efforts in the molecular drugs-design are shown that the substituents at the 3- and 5-position increased significantly the binding affinity to the studied receptor loops [6]. The functionalizing of the Cyt molecular core with nucleosidic residues is inspired by recent findings, strongly suggesting that such derivative has significant affinity to the nAChRs, and in particular to the a7 sub-units, playing a chiefly role in cancer predisposition and clinical efficacy of anticancer nucleoside based medications [6]. So that, nAChRs are important for a comprehensive understanding of the biochemical mechanisms of Schizophrenia, and anticancer activity of the corresponding agonists [5,6]. This paper represented an effort in the development of the new potential derivatives, based on Cyt molecular template (Schemes 1 and S1). Comprehensively were analyzed the theoretical and experimental drugs–receptor bindings affinity, as well as the physical properties of the successfully synthesised and isolated ten (1)–(10) alkaloids, as marked models for further pharmacological and clinical screening. The data would be of interest as well in the field of analytical chemistry, and in particularly the forensic chemistry, since fatal Cyt-intoxication from plant material has been reported recently [7a].

2. Results and discussion 2.1. Mass spectrometric data The described approaches for synthesis of Cyt, possessed limitations in terms of a broader utilizing [1a,8]. Thus, a detail elucidation of the chemistry on the isolation of Cyt-substituted cores I1– I4 (Scheme S3), is important for further pharmacological screening of most promising biologically active molecules. In contrast, to the synthesis of Cyt, the compounds I1–I4, revealed MS peaks at m/z 191, 207, 235 and 224/226 assigned to [M+H]+ cations, i.e. [C11H15N2O]+, [C11H15N2O2]+, [C12H15N2O3]+, and [C11H13N2OCl]+, respectively (Fig. 1a). The MS spectra of (1)–(10) showed a low abundant peak at m/z 398, which would associated to a gas-phase stabilized carbohydrate oligomers under APCI experimental conditions (300 °C), moreover its MS/MS spectrum revealed a peak at m/ z 133 (Fig. 2). Nonetheless, those carbohydrates are highly abundant biologically active compounds, their variety of linkage positions, and stereo chemical anomeric configurations, resulted to a quite challenging and problematic mass spectrometric elucidation. For this reason herein are performed a parallel study of the starting G and C nucleosides depending of the pH of the medium. For all of the presented starting reagents, semi-synthetic and synthetic

intermediates; final products of interactions, as well as gas-phase stabilizing species is performed theoretical NBO analysis predicting the chemical reactivity, proton accepting ability and thermodynamic properties. The data are of significant importance, since, the qX(NBO) charges (X = N, or O) depended strongly of the type of the substituents (Scheme S2). Thus, the glycoside bond formation is preferably to O(C3)atom, characterizing with qO(NBO) of 0.788. Nonetheless that the negative-ion operation mode under the ESI-MS ionization conditions, is recommended for the analysis of the oligonucleotides [9], the presented data, achieved using the positive operation mode provided significant structural information about the carbohydrate adducts, mainly monomeric and dimeric species (Fig. 1, Scheme S2). As has been comprehensively described, [9], the common fragmentation of C and G revealed peaks at m/z 152 of purine [C5H5N5O]+ (G) and 112 of pyrimidine [C4H5N3O]+ moieties (C). The cross-ring monosaccharide 0.1A and 1.2 A cleavage yielded the peaks at m/z 194 [C7H8N5O2]+, 180 [C6H6N5O2]+ (G), and 154 [C6H8N3O2]+, 140 [C5H5N3O2]+ (C) [9]. The reaction C and G with the Cyt-cores, is accompanied by a highly competitive yielding of molecular associates (Schemes 2 and 3 and S1). The theoretical results and the tandem MS/MS ones provided essential structural information for them in gas-phase under ESI-MS and APCI-MS experiments. Nevertheless, that (1)– (10) are obtained through the classical Schiff’s synthesis [10], in the presence of kCH3COOH, however, a series of further competitive processes are observed as well. The analysis of the mass chromatogram within the retention times (RT) 1.65–1.95 mines of C, showed five sub-maxima at a high level of confidence of r2 = 0.99991 (Figs. 1 and S1). The UV-traces revealed electronic n ? p and conjugated p ? p transitions within 240–250 and 300–370 nm. The obtained chromatogram profile within RT = 1.55–1.95 mines, indicated the formation of dimers, since the band at 302 nm was typical only for Im1 d2 ,
characterizing with the peaks in the MS at m/z 594 NHþ -adduct . In contrast the Im1 4 d1 + cation was stabilized as a [M+H] one, since peak at 470.32 is observed. The MS shapes observed under ESI-MS and APCI experiments (Fig. 1) showed the typical for oligonucleotides multiple MS profile, result of an exchange of protons versus alkali and NHþ 4 ions [9]. The peak at m/z 228 at the RT = 1.73 and 1.79 mines is associated to monomeric [CAH2O + H]+ cation. A dimeric associate of an unsaturated nucleoside IIIa is assigned to the peak at m/z 448, respectively. Nonetheless of the possible intermediates typical for the unsaturated nucleosides [11i,j], in the MS spectra of the studied systems, only low yields of III are identified. Nonetheless that in the MS chromatogram a sub-component at RT = 1.76 min presented, the obtained UV-trace is a superposition of the spectroscopic curves of the two types of dimmers, so that it has not real physical contribution. In such cases, a parallel analysis evaluating the peak purity (PP) and the standard deviations (SDs) of the curve-fitted patterns is especially informative, since PP = 728 was found in C, while in G, the corresponding values, revealed the two submaxima, at the RT = 6.48 and 6.50 mines (UV-traces: 224 and 408 nm) are PP = 827 and 999, respectively [2j]. Nonetheless of the high level of confidence r2 = 0.99994, the UV-trace and the MS spectra evidenced that both sub maxima would assigned to the one compounds, i.e. the intensity corresponded to the

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175

Fig. 1. HPLC-ESI-MS spectrum and chemical diagram of I1 (a), C (b–d); chemical diagrams of the monomeric and oligimeric species according the labelling in Schemes 2 and 3c; the corresponding mass chromatogram, treated mathematically by the non-linear curve-fitting and peak purity approach as well as the UV-traces of C (e); UV-traces and ESI-MS spectra of III (f).

quantitative amounts summing the peak areas of both submaxima. These results are of importance for further establishments of the analytical protocols, since depending of the complexity of the carbohydrate residue the formation of possible synthetic or naturally occurred oligomers increased dramatically (Fig. 2) [11]. At RT = 6.61 min corresponded a MS spectrum revealing the peaks at m/z 271 of monomeric G, similar to this at the RT = 6.48 min, determining its origin as impurity of the second enantiomer of 8.48%. All NHþ 4 addict are characterized with daughter ion under MS/MS experiment by a loss of 18 (Fig. 2). Thus, the
NHþ 4 -adduct of Id2 under the APCI-MS/MS experiments at 487

scan, revealed peak at m/z 244. The series of peaks within m/z 820–900, are associated to dimeric associates such the corresponding one at m/z 887 of 2  Im1 d2 , which MS/MS spectrum revealed a daughter ion at m/z 869. In G, the MS peaks at m/z 551, 557, and 593 are assigned to [m3+H]+, and K+-adducts of IId3 and IId4, respectively. The monomeric species m4–m7, were products of the aldol reaction in the acidic medium. Comparable results were obtained previously on the non-substituted carbohydrates, yielding the series of the highly stereo selective species [11]. In contrast, however, with steric factors, i.e. the presence of the base in C and G is explained the fact that the C1AO-associates are not observed in

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Fig. 2. ESI-MS spectrum, chemical diagram and the theoretical qX(NBO) (X = O or N) data of (1) (a); mass chromatogram (b), treated using the peak purity and the non-linear curve fitting approach as well as the chemometric data; ESI and APCI-MS spectrum of (10) with the fragmentation scheme in a single MS (c) and tandem MS/MS operation mode (d).

-0.676

HO

O

-0.838

-0.618

O

N

NH2

- 0.795

m2

O

O

OH

HO

C

-0.787

N

O Id2

N

OH

N

Im2d1 Im2d2

N

-0.590 O

HO

OH

-0.683 HOOC -0.629

OH

-0.782

G

N

-0.645 NH -0.864 N NH2 -0.595

-0.391 N -0.588 O

COOH -0.697 -0.617 OH -0.790

Im4d1 Im4d2 IIm3d3 IIm4d3

OH

IId3 IId4

m5

Im1d1 Im1d2 OH

O H2N N

N

O

O

N

d2

HO HO

HN

N N

O

O

N

d3

NH NH2

O

O

N

OH

OH

d4

m7

O N

NH

N N

OH

O

O

OH

N N

Im6d3 Im6d4

O

O

H2N

OH O

N NH2

d1

-0.786 HO

HO -0.789

HO

N

-0.659 O -0.504 N

m4

-0.594 -0.692 O O -0.432 -0.620 N N -0.838 OH NH2 -0.786

-0.795 HO

-0.788

OH

-0.782

-0.788 OH

NH2

O

O OH

m3

m6

-0.860

NH2

OH

NH2

NH N -0.627

NH

G

C -0.615

-0.398 N

O

m1

Id1

-0.644 O

N

N

N O

-0.797

NH2 -0.502

O

-0.587

N

O

N

NH2 HO O

m5

I

d1

m5

I

NH2

O

O

O

HO d2

Im7d3 Im7d4

Scheme 2. Chemical diagrams of the different monomeric (mi) and dimeric associated (dj) (I = 1–7, j = 1–4) of the Cytidine I and Guanine (G); the theoretical qX(NBO) charges, where X = N or O) were presented.

the MS spectra of (1)–(10). In the MS spectra of the isolated alkaloids, the dominating processes related the fragmentation of the carbohydrate residues are those related mainly the saccharide bond cleavage and the cross-ring cleavage of type 1.2A.

2.2. Electronic absorption and circular dichroic spectroscopy The EAs within the UV-spectroscopic region of (1)–(10) are localized within the frame of the pyrimidine and purine molecular

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R1

NH

N

N

N

Alkaloid

N

(a)

NH

Nucleobase

N O OH

O

OH OH Carbohydrate

(b)

α7-(10)-c

(c)

α7-(2)-d

(d)

Scheme 3. Hydrophobic (a) and hydrophylic active a7 receptor sub-unit loop using the crystal structure PDB 2WN9 (a and b) formed by the D and E proteine chains [15]; chemical diagram of the designed molecules (c); optimized a7-drugs macromolecular systems a7–(10)–c and a7–(2)–d; electrostatic potential surphases of (10) in a7–(10)– c (d); the hydrogen bonds are shown with the blue solid lines, whihle the short contacts – with the orange solid ones, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

fragments and the conjugated C@CAC@O one in the alkaloid residues, resulting to the overlapped bands of conjugated p ? p and n ? p transitions (Fig. 3) at about 223 (em, 19,450 L mol1 cm1) 250 (em, 8700 L mol1 cm1), 265 (em, 2000 L mol1 cm1) and 311–349 nm. The last one is attributed to an intramolecular charge transfer (ICT), observed within the frame of d1 and d3, stabilized usually in condense phase. The EAs of (7), is characterized with bands at 265 and 311 nm of the n ? p and ICT within the frame of the purine-residue. The mentioned quantities are achieved after

the application of the curve fitting procedure. The analytical meaning of both lower-wavelength bands is far of the really evaluation, since as illustrated on the mathematically non-procedures spectrum, their strong intensity difficult a precise determination at the shown concentrations, measurements caused of the lowintensity of the bands 260–350 nm. The observed maxima about 280 nm are overlapped with the C one at 271 nm (em, 12,700 L mol1 cm1) [12] in (1)–(5), respectively. The CD spectra of (1)–(10) (Fig. 3) are correlated to the optical CD effects in the

Fig. 3. Electronic absorption spectra of the isolated alkaloids; curve fitted spectrum of (7) after the application of the baseline correction approach with corresponding chemometric analysis (a); circular dichroic spectra of the studied compounds (b); the noise area within 200–250 nm is a result of the used solvent dimethylformamide; the peak band positions xci (i = 1–4) and the integral absorbance (Ai, i = 1–4), obtained by the nonlinear curve fitting method.

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non-substituted alkaloids. The observed [a]D data are within the reported quantities for above discussed NPs of about (+10.3)–(–140.0°) [12]. Interestingly is the obtained spectrum for (4), where a negative Cotton effect is observed at 248 and 280 nm, associated with the hydrogen bonding dimers with participation of ACOOH group already described for other alkaloid classes of NPs [2d,f,g]. The decreasing of the pH of the medium perturbed strongly the CD spectra. So that the protonated and the neutral forms of the studied alkaloids (Scheme S2) showed a perturbation of kmax of 4–16 nm and [a]D values of about |40°|, respectively. Interestingly, the Cotton effect within 200–280 nm in the CD spectra of (1)–(10) is caused by the alkaloidic residues, taking into account that the studied nucleosides themselves [12] are characterized with the B2u at 270 nm, and low [a]D values of about (+10.0)–(+15.0)°. 2.3. Raman spectroscopic data The vibrational analysis of the (1)–(10) is difficulties significantly both IR- and the Raman methods (Figs. 4 and 5), since in the first case the strong overlapping effects and broad spectroscopic profile is observed within the mid-IR region (Fig. S2). In contrast to the Raman spectra of the nucleosides themselves, where a decreasing of the Raman intensity due to the strong nucleobase– nucleobase interactions, known as well as Raman hypochromic [13] is observed, the bulk alkaloid fragment localized the interactions within the frame of the formation the d1, d3 type of dimers

(Fig. 4), and prevent the stacking interactions, which are evaluated by the observed Raman spectroscopic shifting and relatively strong intensity of the frequencies within the mid-IR region. As expected the theoretically predicted mOH stretching vibrations within 3700– 3600 cm1 of the carbohydrate fragments depended strongly of the type of the intramolecular hydrogen bonding [14]. In the case of (6), the pairs of symmetric and asymmetric stretching vibrations are predicted, due to the shown most stable conformation of the studied alkaloid characterizing with the moderate intramolecular OH  O(H) bond (2.765 Å). Contrast the experimental IR-spectra showed a broad band within 3400–3200 cm1, while the RS ones are low-intensive frequencies within the same region of the electromagnetic spectrum. In (3) and (8) the OH of the substituent at the alkaloid fragment is predicted at 3510 cm1 and experimentally found at about 3389 cm1 (3) and 3484 cm1 (8) in the IR-spectra. The shifting is explained with the participation of the mOH group in the intermolecular hydrogen bonding networks. The intensive RS mArH stretching vibrations of the C and G are obtained within the 3100–3020 cm1, both theoretically as well as experimentally. The 1800–1450 cm1 region is characterized with the broad low intensive modes of the dNH vibration of the amide skeleton as well as the G one within 1500–1525 cm1 (Fig. 5). Similar to the CD spectra of the (1)–(10) most characteristic in the RS appeared the mC@O stretching vibration of the alkaloid fragment, in contrast to the nucleobase ones observed within 1657–1636 cm1, since as above discussed, the typical dimers d1, d3 are observed in the condense phase of nucleosides. The Cl-substituent in (2) and (7) weakly

Fig. 4. Theoretical IR- and Raman spectra of the isolated alkaloids; visualization of the selected transition moments and the directions of the molecular vibration (blue pointer) as well as the total direction (brown pointer). The intensities are shown in the [a.u.]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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179

Fig. 5. Mathematically non-procedured experimental RS in solid-state within 3600–30 cm1 (a); experimental spectra within 1700–1500 cm1 after the baseline correction (b); the intensity of the experimental Raman spectra are presented in arbitrary units.

perturbed the mCH in-plane stretching vibrations of about 5 cm1. Generally the mC@O of the G-fragment in (6)–(10) are characterized with the higher RS intensity than the corresponding mC@O ones of the C-residue in (1)–(5) (Fig. 4). As could expected the conjugation of the C@O group in the alkaloid residues resulted to a lowfrequency shifting of the mC@O mode at about 1680–1668 cm1. The corresponding vibration of the COOH-group in (4) and (9) appeared at about 1700 cm1 (Fig. 5). 2.4. Nuclear magnetic resonance The 1H NMR spectra of the show many identical resonances to those of the corresponding Cyt, I1–I4, C and G themselves (Fig. 6). At the same pH for the protons of the carbohydrate rings and the alkaloid moiety such as CH2(f), give more complex resonances as a result of the overlapping of the signals, i.e. multiple at d = 2.90 ppm for CH2(f), multiples at d = 2.95, 2.63, 2.55 and 2.32 ppm respectively. The overlapped AB profile within d = 3.37– 3.60 ppm region for the CH2 protons of the alkaloid fragment bonded to the N-heterocyclic atoms are quite similar to those of the non-substituted residues, since the functionalization of the molecular skeleton is localized to the C@O group. 2.5. Binding affinity to a7 sub-unit of nAChRs The binding affinity of (1)–(10) to a7 sub-unit is studied, using the crystallographic data (PDB 2WN9, Protein Data Bank [4]). The receptor active loop involved the Trp147.E, Tyr195.E, Tyr95.E, Ser167.D, Ser166.D, Asp164.D and Thr36.D amino acid residues as shown

between D and E protein chains (Scheme 3). The macromolecular conformational disposition of these fragments formed two well defined hydrophobic and hydrophilic cavities (Scheme 3a and b), thus causing a specific molecular model of the drugs, consisted on two related fragments: a hydrophobic one of alkaloid skeleton and nucleobase and a hydrophilic residue, containing carbohydrate moieties (Scheme 3c). Since two solvent water molecules are found crystallographically (H2O2010.D and H2O2030.D), the optimization of the drugs–receptor macromolecular complexes (Scheme 3) is performed using their coordinates as well. Five most stable drugs– macromolecular complex conformations are found within DG (free Gibbs energy) values of 23.91–5.78 kcal/mol ((1)–(5)) and 15.19– 17.33 kcal/mol ((6)–(10)). The molecular binding affinity is evaluated both calculating the neutral and the monocations (Schemes 3 and S2 and Fig. S1). The results showed that most stable are the interactions with the ionic forms, characterizing with D(DG) of 0.14–1.34 kcal/mol. The R1-substituent (Scheme 3c) effect insignificantly to the binding affinity, contributing mainly to the dissolving properties. In contrast, the hydrogen bonding network to the receptor active site with the participation of carbohydrate residues influenced strongly the thermodynamic parameters, since the most stable macromolecular complex is the a7–(2)–d one (Scheme S2, DG = 4.71 kcal/mol), characterizing with the OH  OSer166.D (2.231 Å) and a intramolecular OH  O (2.687 Å) bonds. As has been hypothesized [5], and formerly evidenced studying a larger group of NPs with established psychoactive functional profile and activity on the CNS receptors such as serotonin or dopamine ones [5], the hydrophobic interactions consisted chiefly on the p-stacking effect between the substituted aromatic plane of

Fig. 6. 1H NMR spectra of (1) (a) and (5) (b) in CD3CN.

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the alkaloidic residues and the plane of the Trp147.E amino acid in the receptor loop (Scheme S3). In contrast to other systems, however, the reported data showed a small angle of 24.6(2)°. In addition a (alkaloid)NH  p interaction with participation of the Trp147.E amino acid is also found. The conformational environment around the receptor active loop and the disposition of the discussed amino acids caused the influential role of the van der Waals and electrostatic interactions, where Trp147.D is the key residue of great value to the binding energy. Taking into account that the last thermodynamic parameter, evaluated the above mentioned factors, as well as the solvation energy and the entropy of the system, the obtained DG values assumed that the non-polar solvation energies contributed only slightly. For (6)–(10) moderate (nucleobase)(C)@O  HOSer167.D interactions (3.488–3.431 Å, Scheme S3), are found, however, generally these macromolecular complexes with the a7 subunit are characterized with the lower stability.

3. Experimental 3.1. Synthesis The alkaloid core of the (1)–(10) was synthesised according the [15]. The nucleosides 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (C) and 2Amino-7-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)1,4,5,7-tetrahydro-purin-6-one (G) were trade Sigma–Aldrich products. 1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2yl)-4-(1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-ylideneamino)-1H-pyrimidin-2-one (1): Found, C, 57.7; H, 5.9; Calcd. For [C20H25N5O5]: C, 57.8; H, 6.1%; 4-(11-Chloro1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8ylideneamino)-1-(3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (2): Found, C, 53.3; H, 5.3; Calcd. For [C 20 H 24 N 5 O 5Cl]: C, 53.4; H, 5.4%; 1-(3,4-Dihydroxy5-hydroxymethyl-tetrahydro-furan-2-yl)-4-(11-hydroxy-1,2,3,4,5, 6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-ylideneamino)-1H-pyrimidin-2-one (3): Found, C, 55.4; H, 5.6; Calcd. For [C20H25N5O6]: C, 55.6; H, 5.8%; 8-[1-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4ylimino]-1,3,4,5,6,8-hexahydro-2H-1,5-methano-pyrido[1,2-a][1,5] diazocine-11-carboxylic acid (4): Found, C, 54.7; H, 5.3; Calcd. For [C21H25N5O7]: C, 54.9; H, 5.5%; 4-(11-Amino-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-ylideneamino)1-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1Hpyrimidin-2-one (5): Found, C, 55.5; H, 6.0; Calcd. For [C20H26N6O5]: C, 55.8; H, 6.1%; 7-(3,4-Dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-2-(1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-ylideneamino)-1,4,5,7-tetrahydro-purin-6-one (6): Found, C, 55.0; H, 5.8; Calcd. For [C21H27N7O5]: C, 55.1; H, 6.0%; 2(11-Chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5] diazocin-8-ylideneamino)-7-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1,4,5,7-tetrahydro-purin-6-one (7): Found, C, 51.4; H, 5.2; Calcd. For [C21H26N7O5Cl]: C, 51.3; H, 5.3%; 7-(3,4-Dihydroxy5-hydroxymethyl-tetrahydro-furan-2-yl)-2-(11-hydroxy-1,2,3,4,5, 6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-ylideneamino)-1,4,5,7-tetrahydro-purin-6-one (8): Found, C, 53.2; H, 5.7; Calcd. For [C21H27N7O6]: C, 53.3; H, 5.8%; 8-[7-(3,4-Dihydroxy-5hydroxymethyl-tetrahydro-furan-2-yl)-6-oxo-4,5,6,7-tetrahydro1H-purin-2-ylimino]-1,3,4,5,6,8-hexahydro-2H-1,5-methano-pyrido [1,2-a][1,5]diazocine-11-carboxylic acid (9): Found, C, 52.1; H, 5.4; Calcd. For [C22H27N7O7]: C, 52.7; H, 5.4%; 2-(11-Amino-1,2,3,4,5,6hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-ylideneamino)-7-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1, 4,5,7-tetrahydro-purin-6-one (10): Found, C, 53.1; H, 5.9; Calcd. For [C21H28N8O5]: C, 53.4; H, 6.0%.

3.2. Physical methods The UV–VIS spectra between 200 and 800 nm, using solvents water, methanol, and acetonitrile (Uvasol, Merck products) at a concentration of 1  105–2.5  105 M in 0.921 cm quartz cells are recorded on Tecan Safire Absorbance/Fluorescence XFluor 4 V 4.40 spectrophotometer. The CD spectra were measured on JASCO J-715 polarimeter with ±0.5 nm resolution. HPLC-ESI-MS/MS measurements were made using TSQ 7000 instrument (Thermo Fisher Inc.). Two mobile phase compositions were used: (A) 0.1% v/v aqueous HCOOH and (B) 0.1% v/v HCOOH in CH3CN. A triple quadrupole mass spectrometer (TSQ 7000 Thermo Electron) equipped with an ESI 2 source was used and operated at the following conditions: capillary temperature 180 °C; sheath gas 60 psi, corona 4.5 lA and spray voltage 4.5 kV. Sample was dissolved in acetonitrile (1 mg mL1) and was injected in the ion source by an autosampler (Surveyor) with a flow of pure acetonitrile (0.2 mL min1). Data processing was performed by Excalibur 1.4 software. Chromatographic confirmation about the purity of the studied compounds was performed with a Gynkotek (Germering) HPLC instrument, equipped with a preparative Kromasil 100 C18 column (250  20 mm, 7 lm; Eka Chemicals) and a UV detector set at 250 nm. The mobile phase was acetonitrile:water (90:10, v/v) at a flow rate of 4 mL min1. The analytical HPLC was performed on a Phenomenex (Torrance) RP-18 column (Jupiter 300, 150 mm  2 mm, 3 lm) under the same chromatographic conditions as above. The analysis was performed on a Shimadzu UFLC XR (Kyoto) instrument, equipped with an auto sampler, an on-line degasser and column thermostat. As stationary phase a Phenomenex Luna Phenyl-Hexyl column (150 mm  3 mm i.d., 3 lm particle size) was used. The mobile phase consisted of 0.02% (v/v) TFA in water (solvent A) and acetonitrilemethanol 75:25 (v/v; solvent B). Separation was achieved by a gradient analysis starting with 55A–45B, increasing the amount of solvent B in 30 min to 75% and 30.1 min to 100% B, stop time 40 min. For equilibration a post time of 15 min was applied. Other parameters: flow rate 0.30 mL min1, injection volume 5 ll, detection wavelength 280 nm; column temperature 35 °C. Raman spectra (RS) in solid-state were recorded on: (i) Nicolet NXR 9610 FT-Raman spectrometer (both instruments were products of Thermo Electron Corporation, Baltimore, MD, USA), equipped with the semiconductor laser operating source at 976 nm. The resolution of 0.09 cm1 was over the spectral range 100–3705 cm1 and (ii) Horiba Jobin–Yvon Inc. (Edison, NJ, USA) 60000 triple monochromator spectrometer equipped with a Spectra-Physics Inc. (Mountain View, CA, USA) model 164 argon ion laser operated on the 514.5 nm line. The resolution of 1.0 cm1 was over the spectral range 20–2500 cm1. A triple integrated laser system was used for the variation of the excitation energy at 532, 633 and 785 nm, respectively. The laser power used was 100 mW, with a spectral band-space of 3 cm1. The spectra were recorded at ambient conditions (T = 298 K, P = 1 atm). The spectra were measured in a glass (quartz) capillary. 1 H and 13C NMR spectroscopy was performed with a Varian (Palo Alto, CA, USA) Inova 600 instrument, with anhydrous CD3CN solvent, recorded in 1D and 2D modes. The 1D mode involved 1Hand 13C-APT spectra. 2D-NMR techniques included correlation spectroscopy COSY, heteronuclear multibond correlation, and heteronuclear single quantum coherence. The first one was performed to study the coupling of two protons. 3.3. Computational methods Quantum chemical calculations were performed with GAUSSIAN 09 and Dalton2011 program packages [16] The geometries of the studied species were preoptimized employing B3LYP method,

181

B. Ivanova, M. Spiteller / Journal of Molecular Structure 1034 (2013) 173–182 Table 1 Curve-fitted mass chromatographic data for the C, G and their dimeric adducts. Cyt 1.66225 1.69658 1.73623 1.79079 1.76569 v2/DoF r2

(G) ±0.02437 ±0.02148 ±0.11351 ±0.04656 ±0.04347 1.00961 0.99991

27630.35739 24916.29616 26672.26459 7703.57391 72321.72799

±5.51121 ±0.81114 ±1.90771 ±3.34458 ±9.14872

6.48004 6.50018 6.61021

±0.00019 ±0.00355 ±0.00139

575.25431 218.36867 67.47649

±0.11229 ±0.15356 ±2.22182

0.08542 0.99994

C 3.0124 3.06971 3.12555 3.18586 v2/DoF r2

±0.00864 ±0.00632 ±0.00781 ±0.00894 64.86068 0.99991

CAM-B3LYP, and M06-2X functional according the algorithms [16]. The calculations of the molecular vibrations were utilized by the 6-31+G(d,p) and aug-cc-pVDZ basis sets. The UV–VIS spectra are calculated, using TDDFT method as above levels and PCM (respectively IPCM) approach. To describe the species in aqueous solution were used an explicit super molecule and micro-hydration approach. The geometries of all the super molecules are obtained by a similar approach, utilizing the polarized SBK basis set. For the very largest species considered, are employed the ONIOM method, using different basis sets or even different quantum methods. Molecular mechanics calculations are performed, using consequently, DREIDING and UFF force fields. The charges are assigned to atoms using the DFT calculations and NBO values [2c–f,16].

37.50556 55.52168 191.02221 31.39601

[2]

[3]

3.4. Chemometrics The experimental and theoretical spectroscopic patterns were processed by R4Cal OpenOffice STATISTICs for Windows 7 program package [17]. Baseline corrections, smoothing and non-linear curve-fitting procedures are applied [3]. The statistical significance of each regression coefficient was checked by t-test, while the model fit – by F-test, respectively. The chemometric approaches are applied to evaluate the mass-chromatographic data, which firstly are reported in [2j] (Table 1).

[4]

Acknowledgments [5]

The authors thank the Deutscher Akademischer Austausch Dienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG), the central instrumental laboratories for structural analysis at Dortmund University (Germany) and the analytical and computational laboratory clusters at the Institute of Environmental Research (INFU) at the same University. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.molstruc.2012. 08.025. References [1] (a) D. Gray, T. Gallagher, Angew. Chem., Int. Ed. 45 (2006) 2419; (b) C. Hirschhäuser, C. Haseler, T. Gallagher, Angew. Chem., Int. Ed. 50 (2011) 5162; (c) E. Peerez, C. Mendez-Galvez, B. Cassels, Nat. Prod. Rep. 29 (2012) 555; (d) J. Coe, P. Brooks, M. Vetelino, M. Wirtz, E. Arnold, J. Huang, S. Sands, T. Davis, L. Lebel, C. Fox, A. Shrikhande, J. Heym, E. Schaeffer, H. Rollema, Y. Lu, R.

[6]

±0.11867 ±0.32888 ±2.14119 ±0.24605

Mansbach, L. Chambers, C. Rovetti, D. Schulz, F. Tingley III, B. O’Neill, J. Med. Chem. 48 (2005) 3474. (a) N. Grobe, M. Lamshoeft, R. Orth, B. Draeger, T. Kutchan, M. Zenk, M. Spiteller, Proc. Natl. Acad. Sci. USA 107 (2010) 8147; (b) X. Han, M. Lamshöft, N. Grobea, H. Ren, A. Fist, M. Kutchan, M. Spiteller, M. Zenk, Phytochemistry 71 (2010) 1305; (c) B. Ivanova, M. Spiteller, Nat. Prod. Commun. 7 (2012) 157; (d) B. Ivanova, M. Spiteller, Nat. Prod. Res. (2012). doi:http://dx.doi.org/ 10.1080/14786419.2012.676546; (e) B. Ivanova, M. Spiteller, Nat. Prod. Commun. 7 (2012) 581–586; (f) B. Ivanova, M. Spiteller, J. Mol. Struct. 1024 (2012) 18; (g) M. Kumara, S. Zuehlke, V. Priti, B. Ramesha, S. Shweta, G. Ravikanth, R. Vasudeva, T. Santhoshkumar, M. Spiteller, R. Shaanker, Antonie van Leeuwenhoek, Int. J. Gen. Mol. Microbiol. 101 (2012) 323; (h) B. Ramesha, S. Zuehlke, R. Vijaya, V. Priti, G. Ravikanth, K. Ganeshaiah, M. Spiteller, R. Shaanker, J. Chem. Ecol. 37 (2011) 533; (i) S. Kusari, S. Zühlke, M. Spiteller, Phytochem. Anal. 22 (2011) 128; (j) B. Ivanova, M. Spiteller, J. Mol. Struct. 1029 (2012) 106–118. (a) B. Ivanova, M. Spiteller, Talanta 94 (2012) 9; (b) B. Ivanova, M. Spiteller, Analyst 137 (2012) 3355; (c) B. Ivanova, B. Spiteller, Anal. Lett. (2012). doi:http://dx.doi.org/10.1080/ 00032719.2012.700470; (d) B. Ivanova, M. Spiteller, Anal. Lett. (2012). doi:http://dx.doi.org/10.1080/ 00032719.2012.682239; (e) B. Ivanova, M. Spiteller, Anal. Methods 137 (2012) 3355. (a) S. Hansen, G. Sulzenbacher, T. Huxford, P. Marchot, P. Taylor, Y. Bourne, EMBO J. 24 (2005) 3635; (b) N. Unwin, J. Mol. Biol. 346 (2005) 967; (c) D. Bertrand, S. Bertrand, S. Cassar, E. Gubbins, J. Li, M. Gopalakrishnan, Mol. Pharmacol. 74 (2008) 5; (d) M. Zouridakis, P. Zisimopoulou, K. Poulas, S. Tzartos, IUBMB Life 61 (2009) 407; (e) R. Hibbs, G. Sulzenbacher, J. Shi, T. Talley, S. Conrod, W. Kem, P. Taylor, P. Marchot, Y. Bourne, EMBO J. 28 (2009) 3040; (f) R. Hilf, R. Dutzler, Nature 452 (2008) 375. (a) A. Thompson, H. Lester, S. Lummis, Q. Rev. Biophys. (2012) 1–51 (Cambridge University Press); (b) L. Martin, W. Kem, R. Freedman, Psychopharmacology 174 (2004) 54; (c) L. Adler, M. Waldo, R. Freedman, Biol. Psychiatry 20 (1985) 1284; (d) B. Clementz, Psychophysiology 35 (1998) 648; (e) D. Combs, C. Advokat, Schizophr. Res. 46 (2000) 129; (f) H. Coon, R. Plaetke, J. Holik, M. Hoff, M. Myles-Worsley, M. Waldo, R. Freedman, W. Byerley, Biol. Psychiatry 34 (1993) 277; (g) R. Freedman, L. Adler, P. Bickford, W. Byerley, H. Coon, C. Cullum, J. Griffith, J. Harris, S. Leonard, C. Miller, M. Myles-Worsley, H. Nagamoto, G. Rose, M. Waldo, Harvard Rev. Psychiatry (1994) 179; (h) A. Grottick, R. Wyler, G. Higgins, Psychopharmacology 150 (2000) 233; (i) L. Judd, L. McAdams, B. Budnick, D. Braff, Am. J. Psychiatry 149 (2002) 488; (j) M. Olincy, G. Harris, L. Johnson, V. Pender, S. Kongs, D. Allensworth, J. Ellis, G. Zerbe, S. Leonard, K. Stevens, J. Stevens, L. Martin, L. Adler, F. Soti, W. Kem, R. Freedman, Arch. Gen. Psychiatry 63 (2006) 630. (a) L. Paleari, E. Negri, A. Catassi, M. Cilli, D. Servent, R. D’Angelillo, A. Cesario, P. Russo, M. Fini, Am. J. Respir. Crit. Care Med. 179 (2009) 1141; (b) V. Damaraju, S. Damaraju, J. Young, S. Baldwin, J. Mackey, M. Sawyer, C. Cass, Oncogene 22 (2003) 7524; (c) P. Dasgupta, W. Rizwani, S. Pillai, R. Kinkade, M. Kovacs, S. Rastogi, S. Banerjee, M. Carless, E. Kim, D. Coppola, E. Haura, S. Chellappan, Int J Cancer. 124 (2009) 36; (d) A. Grozio, L. Paleari, A. Catassi, D. Servent, M. Cilli, F. Piccardi, M. Paganuzzi, A. Cesario, P. Granone, G. Mourier, P. Russo, Int. J. Cancer. 122 (2008) 1911; (e) L. Paleari, A. Catassi, M. Ciarlo, Z. Cavalieri, C. Bruzzo, D. Servent, A. Cesario, L. Chessa, M. Cilli, F. Piccardi, P. Granone, P. Russo, Cell Prolif. 41 (6) (2008) 936–959;

182

[7] [8] [9]

[10]

[11]

B. Ivanova, M. Spiteller / Journal of Molecular Structure 1034 (2013) 173–182 (f) P. Ambrosi, A. Becchetti, Recent Pat. Anticancer Drug Discov. (2012). PMID: 22537644. (a) F. Musshoff, B. Madea, Forensic Sci. Int. 186 (2009) e1. (a) E. Marriere, J. Rouden, V. Tadino, M. Lasne, Org. Lett. 2 (2000) 1121. (a) K. Busch, G. Glish, S. McLuckey, Mass Spectrometry/Mass Spectrometry, VCH Publishers Inc., Weinheim, 1988, pp. 1–334; (b) J. Gross, Mass Spectrometry, second ed., Springer Verlag, Heidelberg, 2011, pp. 1–753; (c)R. Cole (Ed.), Electrospray and MALDI Mass Spectrometry, second ed., Wiley, Hoboken, New Jersey, 2010. pp. 1–847; (d) G. de Bellis, G. Salani, C. Battaglia, E. Rosti, E. Mauri, Rapid Commun. Mass Spectrom. 14 (2000) 243; (e) K. Bursch, G. Glish, S. McLuckey, Mass Spectrometry/Mass Spectrometry: Techniques and Application of Tandem Mass Spectrometry, VCH Publishers Inc., Weinheim, 1988. pp. 1–333; (f) A. Nebbioso, A. Piccolo, M. Spiteller, Rapid Commun. Mass Spectrom. 24 (2010) 3163; (g) S. Shweta, S. Zuehlke, B. Ramesha, V. Priti, P. Kumar, G. Ravikanth, M. Spiteller, R. Vasudeva, R. Shaanker, Phytochemistry 71 (2010) 117; (h) A. Piccolo, M. Spiteller, Anal. Bioanal. Chem. 377 (2003) 1047; (i) P. Sukul, M. Spiteller, Rev. Environ. Contam. Toxicol. 164 (2000) 1; (j) U. Klaus, T. Pfeifer, M. Spiteller, Environ. Sci. Technol. 34 (2000) 3514; (k) M. Spiteller, Org. Geochem. 8 (1985) 111; (l) A. Dahab, N. Smith, Anal. Methods 4 (2012) 2247. (a) M. Lamshöft, C. Stolle, J. Storp, B. Ivanova, M. Spiteller, Inorg. Chim. Acta 382 (2012) 96; (b) H. Schiff, Justus Liebigs. Ann. Chem. 17 (Suppl. III) (1866) 770; (c) H. Schiff, Justus Liebigs Ann. Chem. 140 (1866) 92; (d) B. Ivanova, M. Spiteller, J. Incl. Phenom. Macrocycl. Chem. (2012), http:// dx.doi.org/10.1007/s10847-012-0163-3. (a) B. Voigt, U. Scheffler, R. Mahrwald, ChemCommun 48 (2012) 5304; (b) O. Makabe, M. Nakamura, S. Umezawa, J. Antibiot. 28 (1975) 492; (c) L. Tpownsend (Ed.), Chemistry of Nucleosides and Nucleotides, vol. 3, Plenum Press, 1994, New York; (d) L. Tpownsend (Ed.), Chemistry of Nucleosides and Nucleotides, vol. 1, Plenum Press, 1988, New York; (e) R. Sanchez, L. Orgel, J. Mol. Biol. 47 (1970) 531; (f) R. Duchinski, T. Gabriel, W. Tautz, A. Nussbaum, M. Hoffer, E. Grunberg, J. Burchenal, J. Fox, J. Med. Chem. 10 (1967) 47; (g) H. Tagusi, S. Wang, J. Org. Chem. 44 (1979) 4386; (h) K. Kondo, I. Inoue, J. Org. Chem. 45 (1980) 1577;

[12]

[13] [14]

[15]

[16]

[17]

(i) J. Zemlicka, J. Fraisler, R. Gasser, J. Horwitz, J. Org. Chem. 38 (1973) 990; J. Zelicka, R. Gasser, J. Horwitz, J. Am. Chem. Soc. 92 (1970) 4744. (a) D. Miles, M. Robins, R. Robins, M. Winkley, H. Eyring, J. Am. Chem. Soc. 91 (1969) 831; (b) D. Miles, W. Inskeep, M. Robins, M. Winkley, R. Robins, H. Eyring, J. Am. Chem. Soc. 92 (1970) 3872. (a) W. Small, W. Peticolas, Biopolymers 10 (1971) 1377; (b) W. Small, W. Peticolas, Biopolymers 10 (1971) 69. (a) T. Kolev, B. Koleva, M. Spiteller, W. Sheldrick, H. Mayer-Figge, J. Mol. Struct. 879 (2008) 30; (b) B. Koleva, M. Spiteller, T. Kolev, Amino Acids 38 (2010) 295. (a) C. Botuha, C. Galley, T. Gallagher, Org. Biomol. Chem. 2 (2004) 1825; (b) B. O’Neill, D. Yohannes, M. Bundesmann, E. Arnold, Org. Lett. 2 (2000) 4201; (c) B. Danieli, G. Lesma, D. Passarella, A. Sacchetti, A. Silvani, A. Virdis, Org. Lett. 6 (2004) 493; (d) K. Sheela, C. Yingxian, X. Werner, T. Kenneth, J. Kellar, A. Kozikowski, J. Med. Chem. 49 (2006) 2673; (e) J. Coe, Org. Lett. 28 (2000) 4205. (a) M. Frisch et al., Gaussian 09w, Gaussian, Inc., Pittsburgh, PA, 2009; (b) Dalton, Program Package, 2011; (c) Y. Zhao, D. Truhlar, Acc. Chem. Res. 41 (2008) 157; (d) N. Schultz, Y. Zhao, D. Truhlar, J. Comput. Chem. 29 (2008) 185; (e) Y. Zhao, D. Truhlar, Theor. Chem. Acc. 120 (2008) 215; (f) H. Hay, W. Wadt, J. Chem. Phys. 82 (1985) 270; (g) D. Woon, T. Dunning, J. Chem. Phys. 98 (1993) 1358; (h) P. Hay, W. Wadt, J. Chem. Phys. 82 (1985) 299; (i) M. Dolg, U. Wedig, H. Stoll, H. Preuss, J. Chem. Phys. 86 (1987) 866; (j) D. Andrae, U. Haussermann, M. Dolg, H. Stoll, H. Preuss, Theor. Chim. Acta 77 (1990) 123; (k) K. Nguyen, R. Pachater, J. Chem. Phys. 114 (2001) 10757; (l) T. Dunning, J. Chem. Phys. A 104 (2000) 9062. (a) http://de.openoffice.org; (b) P. Stephens, D. McCann, J. Cheeseman, M. Frisch, Chirality 17 (2005) S52; (c) P. Stephens, F. Devlin, J. Cheeseman, M. Frisch, O. Bortolini, P. Besse, Chirality 15 (2003) S57; (d) A. Yildiz, P. Selvin, Acc. Chem. Res. 38 (2005) 574; (e) C. Kelley, Iterative Methods for Optimization, SIAM Frontiers in Applied Mathematics, 18, 1999; (f) K. Madsen, H. Nielsen, O. Tingleff, Informatics and Mathematical Modelling, second ed., DTU Press, 2004; (g) D. Marquardt, J. Soc. Ind. Appl. Math. 11 (1963) 431.