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Article

Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines

by
Cristina Maria Al Matarneh
,
Roxana Maria Amarandi
,
Anda Mihaela Craciun
,
Ionel I. Mangalagiu
,
Gheorghita Zbancioc
* and
Ramona Danac
*
Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(3), 527; https://doi.org/10.3390/molecules25030527
Submission received: 16 December 2019 / Revised: 21 January 2020 / Accepted: 23 January 2020 / Published: 25 January 2020
(This article belongs to the Section Medicinal Chemistry)
Browse Figures
Versions Notes

Abstract

:
Three series of fused pyrrolophenanthroline derivatives were designed as analogues of phenstatin and synthesized in two steps starting with 1,7-phenanthroline, 4,7-phenanthroline and 1,10-phenanthroline, respectively. Two (Compounds 8a and 11c) of the four compounds tested against a panel of sixty human cancer cell lines of the National Cancer Institute (NCI) exhibited significant growth inhibition activity on several cell lines. Compound 11c showed a broad spectrum in terms of antiproliferative efficacy with GI50 values in the range of 0.296 to 250 μM. Molecular docking studies indicated that Compounds 8a and 11c are accommodated in the colchicine binding site of tubulin in two different ways.

Graphical Abstract

1. Introduction

Phenanthrolines are versatile moieties which have found use in many applications [1,2,3] due to a wide variety of interesting properties (complexation [1,2,3], luminescence [1,2,4], biological activities [4,5,6,7], semiconductors [8,9,10]). These polycyclic compounds are also naturally occurring in morphine alkaloids, sterols or hormones [11], which makes the phenanthroline scaffold an excellent choice in the generation of unique bioactive compounds.
At the same time, the fusion of two or more heterocycle rings can lead to novel classes of ligands, many with new interesting properties, including anticancer activity. For example, substituted benzo[c]phenanthroline analogues of nitidine and fagaronine showed cytotoxic properties associated with DNA intercalation and induced G2/M phases arrests [12]. Synthetic pyrido [1,8] or [1,9] phenanthroline analogues of amphimedine exhibited cytotoxic activities in various cancer cell lines [13,14]. Recently, our group also reported several fused pyrrolo [1,7] or [4,7] phenanthrolines which showed moderate antiproliferative activity [15,16,17].
Despite the great progress achieved in chemotherapy, cancer remains a leading cause of mortality worldwide [18,19]. Among the most promising strategies in cancer therapy, the discovery of compounds capable of interfering with tubulin assembly gained lots of attention in recent years, due to the role of microtubules in eukaryotic cell proliferation [20,21]. Phenstatin, one of the simplest tubulin polymerization inhibitors [22,23], acts by interacting with the colchicine binding site of tubulin and exhibits anticancer activity comparable to combretastatin A-4 [24], which is currently being investigated as a neoplastic agent in a number of clinical trials. The structural simplicity of phenstatin has inspired many researchers in designing new anticancer compounds, the recent literature being plentiful of phenstatin-derived pharmacomodulators [25,26,27,28,29].
Encouraged by the above considerations (especially by the cytotoxic properties of the reported fused phenathrolines) and as part of our ongoing research aimed at investigating new anticancer drugs [15,16,28], we designed a new series of phenstatin analogues by replacing the 3-hydroxy-4-methoxyphenyl ring of phenstatin (ring B) with three different classes of substituted pyrrolophenanthrolines (Figure 1).
We furthermore considered some modifications at the 3,4,5-trimethoxyphenyl ring of phenstatin (ring A), generating either a 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or a 4-bromophenyl ring.
In this way, we incorporated the trimethoxyphenyl ring of phenstatin and our fused pyrrolophenanthroline system into a single molecule, in order to investigate their impact on the anticancer activity of the parent compound. Thus, we report here the synthesis and biological evaluation of novel compounds with 1,7-, 4,7-, and 1,10-phenanthroline scaffolds.

2. Results and Discussion

2.1. Chemistry

Compounds 5a–d were successfully synthesized using a two-step procedure starting from 1,7-phenanthroline 1. The first step comprised the formation of monoquaternary 1,7-phenanthrolin-7-ium salts 3a–d by the nucleophilic substitution of phenanthroline 1 to 2-bromoacetophenones 2a–d (Compounds 2b, 2c and 2d were obtained using reported procedures [30]).
The second step consisted of the in situ generation of the cycloimmonium ylides 4a–d from the corresponding salts 3a–d under triethylamine treatment. The in situ-formed ylides acted as 1,3-dipoles when reacted with ethyl propiolate, following a Huisgen 3 + 2 cycloaddition. Initially formed unstable intermediates 5′a–d undergo an aromatization process under the current reaction conditions, leading to target compounds 5a–d in 50–88% yields (Scheme 1).
We employed a similar strategy in the synthesis of pyrrolo[2,1-c][4,7]phenanthrolines 8a–d and pyrrolo[1,2-a][1,10]phenanthrolines 11a–d, by reacting phenanthrolinium monoylides (derived from 4,7- and 1,10-phenanthrolinium salts 7a–d and 10a–d, respectively) with ethyl propiolate (Scheme 2).
All synthesized compounds (including intermediate phenanthrolinium salts) were identified by NMR and IR. Compounds 3d, 5d, 10d and 11d, which have already been reported in the literature, showed spectral data in agreement with the reported data [16,31,32,33].

2.2. Anticancer Evaluation

Compounds 5a–d, 8a–d and 11a–d were submitted to the National Cancer Institute (NCI, USA) and four compounds were selected for the evaluation of their antiproliferative activity against their panel of 60 human cancer cell lines. The NCI panel is organized into nine sub-panels representing leukemia, lung, colon, central nervous system (CNS), melanoma, ovary, kidney, breast and prostate cancer cells. The panel also includes several multidrug-resistant tumor cell lines (RXF393, HCT-15, UACC-62, SF-539). The four compounds—5c, 8a, 8b and 11c—selected by NCI were first tested at a single high dose (10−5 M) in the full 60-cell panel, selected results being presented in Table 1. Compounds 8a and 11c showed very good growth inhibition of several cancer cell lines. The best efficacy in terms of growth inhibition was shown by Compound 11c against the HL-60(TB) RPMI-8226 leukemia cell line, NCI-H522 non-small cell lung cancer line, COLO205 and HT-29 colon cancer cell line, SF-539 CNS cancer cell line, MDA-MB-435 and M14 melanoma cell lines, OVCAR-3 ovarian cancer cell line and A498 renal cancer cell line, these results being comparable or better than phenstatin, which was used as a control. Compound 11c also showed cytotoxic activity against the COLO205, MDA-MB-435 and A498 cell lines. An important growth inhibition effect was also observed for Compound 8a against MDA-MB-435 melanoma cells and K-562, SR and HL-60(TB) leukemia cells. Thus, replacement of ring B of phenstatin with a pyrrolo[1,2-i][1,7]phenanthroline moiety does not look favorable in terms of anticancer activity, while the replacement with a pyrrolo[2,1-c][4,7]phenanthroline or a pyrrolo[1,2-a][1,10]phenanthroline group retains the growth inhibition properties of phenstatin. The more active Compound 8a, by comparison with 8b, retains the three methoxy groups of the more active phenstatin. Therefore, the lack in the methoxy substituent in para position of the ring B appears to be not favorable for the anticancer activity, at least in the case of compounds type 8.
Compound 11c, which had the best growth inhibition profile among the tested compounds, progressed to the full five-dose assay. Selected GI50 values are presented in Table 2. The in vitro screening results revealed that Compound 11c possess excellent to moderate antiproliferative activity with GI50 values ranging from 0.296 to 3.78 μM against 40 cancer cell lines from all nine sub-panels. In particular, Compound 11c showed the best GI50 and TGI (the drug concentration resulting in total growing inhibition) values (296 nM and 981 nM respectively) against MDA-MB-435 melanoma cells. Promising GI50 values were also obtained for against NCI-H522 lung cancer cells, HCT-116 colon cancer cells and M14 melanoma cells. However, when comparing to control phenstatin, there are only a few cell lines against which Compound 11c is more potent (HT29 colon cancer cells, SK-MEL-28 melanoma cells and T-47D breast cancer cells) or shows similar antiproliferative activity (MDA-MB-468 breast cancer cells and A498 renal cancer cells).

2.3. Molecular Modeling

In order to verify if our target phenstatin analogues retain the ability of their parent compound to fit in the colchicine binding site of tubulin, docking studies were performed on the four NCI-tested compounds in the colchicine binding site of the α,β-tubulin heterodimer (PDB:1SA0). The in silico study aimed to evaluate the shape and electrostatic complementarity between the tested ligands and the α,β-tubulin heterodimer interface, which could account for the observed antiproliferative effects in the case of 8a and 11c and the lack of activity in the case of 5c and 8b.
Molecular docking of Compounds 8a and 8b in the colchicine binding site of tubulin revealed a similar accommodation to previously reported ligands [28], both having ring A overlapping with the trimethoxyphenyl subunit of phenstatin (Figure 2a–d), and interacting with the protein through hydrogen bonding with βCys241. The ligands are further stabilized in the binding pocket through hydrophobic interactions with βLeu242, βLeu248, βAla250 and βLeu255. In addition, Compound 8a interacts with βLys254 through the N1 nitrogen of the 4,7-phenanthroline subunit, forming a hydrogen bond, and with βAsn258 through its ester functional group, interactions which are absent in the case of analogue 8b. These two amino acids have been previously identified as key interaction partners for other microtubule depolymerizing agents [34] or inhibitors of tubulin polymerization [35]. Thus, removal of the 4-methoxy subunit in 8b leads to the loss of one hydrogen bond between the ligand and βCys241, and subsequent inability to interact with βLys254 and βAsn258, which could account for the lack of activity observed for 8b. Further mutagenesis studies could confirm the involvement of βLys254 and βAsn258 in the observed activity of 8a.
Compound 5c is accommodated in a similar fashion to 4,7-phenanthroline analogue 8b, with ring A overlapping with the trimethoxyphenyl subunit of phenstatin, and forming hydrophobic contacts with βLeu242, βLeu248, βAla250 and βLeu255. In addition, it forms a hydrogen bond with βCys241, but does not interact through other types of contact with tubulin residues (Figure 2e). The lack of stronger electrostatic interactions between this compound and tubulin could account for its reduced antiproliferative effect when compared to active analogue 8a. Subsequent inhibition binding experiments against colchicine could confirm the accommodation of this compound and analogues 8a and 8b in the proposed modes.
Interestingly, the best-scoring pose of 1,10-phenanthroline derivative 11c is accommodated in the colchicine binding site of tubulin in a different manner, so as to permit a hydrogen bond interaction with αAsn101 (Figure 2f), which has been identified as an important interaction partner for other tubulin polymerization inhibitors which bind to the colchicine binding site [36]. In addition, the pyrrolo[1,2-a][1,10]phenanthroline moiety of 11c is stabilized in the binding pocket through an extensive hydrophobic network formed by βLeu248, βAla354 and βLys352, while the 3,4-dimethoxyphenyl ring is stabilized by contacts with βLeu255, βVal315 and βMet259. Other binding site residues from the α subunit include αThr179, αAla180 and αVal181. It is unclear if the observed superior antiproliferative effects of 11c compared to 1,7- and 4,7- analogues are due to a different binding mechanism, and therefore further mutagenesis experiments are required.

3. Materials and Methods

3.1. Chemistry

All of the commercially available reagents and solvents employed were used without further purification. The melting points were recorded on an A. Krüss Optronic Melting Point Meter KSPI and are uncorrected. Analytical thin-layer chromatography was performed with commercial silica gel plates 60 F254 (Merck Darmstadt, Germany) and visualized with UV light (λmax= 254 or 365 nm). The NMR spectra were recorded on a (Bruker Vienna, Austria) Avance III 500 MHz spectrometer or a BrukerAvance 400 DRX (400 MHz). Chemical shifts were reported in delta (δ) units, part per million (ppm) and coupling constants (J) in Hz. The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. Infrared (IR) data were recorded as films on potassium bromide (KBr) pellets on a FT-IR (Shimadzu Kyoto, Japan) Prestige 8400s spectrophotometer or a Jasco 660 Plus FTIR spectrophotometer. Analyses indicated by the symbols of the elements or functions were within ±0.4% of the theoretical values.

3.1.1. General Procedure for the Synthesis of Monoquaternary Salts 3a–d, 7a–d and 10a–d

1 mmol of heterocycle (1,7-phenanthroline (1), 4,7-phenanthroline (6) or 1,10-phenanthroline (9)) was dissolved in minimum volume of acetone. Then, 1.1 mmol of reactive halide (2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone 2a, 2-bromo-1-(3,5-dimethoxyphenyl) ethanone 2b, 2-bromo-1-(3,4-dimethoxyphenyl) ethanone 2c or 2-bromo-1-(4-bromophenyl) ethanone 2d) was added and the resulting mixture was stirred overnight at room temperature. The formed precipitate was filtered and washed with diethyl ether to give the desired product which was used in the next reaction without any further purification.

3.1.2. General Procedure for the Preparation of Compounds 5a–d, 8a–d and 11a–d

The cycloimmonium salt (3, 7 or 10) (1 mmol) and ethyl propiolate (1.1 mmol) were added to dichloromethane (DCM) and the obtained suspension was stirred at room temperature. Then, a solution of triethylamine (TEA) (3 mmol) in DCM (3 mL) was added drop-wise over 1 h (magnetic stirring) and the resulting mixture was then stirred overnight at room temperature. Methanol (10 mL) was added and the resulting solid was collected by filtration to give a solid which was washed with 5 mL methanol. The product was then crystallized from dichloromethane/methanol (1:1, v/v).

3.1.3. 7-(2-Oxo-2-(3,4,5-trimethoxyphenyl)ethyl)-1,7-phenanthrolin-7-ium Bromide 3a

Beige powder; yield: 50%; mp 120–122 °C; IR (KBr), νmax 2997, 2915, 1676, 1583, 1416, 1344, 1165, 1124 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 7.20 (2H, s, H-15), 7.50 (2H, s, H-18,22), 8.03 (1H, dd, J = 8.0, 3.0 Hz, H-3), 8.42 (1H, d, J = 9.5 Hz, H-6), 8.54 (1H, dd, J = 8.5, 6.0 Hz, H-9), 8.71 (1H, d, J = 9.5 Hz, H-5), 8.77 (1H, dd, J = 8.0 Hz, H-4), 9.32 (1H, dd, J = 4.0, 1.0 Hz, H-2), 9.60 (1H, d, J = 5.5 Hz, H-8), 10.40 (1H, d, J = 8.0 Hz, H-10); 13C NMR (125 MHz, DMSO-d6) δ 56.4 (2 × OCH3), 60.4 (OCH3), 63.9 (C-15), 106.5 (C-18, C-22), 117.2 (C-6), 123.7 (C-9), 125.3 (C-3), 126.0 (C-11), 128.7 (C-13), 128.8 (C-17), 136.8 (C-5), 137.4 (C-4), 141.1 (C-12), 143.1 (C-10), 143.2 (C-20), 143.3 (C-14), 149.9 (C-8), 152.6 (C-2), 153.0 (C-19, C-21), 189.6 (C-16); Anal. Calcd. for C23H21BrN2O4 C, 58.86; H, 4.51; N, 5.97. Found C, 58.90; H, 4.48; N, 6.00.

3.1.4. 7-(2-(3,5-Dimethoxyphenyl)-2-oxoethyl)-1,7-phenanthrolin-7-ium Bromide 3b

Beige powder; yield 72%; mp 185–180 °C; IR (KBr), νmax 3069, 2923, 1678, 1591, 1447, 1343, 1300, 1220, 839 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.88 (6H, s, 2 × OCH3), 6.96 (1H, bs, H-20), 7.18 (2H, s, H-15), 7.18 (2H, d, J = 2.0 Hz, H-18, H-22), 8.03 (1H, dd, J = 8.0, 3.5 Hz, H-3), 8.43 (1H, d, J = 10.0 Hz, H-6), 8.52 (1H, dd, J = 8.0; 6.0 Hz, H-9), 8.70 (1H, d, J = 9.5 Hz, H-5), 8.77 (1H, d, J = 7.5 Hz, H-4), 9.30 (1H, d, J = 3.0 Hz, H-2), 9.64 (1H, d, J = 5.0 Hz, H-8), 10.38 (1H, d, J = 8.5 Hz, H-10). 13C-NMR, (125 MHz, DMSO-d6) δ 55.8 (OCH3), 64.1 (C-15), 106.5 (C-18, C-22), 106.6 (C-20), 117.3 (C-6), 123.7 (C-9), 125.4 (C-3), 126.1 (C-11), 128.7 (C-13), 135.4 (C-17), 136.8 (C-5), 137.4 (C-4), 141.1 (C-12), 143.1 (C-14), 143.2 (C-10), 150.0 (C-8), 152.6 (C-2), 160.8 (C-19, C-21), 190.6 (C-16); Anal. Calcd. for C22H19BrN2O3 C, 60.15; H, 4.36; N, 6.38. Found C, 60.26; H, 4.30, N 6.40.

3.1.5. 7-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-1,7-phenanthrolin-7-ium Bromide 3c

Beige powder, yield 59%; mp 231–235 °C; IR (KBr) νmax 3092, 2930, 1680, 1609, 1582, 1447, 1348, 1271, 1130 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.87 (3H, s, OCH3), 3.94 (3H, s, OCH3), 7.09 (2H, s, H-15), 7.29 (1H, d, J = 8.5 Hz, H-21), 7.59 (1H, s, H-18), 7.90 (1H, d, J = 8.0 Hz, H-22), 8.03 (1H, dd, J = 7.5, 4.5 Hz, H-3), 8.40 (1H, d, J = 9.5 Hz, H-6), 8.52 (1H, t, J = 7.0 Hz, H-9), 8.70 (1H, d, J = 9.5 Hz, H-5), 8.76 (1H, d, J = 7.5 Hz, H-4), 9.33 (1H, d, J = 3.0 Hz, H-2), 9.58 (1H, d, J = 4.0 Hz, H-8), 10.40 (1H, d, J = 8.5 Hz, H-10); 13C NMR (125 MHz, DMSO-d6) δ 55.8 (OCH3), 56.1 (OCH3), 63.6 (C-15), 110.7 (C-18), 111.3 (C-21), 117.3 (C-6), 123.7 (C-9), 123.9 (C-22), 125.4 (C-3), 126.0 (C-11), 126.3 (C-17), 128.7 (C-13), 136.8 (C-5), 137.4 (C-4), 141.2 (C-12), 143.1 (C-14), 143.12 (C-10), 148.9 (C-19), 150.0 (C-8), 152.6 (C-2), 154.5 (C-20), 188.9 (C-16); Anal. Calcd. for C22H19BrN2O3 C, 60.15; H, 4.36; N, 6.38. Found C, 61.16; H, 4.31; N, 6.42.

3.1.6. 7-(2-(4-Bromophenyl)-2-oxoethyl)-1,7-phenanthrolin-7-iumbromide 3d

Yield 65%; All physical and spectral data are in agreement to literature [31].

3.1.7. 4-(2-(3,4,5-Trimethoxyphenyl)-2-oxoethyl)-4,7-phenanthrolin-4-ium bromide 7a

Beige powder; yield 70%; mp 220–222 °C; IR (KBr) νmax 2909, 1674, 1584, 1503, 1346, 1165, 1128 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.83 (3H, s, OCH3), 3.93 (6H, s, 2 × OCH3), 7.21 (2H, s, H-15), 7.49 (2H, s, H-18, H-22), 8.06 (1H, dd, J = 8.5, 4.0 Hz, H-9), 8.55 (1H, d, J = 10.0 Hz, H-6), 8.57 (1H, dd, J = 8.5, 6.0 Hz, H-2), 8.66 (1H, d, J = 10.0 Hz, H-5), 9.27 (1H, d, J = 4.0 Hz, H-10), 9.58 (1H, d, J = 6.0 Hz, H-8), 9.60 (1H, d, J = 8.5 Hz, H-1), 10.32 (1H, d, J = 8.5 Hz, H-3); 13C NMR (125 MHz, DMSO-d6) δ 56.4 (2 × OCH3), 60.4 (OCH3), 64.1 (C-15), 106.5 (C-18, C-22), 120.3 (C-6), 123.6 (C-2), 123.9 (C-13), 124.6 (C-9), 128.0 (C-14), 128.7 (C-17), 133.0 (C-1), 138.4 (C-5), 139.5 (C-11), 143.2 (C-3), 143.4 (C-20), 146.2 (C-12), 149.2 (C-8), 153.4 (C-1), 153.0 (C-19, C-21), 189.6 (C-16); Anal. Calcd. for C23H21BrN2O4 C, 58.86; H, 4.51; N, 5.97. Found C, 58.85; H, 4.58; N, 5.93.

3.1.8. 4-(2-(3,5-Dimethoxyphenyl)-2-oxoethyl)-4,7-phenanthrolin-4-ium Bromide 7b

Beige powder; yield 57%; mp 240–243 °C; IR (KBr) νmax 3051, 2930, 1692, 1591, 1505, 1354, 1296, 1206, 1157, 837 cm−1; 1H NMR (500 MHz, DMSO-d6) δ3.88 (6H, s, 2 × OCH3), 6.96 (1H, s, H20), 7.21 (2H, s, H-15), 7.23 (2H, s, H-18, H-22), 8.04 (1H, dd, J = 8.5, 4.5 Hz, H-9), 8.57–8.64 (3H, m, H-5, H-2, H-6), 9.25 (1H, d, J = 3.5 Hz, H-10), 9.60 (1H, d, J = 8.5 Hz, H-1), 9.63 (1H, d, J = 5.5 Hz, H-8), 10.30 (1H, ad, J = 8.5 Hz, H-3); 13C NMR (125 MHz, DMSO-d6) δ55.9 (2 × OCH3), 64.2 (C-15), 106.5 (C-18, C-22, C-20), 120.5 (C-6), 123.5 (C-2), 123.9 (C-14), 124.5 (C-9), 128.0 (C-13), 133.0 (C-8), 135.4 (C-17), 138.3 (C-5), 139.4 (C-11), 143.2 (C-3), 146.2 (C-12), 149.2 (C-1), 153.3 (C-10), 160.8 (C-19, C-21), 190.5 (C-16); Anal. Calcd. for C22H19BrN2O3; C, 60.15; H, 4.36; N, 6.38. Found C, 60.14; H, 4.39; N, 6.43.

3.1.9. 4-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-4,7-phenanthrolin-4-ium Bromide 7c

Orange solid; yield 50%; mp 223–226 °C; IR (KBr) νmax 3011, 2918, 1676, 1586, 1518, 1341, 1269, 1161, 1021 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.87 (3H, s, OCH3), 3.94 (3H, s, OCH3), 7.11 (2H, s, H-15), 7.29 (1H, d, J = 8.5 Hz, H-21), 7.59 (1H, d, J = 2.0 Hz, H-18), 7.90 (1H, dd, J = 8.5; 4.0 Hz, H-22), 8.06 (1H, dd, J = 8.5, 4.5 Hz, H-9), 8.54 (1H, d, J = 9.0 Hz, H-6), 8.56 (1H, dd, J = 8.5, 6.0 Hz, H-2), 8.65 (1H, d, J = 9.5 Hz, H-5), 9.27 (1H, dd, J = 4.0; 1.5 Hz, H-10), 9.57 (1H, d, J = 5.5 Hz, H-8), 9.60 (1H, d, J = 8.0 Hz, H-1), 10.30 (1H, d, J = 8.5 Hz, H-3); 13C NMR (125 MHz, DMSO-d6) δ 55.8 (OCH3), 56.1 (OCH3), 63.8 (C-15), 110.7 (C-18), 111.3 (C-21), 120.5 (C-6), 123.4 (C-2), 123.90 (C-13), 123.92 (C-22), 124.5 (C-9), 126.2 (C-17), 128.0 (C-14), 133.0 (C-1), 138.3 (C-5), 139.5 (C-11), 143.1 (C-3), 143.4 (C-20), 146.2 (C-12), 148.9 (C-8), 149.3 (C-19), 153.4 (C-10), 154.6 (C-20), 188.9 (C-16); Anal. Calcd. for C22H19BrN2O3 C,60.15; H, 4.36; N, 6.38. Found C, 60.16; H, 4.39; N, 6.40.

3.1.10. 4-(2-(4-Bromophenyl)-2-oxoethyl)-4,7-phenanthrolin-4-ium Bromide 7d

Beige powder;yield 94%; mp 253–255 °C; IR(KBr) νmax 3037, 2966, 1703, 1586, 1341, 1223, 1180, 1067, 833 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 7.13 (2H, s, H-15), 7.95 (2H, bs, H-19, H-21), 8.09 (3H, bs, H-9, H-18, H-22), 8.56–8.64 (3H, m, H-5, H-2, H-6), 9.27 (1H, bs, H-10), 9.58 (2H, m, H-1, H-8), 10.32 (1H, bs, H-3); 13C NMR (125 MHz, DMSO-d6) δ 64.0 (C-15), 129.0 (C-20), 120.6 (C-6), 123.4 (C-2), 123.9 (C-14), 124.5 (C-9), 128.0 (C-13), 130.6 (C-18, C-22), 132.2 (C-19, C-21), 132.7 (C-17), 133.0 (C-8), 138.3 (C-5), 139.6 (C-11), 143.2 (C-3), 146.2 (C-12), 149.3 (C-1), 153.4 (C-10), 190.1 (C-16); Anal. Calcd. for C20H14Br2N2O C, 52.43; H, 3.08; N, 6.11. Found C, 52.47; H, 3.10; N, 6.15.

3.1.11. 1-(2-Oxo-2-(3,4,5-trimethoxyphenyl)ethyl)-1,10-phenanthrolin-1-ium Bromide 10a

Beige powder; yield 68%; mp 161–164°C; IR(KBr) νmax 2997, 2915, 1676, 1611, 1584, 1416, 1344, 1125, 839 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.84 (3H, s, OCH3), 3.91 (3H, s, OCH3), 7.20 (2H, s, H-15), 7.48 (2H, s, H-18, H-22), 7.94 (1H, dd, J = 8.5; 4.5 Hz, H-8), 8.50 (2H, s, H-5, H-6), 8.61–8.65 (2H, m, H-7, H-3), 8.78 (1H, dd, J = 4.5; 1.0 Hz, H-9), 9.61 (1H, d, J = 8.0 Hz, H-4), 9.65 (1H, d, J = 5.5 Hz, H-2); 13C-NMR (125 MHz, DMSO-d6) δ 56.4 (OCH3), 60.4 (2 × OCH3), 69.7 (C-15), 105.80 (C-18, C-22), 124.5 (C-3), 124.8 (C-8), 127.0 (C-5), 129.6 (C-17), 130.7 (C-6), 131.5 (C-11), 132.1 (C-12), 136.3 (C-14), 138.0 (C-9), 138.5 (C-13), 142.6 (C-20), 148.2 (C-4), 149.0 (C-7), 152.0 (C-2), 153.0 (C-19, C-21), 189.7 (C-16); Anal. Calcd. for C23H21BrN2O4 C, 58.86; H, 4.51; N, 5.97. Found C, 58.84; H, 4.48; N, 6.00.

3.1.12. 1-(2-(3,5-Dimethoxyphenyl)-2-oxoethyl)-1,10-phenanthrolin-1-ium Bromide 10b

Beige powder; yield 76%; mp 142–143 °C; IR (KBr) νmax 3026, 2993, 1675, 1585, 1419, 1287, 1248, 1190, 849 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.88 (6H, s, 2 × OCH3), 6.97 (1H, bs, H-20), 7.11 (2H, d, J = 2 Hz, H-18, H-22), 7.29 (2H, s, H-15), 7.93 (1H, dd, J = 8.0; 4.5 Hz, H-8), 8.49 (2H, s, H-5, H-6), 8.56 (1H, dd, J = 8.0; 2.0 Hz, H-7), 8.62 (1H, dd, J = 8.0; 6.0 Hz, H-3), 8.79 (1H, dd, J = 8.0; 2.0 Hz, H-9), 9.60 (1H, d, J = 8.5 Hz, H-4), 9.64 (1H, d, J = 5.5 Hz, H-2); 13C-NMR (125 MHz DMSO-d6) δ 55.7 (2 × OCH3), 65.5 (C-15), 106.4 (C-18,C-22), 106.7 (C-20), 124.9 (C-3), 125.7 (C-8), 127.1 (C-5), 129.7 (C-17), 130.7 (C-6), 131.5 (C-11), 132.1 (C-12), 135.6 (C-17), 136.3 (C-14), 138.1 (C-9), 138.3 (C-13), 148.2 (C-4), 148.8 (C-7), 152.0 (C-2), 160.8 (C-19, C-21), 189.1 (C-16); Anal. Calcd. for C22H19BrN2O3 C, 60.15; H, 4.36; N, 6.38. Found C, 60.08; H, 4.30; N, 6.35.

3.1.13. 1-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-1,10-phenanthrolin-1-ium Bromide 10c

Beige powder; yield 94%; mp 253–255 °C; IR (KBr)νmax 2997, 2915, 1676, 1611, 1584, 1416, 1344, 1125, 839 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 3.84 (3H, s, OCH3), 3.91 (3H, s, OCH3), 7.20 (2H, s, H-15), 7.48 (2H, s, H-18, H-22), 7.94 (1H, dd, J = 8.5; 4.5 Hz, H-8), 8.50 (2H, s, H-5, H-6), 8.61–8.65 (2H, m, H-7, H-3), 8.78 (1H, dd, J = 8.0; 1.0 Hz, H-9), 9.61 (1H, d, J = 8.0 Hz, H-4), 9.65 (1H, d, J = 5.5 Hz, H-2); 13C NMR (125 MHz, DMSO-d6) δ 56.4 (OCH3), 60.4 (2 × OCH3), 69.7 (C-15), 105.80 (C-18, C-22), 124.5 (C-3), 124.8 (C-8), 127.0 (C-5), 129.6 (C-17), 130.7 (C-6), 131.5 (C-11), 132.1 (C-12), 136.3 (C-14), 138.0 (C-9), 138.5 (C-13), 142.6 (C-20), 148.2 (C-4), 149.0 (C-7), 152.0 (C-2), 153.0 (C-19, C-21), 189.7 (C-16); Anal. Calcd. for C23H21BrN2O4 C, 58.86; H, 4.51; N, 5.97. Found C, 58.84; H, 4.48; N, 6.00.

3.1.14. 1-(2-(4-Bromophenyl)-2-oxoethyl)-1,10-phenanthrolin-1-ium Bromide 10d

Beige powder; yield 90%; mp 234–236 °C; IR (KBr) νmax 3022, 2983, 1687, 1580, 1528, 1000 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 7.26 (2H, s, H-15), 7.92 (1H, dd, J = 8.0; 4.0 Hz, H-8), 7.96 (2H, d, J = 8.5 Hz, H-19, H-21), 8.14 (2H, d, J = 8.0 Hz, H-18, H-22), 8.47–8.51 (3H, m, H-5, H-6, H-7), 8.63 (1H, dd, J = 8.0; 6.5 Hz, H-3), 8.78 (1H, d, J = 8.0 Hz, H-9), 9.61 (1H, d, J = 8.5 Hz, H-4), 9.63 (1H, d, J = 5.5 Hz, H-2) 13C NMR (125 MHz, DMSO-d6) δ 69.4 (C-15), 124.8 (C-3), 125.6 (C-8), 127.0 (C-5), 128.3 (C-20), 130.2 (C-18, C-22), 130.7 (C-6), 131.5 (C-12), 132.0 (C-11), 133.3 (C-17), 132.4 (C-19, C-21), 136.2 (C-14), 138.1 (C-9), 138.3 (C-13), 148.2 (C-4), 148.8 (C-7), 152.1 (C-2), 189.9 (C-16); Anal. Calcd. for C20H14Br2N2O C, 52.43; H, 3.08; N, 6.11. Found C, 52.44; H, 3.10; N, 6.09 [32].

3.1.15. Ethyl 9-(3,4,5-trimethoxybenzoyl)pyrrolo[1,2-i][1,7]phenanthroline-7-carboxylate 5a

Beige solid; yield 88%; mp 256–258 °C; IR (KBr) νmax 2980, 1688, 1620, 1584, 1418, 1460, 1339, 1231, 1220, 1171, 1125, 1086 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.43 (3H, t, J = 7.0 Hz, H-20), 3.95 (6H, s, 2 × OMe), 4.01 (3H, s, OMe), 4.42 (2H, q, J = 7.0 Hz, H-19), 7.40 (2H, s, H-23, H-27), 7.57 (1H, dd, J = 7.5, 4.0 Hz, H-2), 7.81 (1H, s, H-8), 7.92 (1H, d, J = 9.5 Hz, H-12), 8.10 (1H, d, J = 9.5 Hz, H-11), 8.27 (1H, d, J = 8.0 Hz, H-1), 8.59 (1H, d, J = 9.5 Hz, H-6), 9.08 (1H, ad, J = 2.5 Hz, H-3), 9.27 (1H, d, J = 9.5 Hz, H-5); 13C NMR (125 MHz, CDCl3) δ 14.7 (C-20), 56.6 (2 × OCH3), 60.4 (C-19), 61.2 (OCH3), 107.5 (C-7), 107.8 (C-23, C-27), 118.3 (C-6), 120.5 (C-11), 122.1 (C-2), 122.9 (C-14), 125.0 (C-5), 125.4 (C-17), 127.6 (C-9), 128.1 (C-12), 130.1 (C-8), 133.5 (C-16), 133.8 (C-22), 136.2 (C-1), 141.2 (C-15), 142.7 (C-25), 145.4 (C-13), 150.6 (C-3), 153.3 (C-24, C-26), 164.2 (C-18), 184.0 (C-21); Anal. Calcd. for C28H24N2O6 C, 69.41; H, 4.99; N, 5.78. Found C, 69.44; H, 4.95; N, 5.80.

3.1.16. Ethyl 9-(3,5-dimethoxybenzoyl)pyrrolo[1,2-i][1,7]phenanthroline-7-carboxylate 5b

Yellow powder; yield 72%; mp 242–244 °C; IR(KBr) νmax3061,2964, 2837, 1700, 1625, 1588, 1439, 1346, 1219, 1154, 1080 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.43 (3H, t, J = 7.0 Hz, H-20),3.89 (6H, s, 2 × OMe), 4.42 (2H, q, J = 7.0 Hz, H-19), 6.77 (1H, bs, H-25), 7.26 (2H, bs, H-23, H-27), 7.58 (1H, dd, J = 8.0, 3.5 Hz, H-2), 7.82 (1H, s, H-8), 7.92 (1H, d, J = 9.5 Hz, H-12), 8.12 (1H, d, J = 9.5 Hz, H-11), 8.27 (1H, d, J = 8.0 Hz, H-1), 8.60 (1H, d, J = 9.5 Hz, H-6), 9.08 (1H, ad, J = 2.5 Hz, H-3), 9.27 (1H, d, J= 9.5 Hz, H-5); 13C NMR (CDCl3,125 MHz) δ 14.7 (C-20), 55.9 (2 × OMe), 60.4 (C-19), 105.5 (C-25), 107.6 (C-7), 108.0 (C-23, C-27), 118.3 (C-6), 120.5 (C-11), 122.1 (C-2), 122.9 (C-14), 125.2 (C-5), 125.4 (C-17), 127.7 (C-9), 128.1 (C-12), 130.8 (C-8), 133.8 (C-16), 136.2 (C-1), 140.5 (C-22), 141.4 (C-15), 145.4 (C-13), 150.6 (C-3), 160.9 (C-24, C-26), 164.2 (C-18), 184.3 (C-21); Anal. Calcd. for C27H22N2O5 C, 71.35; H, 4.88; N, 6.16. Found C, 71.30; H, 4.79; N, 6.17.

3.1.17. Ethyl 9-(3,4-dimethoxybenzoyl)pyrrolo[1,2-i][1,7]phenanthroline-7-carboxylate 5c

Yellow solid; yield 50%; mp 208–216 °C; IR (KBr) νmax 3061, 2963, 2922, 1697, 1624, 1541, 1440, 1259, 1236, 1219, 1076, 1022 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.43 (3H, t, J = 7.0 Hz, H-20), 4.00 (3H, s, OMe), 4.03 (3H, s, OMe), 4.42 (2H, q, J = 7.0 Hz, H-19), 7.02 (1H, d, J = 8.0 Hz, H-26), 7.57 (1H, dd, J = 8.0, 4.5 Hz, H-2), 7.69 (1H, bs, H-23), 7.77 (1H, s, H-8), 7.83 (1H, d, J = 8.5 Hz, H-27), 7.90 (1H, d, J = 9.5 Hz, H-12), 8.09 (1H, d, J = 9.5 Hz, H-11), 8.26 (1H, d, J = 8.0 Hz, H-1), 8.59 (1H, d, J = 9.5 Hz, H-6), 9.08 (1H, ad, J = 3.0 Hz, H-3), 9.25 (1H, d, J= 9.5 Hz, H-5);13C NMR (125 MHz, CDCl3) δ14.7 (C-20), 56.3 (OMe), 56.4 (OMe), 60.4 (C-19), 107.3 (C-7), 110.2 (C-26), 112.1 (C-23), 118.4 (C-6), 120.5 (C-11), 122.1 (C-2), 122.8 (C-14), 124.7 (C-5), 125.36 (C-17), 125.38 (C-27), 127.7 (C-9), 128.0 (C-12), 129.6 (C-8), 131.2 (C-22), 133.8 (C-16), 136.2 (C-1), 140.9 (C-15), 145.5 (C-13), 149.4 (C-24), 150.5 (C-3), 153.6 (C-25), 164.3 (C-18), 184.1 (C-21); Anal. Calcd. for C27H22N2O5 C, 71.35; H, 4.88; N, 6.16. Found C, 71.33; H, 4.77; N, 6.12.

3.1.18. Ethyl 9-(4-bromobenzoyl)pyrrolo[1,2-i][1,7]phenanthroline-7-carboxylate 5d

Yield: 65%. All physical and spectral data are in agreement to the literature [16].

3.1.19. Ethyl 9-(3,4,5-trimethoxybenzoyl)pyrrolo[2,1-c][4,7]phenanthroline-7-carboxylate 8a

Beige powder; yield 88%; mp 280–283 °C; IR (KBr) νmax 2988, 2943, 1703, 1630,1582, 1499, 1427, 1352, 1236, 1169, 1130, 1088 cm−1; 1H NMR (500 MHz, CDCl3) δ1.43 (3H, t, J = 7.0 Hz, H-20), 3.96 (6H, s, 2 × OMe), 4.01 (3H, s, OMe), 4.43 (2H, q, J = 7.0 Hz, H-19), 7.40 (2H, s, H-23, 27), 7.66 (1H, dd, J = 8.5, 4.0 Hz, H-3), 8.25 (2H, s, H-11, H-12), 8.51 (1H, d, J = 9.5 Hz, H-6), 8.60 (1H, d, J = 9.5 Hz, H-5), 8.93 (1H, d, J = 8.5 Hz, H-4), 9.04 (1H, d, J = 3.0 Hz, H-2); 13C NMR (125 MHz, CDCl3) δ14.7 (C-20), 56.6 (2 × OCH3), 60.5 (C-19), 61.2 (OCH3), 107.7 (C-7), 107.8 (C-23, C-27), 118.2 (C-5), 120.7 (C-14), 122.4 (C-6), 122.8 (C-3), 123.4 (C-11), 125.1 (C-13), 127.8 (C-9), 129.6 (C-8), 130.8 (C-12), 131.3 (C-4), 131.8 (C-16), 133.3 (C-22), 140.2 (C-15), 142.8 (C-25), 150.6 (C-2), 146.4 (C-17), 153.3 (C-24, C-26), 164.2 (C-18), 184.1 (C-21); Anal. Calcd. for C28H24N2O6 C, 69.41; H, 4.99; N, 5.78. Found C, 69.43; H, 5,00; N, 5.80.

3.1.20. Ethyl 9-(3,5-dimethoxybenzoyl)pyrrolo[2,1-c][4,7]phenanthroline-7-carboxylate 8b

Beige powder; yield 50%; mp 238–240°C; IR (KBr) νmax2986, 1701, 1638, 1591, 1497, 1356, 1244, 1206, 1157, 1086, 1069 cm−1; 1H NMR (500 MHz, CDCl3) δ1.42 (3H, t, J = 7.0 Hz, H-20), 3.89 (6H, s, 2 × OMe), 4.41 (2H, q, J = 7.0 Hz, H-19), 6.78 (2H, t, J = 2.0 Hz, H-25), 7.27 (2H, s, H-23, H-27), 7.65 (1H, dd, J = 8.0; 4.0 Hz, H-3), 7.81 (1H, s, H-8), 8.22–8.27 (2H, overlapped signals, H-11, H-12), 8.50 (1H, d, J = 9.5 Hz, H-6), 8.60 (1H, d, J = 9.5 Hz, H-5), 8.92 (1H, d, J = 8.5 Hz, H-4), 9.04 (1H, bs, H-2);13C NMR (125 MHz, CDCl3) δ14.7 (C-20), 55.9 (2 × OMe), 60.5 (C-19), 105.7 (C-25), 107.7 (C-7), 108.1 (C-23, C-27), 118.7 (C-5), 120.8 (C-14), 122.4 (C-3), 123.0 (C-6), 123.5 (C-11), 125.1 (C-13), 128.0 (C-9), 130.3 (C-8), 130.8 (C-12), 131.2 (C-22), 131.9 (C-4), 140.3 (C-16), 140.5 (C-15), 146.4 (C-17), 150.6 (C-2), 161.0 (C-24, C2-6), 164.1 (C-18), 184.4 (C-21); Anal. Calcd. for C27H22N2O5 C, 71.35; H, 4.88; N, 6.16. Found C, 71.34; H, 4.90; N, 6.20.

3.1.21. Ethyl 9-(3,4-dimethoxybenzoyl)pyrrolo[2,1-c][4,7]phenanthroline-7-carboxylate 8c

Beigesolid; yield 50%; mp 261–268°C; IR (KBr) νmax 3078, 2978, 2936, 1697, 1630, 1595, 1495, 1344, 1279, 1239, 1170, 1136, 1080, 1024 cm−1; 1H NMR (500 MHz, CDCl3) δ1.42 (3H, t, J = 7.0 Hz, H-20), 4.00 (6H, bs, 2 × OMe), 4.40 (2H, q, J = 7.0 Hz, H-19), 7.03 (2H, bs, H-26), 7.62–7.83 (4H, m, H-3, H-27, H-23, H-8), 8.21 (2H, bs, H-11, H-12), 8.44 (1H, bs, H-6), 8.54 (1H, bs, H-5), 8.88 (1H, bs, H-4), 9.00 (1H, bs, H-2);13C NMR (125 MHz, CDCl3) δ14.7 (C-20), 56.3 (OMe), 56.4 (OMe), 60.4 (C-19), 107.4 (C-7), 110.2 (C-26), 112.1 (C-23), 118.6 (C-5), 120.6 (C-14), 122.3 (C-6), 122.4 (C-3), 123.3 (C-11), 125.0 (C-13), 125.5 (C-27), 127.9 (C-9), 129.2 (C-8), 130.7 (C-12), 130.9 (C-22), 131.2 (C-4), 131.7 (C-16), 139.9 (C-15), 146.3 (C-17), 149.4 (C-24), 150.5 (C-2), 153.7 (C-25), 164.2 (C-18), 184.1 (C-21); Anal. Calcd. for C27H22N2O5 C, 71.35; H, 4.88; N, 6.16. Found C, 71.34; H, 4.85; N, 6.19.

3.1.22. Ethyl 9-(4-bromobenzoyl)pyrrolo[2,1-c][4,7]phenanthroline-7-carboxylate 8d

Beige powder; yield 50%; mp 260–263 °C; IR (KBr) νmax 2915, 1722, 1687, 1622, 1391, 1298, 1157, 1111 cm−1; 1H NMR (500 MHz, CDCl3) δ1.42 (3H, t, J = 7.0 Hz, H-20), 4.41 (2H, q, J = 7.0 Hz, H-19), 7.66–7.75 (4H, m, H-24, H-26, H-8, H-3), 8.02 (2H, d, J = 7.0 Hz, H-23, H-27), 8.25 (2H, bs, H-11, H-12), 8.53 (1H, d, J = 9.5 Hz, H-6), 8.61 (1H, d, J = 9.5 Hz, H-5), 8.93 (1H, d, J = 8.0 Hz, H-4), 9.04 (1H, bs, H-2);13C NMR (125 MHz, CDCl3) δ 14.7 (C-20), 60.4 (C-19), 107.9 (C-7), 118.6 (C-5), 120.9 (C-14), 122.5 (C-3), 123.3 (C-6), 123.4 (C-11), 125.1 (C-13), 127.6 (C-25), 128.3 (C-9), 130.4 (C-8), 130.9 (C-12), 131.3 (C-4), 131.7 (C-23, C-27), 131.9 (C-16), 132.1 (C-24, C-26), 137.3 (C-22), 140.6 (C-15), 146.5 (C-17), 150.7 (C-2), 164.1 (C-18), 183.6 (C-21); Anal. Calcd. for C25H17BrN2O3 C, 63.44; H, 3.62; N, 5.92. Found C, 63.43; H, 3.60; N, 5.89.

3.1.23. Ethyl 11-(3,4,5-trimethoxybenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carboxylate 11a

Beige powder; yield 29%; mp258–260 °C; IR (KBr) νmax 2985, 1702, 1640, 1590, 1497, 1357, 1242, 1208, 1157, 1085, 1070 cm−1; 1H NMR (400 MHz, CDCl3) δ1.42 (3H, t, J = 7.2 Hz, CH3), 3.97 (6H, s, 2 × OMe), 4.02 (3H, s, OMe), 4.42 (2H, q, J = 7.2 Hz, CH2), 7.36 (1H, dd, J =7.6; 4.0 Hz, H-9),7.41 (2H, s, H-20, H-24), 7.61 (1H, s, H-2), 7.78 (1H, d, J = 8.4 Hz, H-6), 7.88 (1H, d, J = 8.4 Hz, H-7), 7.95 (1H, d, J = 8.4 Hz, H-5), 8.20 (1H, d, J = 8.0 Hz, H-8), 8.42 (1H, d, J = 2.4 Hz, H-10), 8.55 (1H, d, J =8.8 Hz, H-4); 13C NMR (100 MHz, CDCl3) δ14.7 (CH3), 56.6 (2 × OCH3), 60.3 (CH2), 61.1 (OCH3), 106.5 (C-3), 107.8 (C-20, 24), 120.2 (C-4), 121.5 (C-2), 122.6 (C-9), 124.7 (C-6), 124.8 (C-5), 125.3 (C-1), 127.6 (C-15), 129.6 (C-14), 127.8 (C-7), 133.1 (C-19), 135.9 (C-8), 138.3 (C-17), 138.6 (C-16), 142.7 (C-22), 146.0 (C-10), 152.6 (C-13), 153.4 (C-21, 23), 164.5 (COO), 184.7 (C-18); Anal. Calcd. for C28H24N2O6: C, 69.41; H, 4.99; N, 5.78. Found: C, 69.45; H, 5,02; N, 5.80.

3.1.24. Ethyl 11-(3,5-dimethoxybenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carboxylate 11b

Beige powder; yield 25%; mp 261–263 °C; IR (KBr) νmax 2985, 2945, 1700, 1633,1581, 1498, 1429, 1355, 1237, 1168, 1132, 1086 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz, CH3), 3.90 (3H, s, OCH3), 4.42 (2H, q, J = 7.2 Hz, CH2), 6.80 (1H, bs, H-22), 7.27 (2H, bs, H-20, H-24), 7.35 (1H, dd, J = 7.2; 4.0 Hz, H-9), 7.57 (1H, s, H-2), 7.82 (1H, d, J = 8.4 Hz, H-6), 7.88 (1H, d, J = 8.4 Hz, H-7), 7.96 (1H, d, J = 8.4 Hz, H-5), 8.20 (1H, d, J = 8.0 Hz, H-8), 8.45 (1H, d, J = 2.8 Hz, H-10), 8.55 (1H, d, J =8.8 Hz, H-4); 13C NMR (100 MHz, CDCl3) δ 14.6 (CH3), 56.0 (2 × OCH3), 60.1 (CH2), 106.0 (C-3), 108.3 (C-20, C-24), 120.1 (C-4), 121.6 (C-2), 122.6 (C-9), 124.7 (C-5), 124.8 (C-6), 125.4 (C-1), 127.5 (C-7), 127.9 (C-15), 129.4 (C-14), 130.4 (C-19), 135.8 (C-8), 138.1 (C-17), 138.5 (C-16), 146.1 (C-10), 152.7 (C-13), 160.8 (C-21, C-23), 164.6 (COO), 184.4 (C-18); Anal. Calcd. for C27H22N2O5: C, 71.35; H, 4.88; N, 6.16. Found: C, 71.34; H, 4.53; N, 6.19.

3.1.25. Ethyl 11-(3,4-dimethoxybenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carboxylate 11c

Beige solid;yield 50%; mp 266–268 °C; IR (KBr) νmax 2932; 1688; 1595, 1514, 1458, 1415, 1261, 1232, 1140, 1024 cm−1; 1H NMR (400 MHz, CDCl3) δ1.42 (3H, t, J = 7.2 Hz, CH3), 3.95 (3H, s, OMe), 4.03 (3H, s, OMe), 4.40 (2H, q, J = 7.2 Hz, CH2), 7.03 (2H, d, J = 8.4 Hz, H-23), 7.37 (1H, dd, J =7.6; 4.0 Hz, H-9), 7.59 (1H, s, H-2), 7.70–7.74 (2H, m, H-20, H-24), 7.80 (1H, d, J = 8.4 Hz, H-6), 7.89 (1H, d, J = 8.4 Hz, H-7), 7.98 (1H, d, J = 8.4 Hz, H-5), 8.19 (1H, d, J = 8.0 Hz, H-8), 8.44 (1H, d, J = 2.8 Hz, H-10), 8.58 (1H, d, J = 9.2 Hz, H-4); 13C NMR (100 MHz, CDCl3)δ 14.6 (CH3), 56.0 (OMe), 56.1 (OMe), 60.0 (CH2), 106.1 (C-3), 110.1 (C-23), 112.2 (C-20), 120.0 (C-4), 121.7 (C-2), 122.5 (C-9), 124.8 (C-5), 125.5 (C-1), 127.7 (C-15), 125.6 (C-24), 124.9 (C-6), 129.6 (C-14), 127.6 (C-7), 130.5 (C-19), 135.8 (C-8), 138.2 (C-17), 138.7 (C-16), 146.2 (C-10), 148.8 (C-21), 152.7 (C-22, C-13), 164.7 (COO), 184.5 (C-18); Anal. Calcd. for C27H22N2O5 C, 71.35; H, 4.88; N, 6.16. Found C, 71.33; H, 4.51; N, 6.19.

3.1.26. Ethyl 11-(4-bromobenzoyl)pyrrolo[1,2-a][1,10]phenanthroline-9-carboxylate 11d

Yield 65%; All physical and spectral data are in agreement to the literature [33].

3.2. Cell Proliferation Assay

The compounds were tested against a panel of 60 human cancer cell lines at the National Cancer Institute, Rockville, MD. The cytotoxicity experiments were realized using a 48-h exposure protocol using sulphorhodamine B assay [37,38,39].

3.3. Molecular Modelling

Flexible docking experiments were carried out as previously reported [28]. Briefly, a 18 × 22 × 22 Å3 gridbox was used, centred on the colchicine binding site of the α,β-tubulin heterodimer crystal structure (PDB: 1SA0) [40] and experiments were carried out using Autodock Vina [41]. One hundred poses were generated for each ligand, and the best ranked models were chosen for further visual inspection in order to assess the consistency of the generated docking solutions relative to the docking poses of the known inhibitors colchicine and phenstatin. Molecular graphics and visual analyses were performed in the PyMOL Molecular Graphics System, Version 1.8.2. (Schrödinger, LLC, New York, NY, USA).

4. Conclusions

Three new classes of potential phenstatin analogues have been synthesized and characterized. Four compounds were selected by NCI and tested against a panel of 60 cell lines at a single concentration of 10−5 M using sulphorhodamine B assay. The results show that the two compounds, 8a and 11c, inhibit cell proliferation in several cancer cell lines, the derivative 11c being the most active and showing cytotoxic activity against the COLO205, MDA-MB-435 and A498 cell lines. Compound 11c was further tested in the full five-dose assay and exhibited significant antiproliferative activity against 40 cell lines on NCI with GI50 values in the range of 0.296–3.78 μM. Docking studies indicate that the tested compounds most likely exert their antiproliferative activity by interacting with specific residues in the colchicine binding site of tubulin, similar to their parent compound, phenstatin, as well as other classes of tubulin polymerization inhibitors. In terms of improving anticancer activity, the substitution of ring B of phenstatin with a pyrrolo[1,2-a][1,10]phenanthroline group appears to be the most beneficial, while the replacement with a pyrrolo[1,2-i][1,7]phenanthroline is detrimental to the growth inhibition properties against cancer cell lines. We can conclude that our phenstatin analogue types 8 and 11 are amenable for further structural optimization in the development of chemotherapeutic agents.

Author Contributions

Design, conception and writing were performed by R.D., G.Z. and I.I.M. Biological data analysis was performed by R.D. and R.M.A. Synthesis and structure elucidation were performed by C.M.A.M. and A.M.C. Molecular modelling experiments were performed by R.M.A. All authors reviewed and approved the final version.

Acknowledgments

Authors are thankful to UEFISCDI Bucharest, Romania, project PN-III-P1-1.1-TE-2016-1205 and the Ministry of Research and Innovation within Program 1 – Development of the national RD system, Subprogram 1.2 – Institutional Performance – RDI excellence funding projects, Contract no. 34PFE/19.10.2018 for financial support. Authors also thank to the POSCCE-O 2.2.1, SMIS-CSNR 13984-901, No. 257/28.09.2010 Project, CERNESIM, for NMR experiments.The authors gratefully acknowledge National Cancer Institute (NCI) for the biological evaluation of compounds on their 60-cell panel: the testing was performed by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis (the URL to the Program’s website: http://dtp.cancer.gov/).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Molecules 25 00527 g001 550
Figure 1. Design for the target pyrrolophenanthroline derivatives.
Figure 1. Design for the target pyrrolophenanthroline derivatives.
Molecules 25 00527 g001
Molecules 25 00527 sch001 550
Scheme 1. Synthesis pathway for the fused pyrrolo[1,2-i][1,7]phenanthroline 5a–d.
Scheme 1. Synthesis pathway for the fused pyrrolo[1,2-i][1,7]phenanthroline 5a–d.
Molecules 25 00527 sch001
Molecules 25 00527 sch002 550
Scheme 2. Synthesis pathways for the fused pyrrolo[2,1-c][4,7]phenanthroline 8a–d and pyrrolo[1,2-a][1,10]phenanthroline 11a–d.
Scheme 2. Synthesis pathways for the fused pyrrolo[2,1-c][4,7]phenanthroline 8a–d and pyrrolo[1,2-a][1,10]phenanthroline 11a–d.
Molecules 25 00527 sch002
Molecules 25 00527 g002 550
Figure 2. Binding modes of (a) colchicine, (b) phenstatin, (c) Compound 8a, (d) Compound 8b, (e) Compound 5c, (f) Compound 11c at the colchicine binding site of tubulin; the α,β-tubulin heterodimer is represented as ribbons; amino acids in the binding site are represented as sticks.
Figure 2. Binding modes of (a) colchicine, (b) phenstatin, (c) Compound 8a, (d) Compound 8b, (e) Compound 5c, (f) Compound 11c at the colchicine binding site of tubulin; the α,β-tubulin heterodimer is represented as ribbons; amino acids in the binding site are represented as sticks.
Molecules 25 00527 g002
Table
Table 1. Results of the in vitro growth inhibition (GI%) caused by Compounds 5c, 8a, 8b and 11c against human cancer cell lines in the single-dose assay a.
Table 1. Results of the in vitro growth inhibition (GI%) caused by Compounds 5c, 8a, 8b and 11c against human cancer cell lines in the single-dose assay a.
Cell TypeCompound5c8a8b11cPhenstatin
Cell LineGI (%) (10−5 M) a
LeukemiaCCRF-CEM03718094
K-562887148591
SR1286247793
HL-60(TB)13872596100 b,f
MOLT-42269236685
RPMI-822603709587
Non-small Cell Lung CancerA549/ATCC33626382
HOP-92045168048
HOP-6283877077
NCI-H46001828993
NCI-H522977199988
Colon CancerCOLO2050670100b,c58
HCT-116078247396
HCT-15856186996
HT-29080209385
SW-62087658778
KM12358117191
CNS CancerSF-295037088100 b,g
SF-539044491100 b,h
SNB-7521351882100 b,i
U25104917579
MelanomaLOX IMVI45306885
M140681992100 b,j
MDA-MB-4350917100b,d100 b,k
UACC-6204205355
SK-MEL-205908140
SK-MEL-5166183100 b,l
Ovarian CancerOVCAR-3039090100 b,m
NCI/ADR-RES666478100 b,n
SK-OV-31622288753
OVCAR-894407186
Renal cancerA4980390100b,e25
RXF39303307599
786-0022067-
Breast cancerMCF71971137894
MDA-MB-468030061100 b,o
HS 578T32747571
BT-549031186788
Prostate cancerPC-31336187880
DU-14501107890
a Data obtained from NCI’s in vitro 60 cell one dose screening at 10−5 M concentration; b Cytotoxic effect; Cell growth percent: c −2; d −26;e −5;f −29;g −9;h −22;I −1;j −4;k −41;l −60;m−7;n v32; o −14.
Table
Table 2. Results of the five-dose in vitro human cancer cell growth inhibition a for Compound 11c and control phenstatin.
Table 2. Results of the five-dose in vitro human cancer cell growth inhibition a for Compound 11c and control phenstatin.
Cell TypeCompound→11cPhenstatin
Cell Line↓GI50 (μM) b
LeukemiaHL-60(TB)2.780.011
SR0.807<0.010
CCRF-CEM3.130.034
Non-small
Cell Lung Cancer		NCI-H4601.580.033
NCI-H5220.6110.027
HOP-623.780.073
Colon CancerHCT-1160.6190.038
HCT-151.25<0.010
HT291.422.95
SW-6200.930<0.010
KM121.30<0.010
CNS CancerSF-2950.8000.367
SF-5392.100.011
SNB-752.04<0.010
U2513.610.043
MelanomaSK-MEL-50.8360.040
M140.648<0.010
MDA-MB-4350.296<0.010
UACC-620.9180.448
LOXIMVI2.600.013
MALME-3M1.24-
SK-MEL-22.670.520
SK-MEL-283.7065.20
Ovarian CancerOVCAR-31.080.021
NCI/ADR-RES0.9480.012
IGROV12.330.18
OVCAR-83.730.042
Renal Cancer786-02.340.905
A4982.822.28
UO-310.8910.074
ACHN2.400.042
RXF 3932.060.016
Breast cancerMCF72.250.033
HS 578T3.040.031
MDA-MB-231/ATCC2.660.029
BT-5491.940.034
T-47D2.3730.4
MDA-MB-4682.832.71
Prostate cancerPC-30.9600.045
DU-1453.440.039
a Data obtained from NCI’s in vitro 60 cell five-dose screening. b GI50 – the molar concentration of tested compound causing 50% growth inhibition of tumor cells.

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Al Matarneh, C.M.; Amarandi, R.M.; Craciun, A.M.; Mangalagiu, I.I.; Zbancioc, G.; Danac, R. Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines. Molecules 2020, 25, 527. https://doi.org/10.3390/molecules25030527

AMA Style

Al Matarneh CM, Amarandi RM, Craciun AM, Mangalagiu II, Zbancioc G, Danac R. Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines. Molecules. 2020; 25(3):527. https://doi.org/10.3390/molecules25030527

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Al Matarneh, Cristina Maria, Roxana Maria Amarandi, Anda Mihaela Craciun, Ionel I. Mangalagiu, Gheorghita Zbancioc, and Ramona Danac. 2020. "Design, Synthesis, Molecular Modelling and Anticancer Activities of New Fused Phenanthrolines" Molecules 25, no. 3: 527. https://doi.org/10.3390/molecules25030527

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