Effect of an industrial chemical waste on the uptake J. Serb. Chem. Soc. 87 (0) 1–9 (2022) Original scientific paper JSCS–11924 Published 18 November 2022 1 Divergent synthesis and antitumour activity of novel conformationally constrained (–)-muricatacin analogues SLAĐANA M. STANISAVLJEVIĆ1, BOJANA M. SREĆO ZELENOVIĆ1*, MIRJANA POPSAVIN1, MARKO V. RODIĆ1, VELIMIR POPSAVIN1,2 and VESNA V. KOJIĆ3 1University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia, 2Serbian Academy of Sciences and Arts, Kneza Mihaila 35, 11000 Belgrade, Serbia and 3University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Put dr Goldmana 4, 21204 Sremska Kamenica, Serbia (Received 13 June, revised 5 August, accepted 18 August 2022) Abstract: Four novel conformationally restricted (–)-muricatacin analogues, bearing a methoxy group at the C-5 position and with an alkoxymethyl group аs the C-7 side chain, have been synthesised and their in vitro antiproliferative activity was evaluated against a panel of seven human tumour cell lines, as well as a single normal cell line. All analogues (9–12) showed diverse antipro- liferative effects against all tested human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A structure–activity relationship study reveals that the introduction of tetrahydrofuran ring, the replacement of C-8 methylene group in the side chain of muricatacin analogues with the O-8 ether functionality, as well as the length of side chain may be beneficial for the antiproliferative effects of these lactones. All novel analogues were more potent than lead compound, (–)-muri- catacin, against HL-60 cell line. Keywords: D-glucose; antitumour agents; muricatacin mimics; furanolactones; cytotoxicity; SAR analysis. INTRODUCTION (–)-Muricatacin (1) is a naturally occurring acetogenin derivative, which has been isolated by McLaughlin and co-workers1 from the seeds of Annona muri- cata L. together with its enantiomer (+)-muricatacin (ent-1). Both natural pro- ducts (1 and ent-1) have received a great deal of attention due to their similar biological profiles: remarkable antiproliferative activities towards various human tumour cells,2,3 antimalarial as well as pesticidal activities.1 * Corresponding author. E-mail: bojana.sreco@dh.uns.ac.rs  Serbian Chemical Society member. https://doi.org/10.2298/JSC220613069S mailto:bojana.sreco@dh.uns.ac.rs https://doi.org/10.2298/JSC220613069S 2 STANISAVLJEVIĆ et al. Many syntheses of 1 from various precursors have been reported.4–16 Also, several muricatacin analogues have been synthesised3,7,17–20 and some of them were evaluated for their antitumour activity.7,19,20 As a part of our ongoing program in the synthesis of oxygenated lactones as potential antitumour agents from abundant monosaccharides, the synthesis of four novel 8-oxa analogues of (–)-muricatacin (9–12, Fig. 1) with furano-fura- none ring system and methoxy group at the C-5 position was achieved from D- -glucose. These molecules represent conformationally constrained oxa-analogues of lactone 1, with methoxy group at the C-5 position. Analogue 9 is a heteroan- nelated mimic of 1 with the restricted geometry of the C4–C6 segment, due to the presence of the tetrahydrofuran (THF) ring. The molecule 10 represents a one- carbon lower homologue of 9, while the molecules 11 and 12 are two- and three- carbon lower homologues of lactone 9. Fig. 1. Design of (–)-muricatacin analogues with a methoxy group (9–12), a benzyl group (13–16) and with a hydroxyl group at C-5 position (17–20): i) THF-ring closure; ii) 5-O-methylation; iii) exchange of C8 methylene group with O8 ether function; iv) substitution of methyl with benzyl group at C-5; v) debenzylation at C-5. Our recent results on the antiproliferative activity of analogues 17–20 showed that they exhibit moderate to submicromolar cytotoxicity.21 That led us to prepare C-5 methoxy derivatives 9–12, and to examine their cytotoxic activity, as well as the cytotoxicity of previously synthesised analogues 13–16,21 for a detailed structure–activity relationship (SAR) analysis. EXPERIMENTAL General procedures Melting points were determined on Büchi 510, or on hot stage microscope Nagema PHMK 05 apparatus and were not corrected. Optical rotations were measured on Autopol IV (Rudolph Research) automatic polarimeter. IR spectra were recorded with a FTIR Nexus 670 (Thermo-Nicolet) spectrophotometer. NMR spectra were recorded on a Bruker AC 250 E or a Bruker Avance III 400 MHz instrument and chemical shifts are expressed in ppm downfield from tetramethylsilane. Low resolution mass spectra were recorded on Finnigan-MAT 8230 (CI) mass spectrometer. High-resolution mass spectra were taken on a Micromass LCT KA111 spectrometer or on LTQ OrbitrapXL (Thermo Fisher Scientific Inc.) mass spectro- meter. TLC was performed on DC Alufolien Kieselgel 60 F254 (E. Merck). Flash column chromatography was performed using Kieselgel 60 (0.040–0.063, E. Merck). All organic ext- (–)-MURICATACIN ANALOGUES 3 racts were dried with anhydrous Na2SO4. Organic solutions were concentrated in a rotary eva- porator under reduced pressure at a bath temperature below 35 °C. Synthesis procedures Methyl (Z)- (4) and (E)-3-O-methyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5- -enofuranuronate (5). To a solution of compound 2 (1.923 g, 7.01 mmol), in dry EtOAc (193 mL), H5IO6 (2.008 g, 8.76 mmol) was added. The mixture was stirred at room temperature for 3 h, then filtered and evaporated to afford crude aldehyde 3. To a stirred and cooled (0 C) solution of 3 (1.530 g, 7.56 mmol) in dry MeOH (35 mL) MCMP (2.558 g, 7.56 mmol) was added and the mixture was stirred for 0.5 h at 0 °C and then for 2.5 h at room temperature. The reaction mixture was evaporated and the residue was purified by flash chromatography (3:2 light petroleum/Et2O). The pure product 4 (1.240 g, 69 %) was first eluted, isolated as a colourless oil. Further elution gave compound 5 which was additionally purified (1:1 iPr2O/ /light petroleum) to give the pure E-olefin 5 (0.133 g, 7 %). Dimethylacetal 2,5-Anhydro-6-deoxy-3-O-methyl-L-ido-hepturono-4,7-lactone (6). A solution of 4 (0.245 g, 0.95 mmol) in dry MeOH (7 mL) which contains 2.5 % H2SO4, was refluxed for 2 h. The mixture was cooled to 35 C and alkalized (pH 9) by adding solid NaHCO3 (0.917 g, 10.92 mmol, 11.5 eq) in three portions every 5 min. After adding the entire amount of base, the suspension was stirred at 35 C for 1 h, then filtered and evaporated. The residue was purified by flash column chromatography (3:2 cyclohexane/EtOAc) to give pure 6 (0.174 g, 79 %). 3,6-Anhydro-2-deoxy-5-O-methyl-L-ido-heptono-1,4-lactone (8). Dimethylacetal 6 (0.769 g, 3.31 mmol) was dissolved in 9:1 TFA/H2O (15.5 mL) and stirred at room tempe- rature for 1 h. After completion of the reaction, the solution was evaporated by co-distillation with toluene. The crude aldehyde 7 was dissolved in dry MeOH (39 mL) and treated with a first portion of NaBH4 (0.094 g, 2.49 mmol, 3 eq). After stirring the mixture at room tempe- rature for 0.5 h, an additional amount of NaBH4 (0.063 g, 1.67 mmol, 2 eq) was added. The mixture was stirred at room temperature for additional hour. The reaction mixture was neutralized with AcOH and evaporated. The residue was purified by flash chromatography (4:1 CH2Cl2/EtOAc) to give pure alcohol 8 (0.399 g, 64 %). General procedure for the synthesis of analogues 9–12 To a solution of compound 8 (1 equiv.) in dry Et2O (2 mL) Ag2O (2.5 equiv.), AgOTf (0.3 eq) and the corresponding alkyl bromide RBr (2.5 equiv.) were added. The mixture was stirred under reflux for 16–27 h (Table I). After completion of the reaction, which was det- ected by thin layer chromatography (TLC), the mixture was purified by flash column chroma- tography (7:3 light petroleum/Et2O). The characterization data for all synthesised compounds (4–6 and 8–12) are given in the Supplementary material to this paper. TABLE I. Preparation of final products 9–12 Entry R Reaction time, h Product Yield, % 1 C9H19 22.5 9 72 2 C8H17 16 10 86 3 C7H15 23 11 80 4 C6H13 27 12 73 4 STANISAVLJEVIĆ et al. Cytotoxic activity Test cells. The in vitro cytotoxicity of test compounds was evaluated against seven human malignant cell lines: myelogenous leukaemia (K562), promyelocytic leukaemia (HL- -60), T cell leukaemia (Jurkat), Burkitt’s lymphoma (Raji), ER+ breast adenocarcinoma (MCF-7), ER- breast adenocarcinoma (MDA-MB 231) and cervix carcinoma (HeLa). Cyto- toxic activity against normal foetal lung fibroblasts (MRC-5) was also estimated. MTT test. Cytotoxic activity was evaluated by using standard MTT assay,22 after expo- sure of cells to the tested compounds for 72 h. RESULTS AND DISCUSSION Chemistry The syntheses of (–)-muricatacin analogues 9–12 are presented in Scheme 1. Starting compound 2 was prepared from D-glucose in two synthetic steps as pre- viously reported by us.23 Methyl derivative 2 was treated with periodic acid in dry ethyl acetate and the crude aldehyde 3 was obtained. Compound 3 reacted with stabilized ylide, Ph3P=CHCO2Me, in anhydrous MeOH and gave the exp- ected Z-olefin 4 (69 %) as the major product of the Wittig olefination. A minor amount of corresponding E-olefin 5 (7 %) was also obtained in this reaction. Scheme 1. Reagents and conditions: a) H5IO6, EtOAc, rt, 3 h; b) Ph3P=CHCO2Me, MeOH, 0 °C, 0.5 h, then rt 1.5 h, 69 % for 4, 7 % for 5 (from 2); c) 2.5 % H2SO4/MeOH, reflux, 2 h, NaHCO3, rt, 1 h, 79 %; d) 9:1 TFA/H2O, rt, 1 h; e) NaBH4, MeOH, rt, 1.5 h, 64 % (from 6); f) C9H19Br for 9, C8H17Br for 10, C7H15Br for 11, C6H13Br for 12, Ag2O, AgOTf, CH2Cl2, reflux, 22.5 h (for 9), 16 h (for 10), 23 h (for 11), 27 h (for 12), 72 % (for 9), 86 % (for 10), 80 % (for 11), 73 % (for 12). An acid-catalyzed methanolysis of 4, in the presence of a catalytic amount of sulphuric acid gave furano-lactone 6 in 79 % yield. Hydrolytic removal of the dimethyl acetal protective group in 6 followed by a subsequent NaBH4 reduction of the resulting aldehyde 7 gave the corresponding primary alcohol 8 in 64 % yield. The stereochemistry of compound 8 was confirmed by single crystal X-ray diffraction analysis (for selected crystallographic and refinement details see the (–)-MURICATACIN ANALOGUES 5 Table S-II of the Supplementary material). The molecular structure of 8 is dep- icted in Fig. 2. All structural parameters of the molecule are within limits found in structures with similar fragments. The furano-lactone ring core is fused in cis manner and both five-membered rings are puckered, details of which are ana- lysed by Cremer–Pople formalism.24 The furanose ring (counting clockwise O3→C3→C4→C5→C6) is moderately puckered (q2 = 36.05(17) pm), and its conformation is close to twisted at C5–C6 bond. The pseudorotational phase angle φ2 = 130.5(3)° indicates its deformation towards the envelope form, as the ring formally traversed 25 % along 6T5→ 6E pseudorotational pathway. Ring sub- stituents C2 (δ = 29.58(13)°), O4 (δ = 16.44(11)°), and O5 (δ = 9.82(11)°) can be classified as axial, while C7 (δ = 65.96(13)°) is equatorial; δ is the angle sub- tended between Cremer–Pople ring mean plane normal and substituent bond vec- tor.25 The lactone ring (counting clockwise O4→C1→C2→C3→C4) is less puckered (q2 = 14.0(2) pm) and its conformation is closer to the envelope form, with C3 as the flap. Its exact conformation is determined by φ2 = 130.5(3)°, which means that the ring formally traversed 37 % along E4→ 3T4 pseudorot- ational pathway. Fig. 2. Molecular structure of 8 determined by single crystal X-ray diffraction. Ellipsoids are drawn at 50 % probability level. Hydrogen atoms are shown as spheres of arbitrary radii. The key intermediate, alcohol 8, readily reacted with an excess of nonyl bromide in ether, in the presence of silver(I)-oxide and a catalytic amount of silver(I)-triflate, to give the expected 7-O-nonyl derivative 9 in 72 % yield. Under similar experimental conditions, the primary alcohol 8 reacted with dif- ferent alkyl bromides (C8–C6) to afford the corresponding ether derivatives 10– –12 in good yields (Scheme 1). In vitro antiproliferative activity After completion of the synthesis, analogues 9–12 were evaluated for their in vitro cytotoxicity against a panel of seven human tumour cell lines (human myel- ogenous leukaemia, K562, promyelocytic leukaemia, HL-60, T cell leukaemia, Jurkat, Burkitt’s lymphoma, Raji, ER+ breast adenocarcinoma, MCF-7, ER− breast adenocarcinoma, MDA-MB 231, and cervix carcinoma, HeLa) and one normal cell line (foetal lung fibroblasts, MRC-5). Cell growth inhibition was eva- luated after 72 h of cells treatment by using the MTT test.22 (–)-Muricatacin (1) 6 STANISAVLJEVIĆ et al. and the commercial antitumour agent doxorubicin (DOX) were used as positive controls in this assay. According to the recorded IC50 (Table II), all tumour cell lines were sensitive to all of the synthesised analogues (9–12). All four (–)-muricatacin mimics (9– –12) demonstrated diverse antiproliferative effects toward MDA-MB 231 and Jurkat cells, in contrast to the lead 1, which was completely inactive against these cell lines. TABLE II. In vitro cytotoxicity ( IC50 * / μM) of (–)-muricatacin (1), DOX and analogues 9– 20 after 72 h Compound Cell line K562 HL-60 Jurkat Raji MCF-7 MDA-MB 231 HeLa MRC-5 1 0.04 25.85 >100 0.1 21.35 >100 0.17 >100 9 10.25 17.70 15.40 21.75 4.85 11.32 13.50 >100 10 18.12 13.68 7.36 35.84 1.11 28.33 9.12 >100 11 5.60 24.54 22.97 28.49 12.31 25.33 11.51 >100 12 7.69 21.18 25.34 27.03 18.33 15.81 15.22 >100 13 8.76 6.12 9.71 15.95 22.18 39.48 68.32 >100 14 9.09 13.92 5.47 16.85 18.77 28.26 18.02 >100 15 8.87 5.67 8.86 17.33 22.87 34.59 10.90 >100 16 5.65 7.42 5.25 11.82 25.31 8.50 33.79 >100 17a 5.66 4.75 6.97 7.25 >100 >100 6.39 >100 18a 0.74 0.68 19.78 4.25 0.34 28.70 3.41 >100 19a 1.02 1.10 11.53 5.98 2.38 9.76 0.56 >100 20a 0.70 4.91 8.87 1.11 12.34 15.62 3.54 >100 DOX 0.25 0.92 0.03 2.98 0.20 0.09 0.07 0.10 aTaken from reference21 Also, all novel analogues (9–12) were more potent than lead 1 against HL-60 cell line. The most active compound against the MCF-7 cells was analogue 10. This molecule exhibited strong cytotoxicity (IC50 = 1.11 μM) although its potency was 5.5 times lower than the activity of DOX (IC50 = 0.20 μM), but 19 times higher than that of the control compound 1 (IC50 = 21.35 μM). The analogue 9 also showed very good activity (IC50 = 4.85 μM) against this cell line, which was 4 times higher than that of lead 1. The conformationally restricted benzyl analogues of 1, compounds 13–16, exhibited cytotoxic activity against all seven malignant cell lines. Against the HL-60 cell line the previously synthesised analogues 13–16 showed from 1.85 * IC50 is the concentration of compound required to inhibit the cell growth by 50 % compared to an untreated control. Values are means of three independent experiments. Coefficients of variation were less than 10 %. (–)-MURICATACIN ANALOGUES 7 times (analogue 14, IC50 = 13.92 μM) to 4.5 times (analogue 15, IC50 = 4.85 μM) better cytotoxicity than natural product 1 (IC50 = 25.85 μM). Against Jurkat cell line benzyl derivatives 13–16 exhibited strong antiproli- ferative effects (IC50 values in the range of 5.25−9.71 μM). However, the parent compound 1 was completely inactive against this cell line. Against the MCF-7 cell line analogues 13–16 demonstrated similar cyto- toxicity (IC50: 18.77−25.31 μM) as parent compound 1 (IC50 = 21.35 μM). All synthesised compounds showed diverse growth inhibitory effects against the tested malignant cells, but were devoid of any significant cytotoxicity toward the normal foetal lung fibroblasts (MRC-5), as well as the natural product 1, in contrast to the commercial antitumour agent doxorubicin (DOX) that exhibited potent cytotoxic activity (IC50 = 0.10 μM) against this cell line. SAR analysis Our previous findings showed that the introduction of an oxygen atom in the side chain of (–)-muricatacin analogues increases the antiproliferative activity.21 In this work we compared (–)-muricatacin analogues with this structural feature and the changes were based on the position C-5, so we compared three series of analogues: with OMe-group (9–12), with OBn-group (13–16) and with OH-group (17–20) at that position. Analogues 9–12 demonstrated better cytotoxicity than the parent compound 1 against most of the cell lines tested in this study (Fig. S-17A of the Supple- mentary material). The corresponding benzyl derivatives (13–16) performed better antiproliferative effects in comparison to the analogues 9–12 (Fig. S-17B). Finally, the analogues with OH-group at C-5 position (17–20) were more potent than benzyl analogues (13–16, Fig. S-17C). So, our further work will be focused on the preparation of a larger number of similar analogues and then we will be able to make a reliable conclusion that the free OH-group at position C-5 inc- reases the cytotoxic activity of conformationally restricted (–)-muricatacin ana- logues. CONCLUSION In conclusion, four novel (−)-muricatacin analogues (9–12) were designed and synthesised from D-glucose as a starting compound. The newly synthesised molecules, as well as the previously synthesised benzyl analogues (13–16), were evaluated for their in vitro cytotoxic activity against seven human malignant cell lines. A SAR study showed that the presence of additional tetrahydrofuran ring, O-8 ether functionality, as well as the length of alkyl chain, may improve the cytotoxicity of analogues toward the majority of cell lines under evaluation. All synthesised compounds demonstrated diverse antiproliferative effects against the human malignant cell lines but were devoid of any significant cyto- toxicity towards the normal foetal lung fibroblasts (MRC-5). Hence, we believe 8 STANISAVLJEVIĆ et al. that this approach may be of use in the search for novel, more potent and selec- tive anticancer agents, derived from the natural product 1. SUPPLEMENTARY MATERIAL Additional data and information are available electronically at the pages of journal website: https://www.shd-pub.org.rs/index.php/JSCS/article/view/11924, or from the corres- ponding author on request. Acknowledgements. This work was supported by research grants from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Contract No. 451-03-68/2020-14/200125). This work has also received funding from the Serbian Academy of Sciences and Arts under the strategic projects programme (Grant agreement No. 01-2019- -F65), as well as from a research project from the same institution (Grant No. F-130). И З В О Д ДИВЕРГЕНТНА СИНТЕЗА И АНТИТУМОРСКА АКТИВНОСТ НОВИХ КОНФОРМАЦИОНО КРУТИХ АНАЛОГА (–)-МУРИКАТАЦИНА СЛАЂАНА М. СТАНИСАВЉЕВИЋ1, БОЈАНА М. СРЕЋО ЗЕЛЕНОВИЋ1, МИРЈАНА ПОПСАВИН1, МАРКО В. РОДИЋ1, ВЕЛИМИР ПОПСАВИН1,2 и ВЕСНА В. КОЈИЋ3 1Универзитет у Новом Саду, Природно–математички факултет, Департман за хемију, биохемију и заштиту животне средине, Трг Доситеја Обрадовића 3, 21000 Нови Сад, 2Српска академија наука и уметности, Кнеза Михаила 35, 11000 Београд и 3Универзитет у Новом Саду, Медицински факултет, Онколошки институт Војводине, Пут др Голдмана 4, 21204 Сремска Каменица Синтетизована су четири нова конформационо крута аналога (−)-мурикатацина са метокси-групом у положају С-5 и са алкоксиметил-групом у бочном низу и испитана је њихова in vitro антипролиферативна активност према седам хуманих туморских и једној здравој ћелијској линији. Сви аналози (9–12) су показали различите антипролиферат- ивне ефекте према свим испитиваним малигним ћелијским линијама, а изостала је цитотоксична активност према ћелијској линији нормалних феталних фибробласта плућа (MRC-5). SAR анализа показује да увођење тетрахидрофуранског прстена, замена С-8 метиленске групе са етарском функцијом у бочном низу, као и дужина бочног ланца, могу бити од значаја за цитотоксичне ефекте ових лактона. Сви новодобијени аналози су били потентнији од водећег једињења (−)-мурикатацина према HL-60 ћелиј- ској линији.. (Примљено 13. јуна, ревидирано 5. августа, прихваћено 18. августа 2022) REFERENCES 1. M. J. Rieser, J. F. Kozlowski, K. V. Wood, J. L. McLaughlin, Tetrahedron Lett. 32 (1991) 1137 (https://doi.org/10.1016/S0040-4039(00)92027-6) 2. C.-C. Liaw, F.-R. Chang, S.-L. Chen, C.-C. Wu, K.-H. Lee, Y. C. Wu, Bioorg. Med. Chem. 13 (2005) 4767 (https://doi.org/10.1016/j.bmc.2005.05.008) 3. A. Cavé, C. Chaboche, B. Figadère, J. C. Harmange, A. Laurens, J. F. Peyrat, M. Pichon, M. Szlosek, J. Cotte-Lafitte, A. M. Quéro, Eur. J. Med. Chem. 32 (1997) 617 (https://doi.org/10.1016/S0223-5234(97)83287-4) 4. M. Chandrasekhar, K. L. Chandra, V. K. 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