Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs
"> Figure 1
<p>(<b>A</b>) HDACi pharmacophore model illustrated on the FDA-approved drug vorinostat (SAHA). (<b>B</b>) Chemical structure of dihydroartemisinin (DHA). (<b>C</b>) Compound design based on DHA as cap connected by C-10 ether or thioether groups to four different linkers and three zinc-binding groups.</p> "> Figure 2
<p>K562 cells were treated with DHA, (β)-<b>7c</b>, and vorinostat (0.4 µM) for 24 h. Subsequently, cell lysates were immunobloted with anti-acetyl-α-tubulin and acetyl-histone H3 antibodies, whereas GAPDH served as a loading control. The experiments were repeated three times (<span class="html-italic">n</span> = 3), and a representative blot is shown here.</p> "> Figure 3
<p>Docking pose of (α)-<b>7c</b> (<b>A</b>) and (β)-<b>7c</b> (<b>B</b>) in the catalytic domain 2 of HDAC6 (PDB: 5EDU [<a href="#B29-pharmaceuticals-15-00333" class="html-bibr">29</a>]). Ligands are colored green and are depicted as sticks. The catalytic Zn<sup>2+</sup>-ion is shown as a gray sphere, and water is shown as a red sphere. The protein backbone is shown as light blue cartoon including the wheat-colored protein surface surrounding the ligand. The binding interactions of the hydroxamic acids are depicted as yellow, dashed lines.</p> "> Figure 4
<p>Survival of the artemisinin-resistant (Dd2 R539T) and sensitive (Dd2) <span class="html-italic">P. falciparum</span> line after treatment with 700 nM of the respective compound (DHA or DHA–HDACi hybrid) in the ring-stage survival assay. Results show the survival in percent of the drug-treated parasites in relation to the untreated control (DMSO) parasites. Each experiment was performed twice in duplicate. All compounds, except <b>7a</b>, were slightly more active, with (α)-<b>7c</b> being significantly more active than DHA alone (unpaired <span class="html-italic">t</span>-test: ** <span class="html-italic">p</span> < 0.005).</p> "> Figure 5
<p>Apoptosis assay via annexin V/PI measurement after 48 h treatment of K562 cells with the respective inhibitors at the depicted concentrations. Significance was calculated using the sum of (early and late) apoptotic cells and necrotic cells vs. vehicle control (DMSO) from three independent measurements, using one-way ANOVA test (nonsignificant or ns, *** <span class="html-italic">p</span> < 0.0005 and **** <span class="html-italic">p</span> < 0.0001).</p> "> Scheme 1
<p>Synthesis of DHA–HDACi hybrids: (<b>a</b>) NaBH<sub>4</sub> (2.5 equiv.), MeOH, 0 °C → r.t., 0.5 h, 98%. (<b>b</b>) Ac<sub>2</sub>O, pyridine, r.t., 20 h, 92% (<b>c</b>) HX-linker-COOH (1.2 equiv.), BF<sub>3</sub> OEt<sub>2</sub> (1.05 equiv.), DCM, −15 °C, 0.5 h, 55–75%. (<b>d</b>) NH<sub>2</sub>-O-THP (1.0 equiv.), EDC.HCl (1.0 equiv.), DMAP (0.5 equiv.), DCM, r.t., 6 h. (<b>e</b>) benzoylchloride (cat.), EtOH, 0 °C, 3 h, 17–35% (over 2 steps). (<b>f</b>) o-phenylenediamine (1.0 equiv.), EDC.HCl (1.05 equiv.), DMAP (0.5 equiv.), DCM, r.t., 6 h, 24%.</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. Design and Synthesis of Dihydroartemisinin–HDACi Hybrids
2.2. HDAC Inhibitory Activities and Selectivity Profiles
2.3. Docking of (α)-7c and (β)-7c
2.4. Antiplasmodial Properties and Parasite Selectivity
2.5. Ring-Stage Survival Assay
2.6. Antileukemia Properties
3. Materials and Methods
3.1. Chemistry
3.2. General Method for the Synthesis of DHA-Coupled Carboxylic Acids 6a–e
3.2.1. (E)-3-(4-((((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)phenyl)acrylic acid (6a)
3.2.2. 6-(((3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)hexanoic acid (6b)
3.2.3. 4-((((3R,5aS,6R,8aS,9R,10R,12S,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)methyl)benzoic acid (6c)
3.2.4. 4-((((3R,5aS,6R,8aS,12R,12aR)-3,6,9-Trimethyldecahydro-12H-3,12-methano[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)benzoic acid (6d)
3.3. General Method for the Synthesis of the Hydroxamic Acids 7a–e
3.3.1. (E)-N-Hydroxy-3-(4-((((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)phenyl)acrylamide (7a)
3.3.2. N-Hydroxy-6-(((3R,5aS,6R,8aS,9R,12S,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)hexanamide (7b)
3.3.3. N-Hydroxy-4-((((3R,5aS,6R,8aS,9R,10R,12S,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)methyl)benzamide ((α)-7c)
3.3.4. N-Hydroxy-4-((((3R,5aS,6R,8aS,9R,10S,12S,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)methyl)benzamide ((β)-7c)
3.3.5. N-Hydroxy-4-((((3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)benzamide (7d)
3.3.6. N-Hydroxy-2-(4-(((3R,5aS,6R,8aS,9R,10R,12S,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)phenyl)acetamide ((α)-7e)
3.3.7. N-Hydroxy-2-(4-(((3R,5aS,6R,8aS,9R,10S,12S,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)thio)phenyl)acetamide ((β)-7e)
3.4. (E)-N-(2-Aminophenyl)-3-(4-((((3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)phenyl)acrylamide (8)
3.5. Biological Evaluation
3.5.1. In Vitro Human HDAC1 and 6 Assay
3.5.2. MTT Cell Viability Assay
3.5.3. Cell Culture (Leukemia Cell Lines and Fibroblasts)
3.5.4. CellTiter-Glo Based Cell Viability Assay
3.5.5. Annexin V-PI Staining
3.5.6. Immunoblotting
3.5.7. In Vitro P. falciparum Growth Inhibition Assay
3.5.8. Ring-Stage Survival Assay (0–3 h)
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- World Health Organization. World Malaria Report 2020—20 Years of Global Progress & Challenges; WHO: Geneva, Switzerland, 2020; pp. 14–15. [Google Scholar]
- Ariey, F.; Witkowski, B.; Amaratunga, C.; Beghain, J.; Langlois, A.-C.; Khim, N.; Kim, S.; Duru, V.; Bouchier, C.; Ma, L.; et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 2014, 505, 50–55. [Google Scholar] [CrossRef] [PubMed]
- Dondorp, A.M.; Nosten, F.; Yi, P.; Das, D.; Phyo, A.P.; Tarning, J.; Lwin, K.M.; Ariey, F.; Hanpithakpong, W.; Lee, S.J.; et al. Artemisinin Resistance in Plasmodium falciparum Malaria. N. Engl. J. Med. 2009, 361, 455–467. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burrows, J.N.; Duparc, S.; Gutteridge, W.E.; van Huijsduijnen, R.H.; Kaszubska, W.; Macintyre, F.; Mazzuri, S.; Möhrle, J.J.; Wells, T.N.C. New developments in anti-malarial target candidate and product profiles. Malar. J. 2017, 16, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Andrews, K.T.; Haque, A.; Jones, M.K. HDAC inhibitors in parasitic diseases. Immunol. Cell Biol. 2012, 90, 66–77. [Google Scholar] [CrossRef] [PubMed]
- Falkenberg, K.J.; Johnstone, R.W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 2014, 13, 673–691. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Seto, E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb. Perspect. Med. 2016, 6, a026831. [Google Scholar] [CrossRef] [Green Version]
- Duffy, M.F.; Selvarajah, S.A.; Josling, G.A.; Petter, M. Epigenetic regulation of the Plasmodium falciparum genome. Brief. Funct. Genom. 2014, 13, 203–216. [Google Scholar] [CrossRef] [Green Version]
- Volz, J.C.; Bártfai, R.; Petter, M.; Langer, C.; Josling, G.A.; Tsuboi, T.; Schwach, F.; Baum, J.; Rayner, J.C.; Stunnenberg, H.G.; et al. PfSET10, a Plasmodium falciparum methyltransferase, maintains the active var gene in a poised state during parasite division. Cell Host Microbe 2012, 11, 7–18. [Google Scholar] [CrossRef] [Green Version]
- Coleman, B.I.; Skillman, K.M.; Jiang, R.H.Y.; Childs, L.M.; Altenhofen, L.M.; Ganter, M.; Leung, Y.; Goldowitz, I.; Kafsack, B.F.C.; Marti, M.; et al. A Plasmodium falciparum histone deacetylase regulates antigenic variation and gametocyte conversion. Cell Host Microbe 2014, 16, 177–186. [Google Scholar] [CrossRef] [Green Version]
- Avelar, L.A.A.; Held, J.; Engel, J.A.; Sureechatchaiyan, P.; Hansen, F.K.; Hamacher, A.; Kassack, M.U.; Mordmüller, B.; Andrews, K.T.; Kurz, T. Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit. Arch. Pharm. 2017, 350, 1600347. [Google Scholar] [CrossRef]
- Chua, M.J.; Arnold, M.S.J.; Xu, W.; Lancelot, J.; Lamotte, S.; Späth, G.F.; Prina, E.; Pierce, R.J.; Fairlie, D.P.; Skinner-Adams, T.S.; et al. Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth. Int. J. Parasitol. Drugs Drug Resist. 2017, 7, 42–50. [Google Scholar] [CrossRef] [PubMed]
- De Vreese, R.; De Kock, C.; Smith, P.J.; Chibale, K.; D’Hooghe, M. Exploration of thiaheterocyclic hHDAC6 inhibitors as potential antiplasmodial agents. Future Med. Chem. 2017, 9, 357–364. [Google Scholar] [CrossRef] [PubMed]
- Diedrich, D.; Stenzel, K.; Hesping, E.; Antonova-Koch, Y.; Gebru, T.; Duffy, S.; Fisher, G.; Schöler, A.; Meister, S.; Kurz, T.; et al. One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. Eur. J. Med. Chem. 2018, 158, 801–813. [Google Scholar] [CrossRef] [PubMed]
- Mackwitz, M.K.W.; Hesping, E.; Antonova-Koch, Y.; Diedrich, D.; Woldearegai, T.G.; Skinner-Adams, T.; Clarke, M.; Schöler, A.; Limbach, L.; Kurz, T.; et al. Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity. ChemMedChem 2019, 14, 912–926. [Google Scholar] [CrossRef]
- Mackwitz, M.K.W.; Hesping, E.; Eribez, K.; Schöler, A.; Antonova-Koch, Y.; Held, J.; Winzeler, E.A.; Andrews, K.T.; Hansen, F.K. Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. Eur. J. Med. Chem. 2021, 211, 113065. [Google Scholar] [CrossRef]
- Rosini, M. Polypharmacology: The rise of multitarget drugs over combination therapies. Future Med. Chem. 2014, 6, 485–487. [Google Scholar] [CrossRef]
- Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: Challenges and opportunities in drug discovery. J. Med. Chem. 2014, 57, 7874–7887. [Google Scholar] [CrossRef] [PubMed]
- Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 2005, 48, 6523–6543. [Google Scholar] [CrossRef]
- Proschak, E.; Stark, H.; Merk, D. Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds. J. Med. Chem. 2019, 62, 420–444. [Google Scholar] [CrossRef]
- Zhang, Z.; Hou, S.; Chen, H.; Ran, T.; Jiang, F.; Bian, Y.; Zhang, D.; Zhi, Y.; Wang, L.; Zhang, L.; et al. Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 2931–2935. [Google Scholar] [CrossRef]
- Botta, L.; Filippi, S.; Bizzarri, B.M.; Zippilli, C.; Meschini, R.; Pogni, R.; Baratto, M.C.; Villanova, L.; Saladino, R. Synthesis and Evaluation of Artemisinin-Based Hybrid and Dimer Derivatives as Antimelanoma Agents. ACS Omega 2020, 5, 243–251. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Çapcı, A.; Lorion, M.M.; Wang, H.; Simon, N.; Leidenberger, M.; Silva, M.C.B.; Moreira, D.R.M.; Zhu, Y.; Meng, Y.; Chen, J.Y.; et al. Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug-Resistant Malaria. Angew. Chem. 2019, 131, 13200–13213. [Google Scholar] [CrossRef] [Green Version]
- Ha, V.T.; Kien, V.T.; Le Binh, H.; Tien, V.D.; My, N.T.T.; Nam, N.H.; Baltas, M.; Hahn, H.; Han, B.W.; Thao, D.T.; et al. Design, synthesis and biological evaluation of novel hydroxamic acids bearing artemisinin skeleton. Bioorg. Chem. 2016, 66, 63–71. [Google Scholar] [CrossRef] [PubMed]
- Maolanon, A.R.; Kristensen, H.M.E.; Leman, L.J.; Ghadiri, M.R.; Olsen, C.A. Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes. Chembiochem 2017, 18, 5–49. [Google Scholar] [CrossRef]
- Zhang, L.; Zhang, J.; Jiang, Q.; Zhang, L.; Song, W. Zinc binding groups for histone deacetylase inhibitors. J. Enzym. Inhib. Med. Chem. 2018, 33, 714–721. [Google Scholar] [CrossRef]
- Gour, R.; Ahmad, F.; Prajapati, S.K.; Giri, S.K.; Karna, S.K.L.; Kartha, K.P.R.; Pokharel, Y.R. Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity. Eur. J. Med. Chem. 2019, 178, 552–570. [Google Scholar] [CrossRef]
- Ontoria, J.M.; Paonessa, G.; Ponzi, S.; Ferrigno, F.; Nizi, E.; Biancofiore, I.; Malancona, S.; Graziani, R.; Roberts, D.; Willis, P.; et al. Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs. ACS Med. Chem. Lett. 2016, 7, 454–459. [Google Scholar] [CrossRef]
- Hai, Y.; Christianson, D.W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 2016, 12, 741–747. [Google Scholar] [CrossRef] [Green Version]
- World Health Organization. Status Report on Artemesinin and ACT Resistance; WHO: Geneva, Switzerland, 2015. [Google Scholar]
- Ashley, E.A.; Dhorda, M.; Fairhurst, R.M.; Amaratunga, C.; Lim, P.; Suon, S.; Sreng, S.; Anderson, J.M.; Mao, S.; Sam, B.; et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 2014, 371, 411–423. [Google Scholar] [CrossRef] [Green Version]
- Suresh, N.; Haldar, K. Mechanisms of artemisinin resistance in Plasmodium falciparum malaria. Curr. Opin. Pharmacol. 2018, 42, 46–54. [Google Scholar] [CrossRef]
- Lam, N.S.; Long, X.; Wong, J.W.; Griffin, R.C.; Doery, J.C.G. Artemisinin and its derivatives: A potential treatment for leukemia. Anticancer Drugs 2019, 30, 1–18. [Google Scholar] [CrossRef] [PubMed]
- Presser, A.; Feichtinger, A.; Buzzi, S. A simplified and scalable synthesis of artesunate. Mon. Chem. 2017, 148, 63–68. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Erdeljac, N.; Bussmann, K.; Schöler, A.; Hansen, F.K.; Gilmour, R. Fluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE. ACS Med. Chem. Lett. 2019, 10, 1336–1340. [Google Scholar] [CrossRef] [PubMed]
- Selg, C.; Schöler, A.; Schliehe-Diecks, J.; Hanl, M.; Sinatra, L.; Borkhardt, A.; Sárosi, M.B.; Bhatia, S.; Hey-Hawkins, E.; Hansen, F.K. Borinostats: Solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile. Chem. Sci. 2021, 12, 11873–11881. [Google Scholar] [CrossRef] [PubMed]
- Straimer, J.; Gnädig, N.F.; Witkowski, B.; Amaratunga, C.; Duru, V.; Ramadani, A.P.; Dacheux, M.; Khim, N.; Zhang, L.; Lam, S.; et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 2015, 347, 428–431. [Google Scholar] [CrossRef] [Green Version]
- Noedl, H.; Bronnert, J.; Yingyuen, K.; Attlmayr, B.; Kollaritsch, H.; Fukuda, M. Simple histidine-rich protein 2 double-site sandwich enzyme-linked immunosorbent assay for use in malaria drug sensitivity testing. Antimicrob. Agents Chemother. 2005, 49, 3575–3577. [Google Scholar] [CrossRef] [Green Version]
- De Carvalho, L.P.; Sandri, T.L.; de Melo, E.J.T.; Fendel, R.; Kremsner, P.G.; Mordmüller, B.; Held, J. Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparum In Vitro. Antimicrob. Agents Chemother. 2019, 63, e00085-19. [Google Scholar] [CrossRef] [Green Version]
- Ritz, C.; Baty, F.; Streibig, J.C.; Gerhard, D. Dose-Response Analysis Using R. PLoS ONE 2015, 10, e0146021. [Google Scholar] [CrossRef] [Green Version]
- R Core Team. A Language and Environment for Statistical Computing; Foundation for Statistical Computing: Vienna, Austria, 2021. [Google Scholar]
- Witkowski, B.; Amaratunga, C.; Khim, N.; Sreng, S.; Chim, P.; Kim, S.; Lim, P.; Mao, S.; Sopha, C.; Sam, B.; et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: In-vitro and ex-vivo drug-response studies. Lancet Infect. Dis. 2013, 13, 1043–1049. [Google Scholar] [CrossRef] [Green Version]
- Witkowski, B.; Menard, D.; Amaratunga, C.; Fairhurst, R.M. Ring-Stage Survival Assays (RSA) to Evaluate the In-Vitro and Ex-Vivo Susceptibility of Plasmodium falciparum to Artemisinins; Procedure RSAv1; Institut Pasteur du Cambodge—National Institutes of Health: Phnom Penh, Cambodia, 2015; Available online: https://www.wwarn.org/sites/default/files/INV10-Standard-Operating-Procedure-Ring-Stage-Survival-Assays.pdf (accessed on 16 February 2022).
Compound | X | Linker | hHDAC1 IC50 [µM] b | hHDAC6 IC50 [µM] b | SI1/6 |
---|---|---|---|---|---|
6a | O | 1 | >10 c | >10 c | / |
7a | O | 1 | 0.546 ± 0.0003 | 0.187 ± 0.004 | 3 |
7b | S | 2 | 0.430 ± 0.046 | 0.045 ± 0.005 | 10 |
(α)-7c | S | 3 | 2.00 ± 0.200 | 0.036 ± 0.008 | 56 |
(β)-7c | S | 3 | 2.79 ± 0.14 | 0.041 ± 0.009 | 68 |
7d | O | 3 | 2.49 ± 0.240 | 0.014 ± 0.002 | 178 |
(α)-7e | S | 4 | >10 c | 1.101 ± 0.075 | >9 |
(β)-7e | S | 4 | >10 c | 1.002 ± 0.130 | >10 |
8 | O | 1 | 41% @3.33 µM d | >10 c | / |
DHA | - | - | >10 c | >10 c | / |
Vorinostat | - | - | 0.107 ± 0.013 | 0.032 ± 0.008 | 3 |
Compound | X | Linker | Pf3D7 IC50 [nM] b | PfDd2 IC50 [nM] b | PfDd2 R539T IC50 [nM] b | A2780 IC50 [µM] c | SIA2780/Pf 3D7 | SIA2780/Pf Dd2 |
---|---|---|---|---|---|---|---|---|
6a | O | 1 | 5.9 ± 0.70 | 5.8 ± 2.8 | n.d. | 3.38 ± 0.21 | 573 | 583 |
7a | O | 1 | 2.6 ± 1.4 | 1.7 ± 0.92 | 1.9 ± 1.4 | 1.95 ± 0.52 | 750 | 1147 |
7b | S | 2 | 5.2 ± 0.4 | 6.6 ± 2.5 | 3.0 ± 1.2 | 1.52 ± 0.05 | 292 | 230 |
(α)-7c | S | 3 | 3.3 ± 1.4 | 3.4 ± 0.12 | 3.3 ± 2.2 | 1.10 ± 0.25 | 333 | 324 |
(β)-7c | S | 3 | 3.6 ± 1.1 | 3.2 ± 0.02 | 2.6 ± 2.0 | 0.88 ± 0.13 | 244 | 275 |
7d | O | 3 | 2.8 ± 1.3 | 2.0 ± 0.7 | 1.2 ± 0.8 | 1.31 ± 0.32 | 468 | 655 |
(α)-7e | S | 4 | 3.1 ± 0.7 | 1.8 ± 0.8 | n.d. | 1.83 ± 0.10 | 590 | 1017 |
(β)-7e | S | 4 | 2.6 ± 1.3 | 1.6 ± 0.8 | n.d. | 2.09 ± 0.42 | 804 | 1306 |
8 | O | 1 | 2.5 ± 1.4 | 2.5 ± 0.14 | n.d. | 1.47 ± 0.98 | 588 | 588 |
DHA | - | - | 3.0 ± 2.7 | 1.8 ± 0.02 | n.d. | 0.97 ± 0.07 | 323 | 539 |
Vorinostat | - | - | 241.8 ± 33.4 | 424.9 ± 1.3 | n.d. | 1.09 ± 0.41 | 5 | 3 |
Compound | X | Linker | K562 b IC50 [µM] | HL60 c IC50 [µM] | NALM6 d IC50 [µM] | HPBALL e IC50 [µM] | MOLM13 c IC50 [µM] |
---|---|---|---|---|---|---|---|
6a | O | 1 | 4.01 ± 0.60 | 2.53 ± 0.56 | 1.31 ± 0.11 | 23.86 ± 4.69 | 0.68 ± 0.09 |
7a | O | 1 | 0.31 ± 0.06 | 1.33 ± 0.14 | 0.15 ± 0.01 | 1.36 ± 0.03 | 0.22 ± 0.04 |
7b | S | 2 | 0.91 ± 0.32 | 2.07 ± 0.03 | 0.26 ± 0.01 | 2.41 ± 0.38 | 0.58 ± 0.19 |
(α)-7c | S | 3 | 0.62 ± 0.06 | 1.02 ± 0.27 | 0.28 ± 0.05 | 6.72 ± 0.44 | 0.33 ± 0.11 |
(β)-7c | S | 3 | 0.41 ± 0.11 | 2.34 ± 0.46 | 0.25 ± 0.01 | 12.33 ± 0.57 | 0.38 ± 0.07 |
7d | O | 3 | 1.00 ± 0.36 | 2.41 ± 0.45 | 0.36 ± 0.05 | 6.81 ± 0.54 | 0.39 ± 0.05 |
(α)-7e | S | 4 | 0.77 ± 0.24 | 1.62 ± 0.12 | 0.44 ± 0.01 | 3.34 ± 0.37 | 0.45 ± 0.18 |
(β)-7e | S | 4 | 1.71 ± 0.33 | 2,76 ± 0.62 | 0.77 ± 0.08 | 20.57 ± 6.13 | 0.64 ± 0.17 |
8 | O | 1 | 0.69 ± 0.11 | 1.64 ± 0.17 | 0.34 ± 0.03 | 1.69 ± 0.19 | 0.49 ± 0.08 |
DHA | - | - | 2.40 ± 0.66 | 3.57 ± 1.04 | 2.50 ± 0.16 | 9.93 ± 1.51 | 0.69 ± 0.17 |
Vorinostat | - | - | 0.28 ± 0.15 | 0.22 ± 0.05 | 0.63 ± 0.06 | 0.59 ± 0.05 | 0.20 ± 0.07 |
Compound | Healthy Fibroblast 1 | Healthy Fibroblast 2 |
---|---|---|
IC50 [µM] | IC50 [µM] | |
7a | 13.10 ± 0.10 | 6.34 ± 0.79 |
(α)-7c | 12.69 ± 0.12 | 7.41 ± 1.40 |
(β)-7c | 14.67 ± 3.42 | 17.75 ± 6.04 |
DHA | >25 | >25 |
Vorinostat | 4.55 ± 0.80 | 3.23 ± 0.66 |
Method A | Method B | Method C | Method D | Method E | |||||
---|---|---|---|---|---|---|---|---|---|
tR [min] | A [%] | tR [min] | A [%] | tR [min] | A [%] | tR [min] | A [%] | tR [min] | A [%] |
0 | 5 | 0 | 5 | 0 | 5 | 0 | 5 | 0 | 5 |
5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
15 | 60 | 20 | 95 | 12 | 95 | 17 | 50 | 17 | 50 |
35 | 60 | 25 | 95 | 22 | 95 | 37 | 50 | 45 | 50 |
37 | 5 | 26 | 5 | 23 | 5 | 39 | 5 | 47 | 5 |
42 | 5 | 31 | 5 | 28 | 5 | 44 | 5 | 52 | 5 |
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von Bredow, L.; Schäfer, T.M.; Hogenkamp, J.; Tretbar, M.; Stopper, D.; Kraft, F.B.; Schliehe-Diecks, J.; Schöler, A.; Borkhardt, A.; Bhatia, S.; et al. Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs. Pharmaceuticals 2022, 15, 333. https://doi.org/10.3390/ph15030333
von Bredow L, Schäfer TM, Hogenkamp J, Tretbar M, Stopper D, Kraft FB, Schliehe-Diecks J, Schöler A, Borkhardt A, Bhatia S, et al. Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs. Pharmaceuticals. 2022; 15(3):333. https://doi.org/10.3390/ph15030333
Chicago/Turabian Stylevon Bredow, Lukas, Thomas Martin Schäfer, Julian Hogenkamp, Maik Tretbar, Daniel Stopper, Fabian B. Kraft, Julian Schliehe-Diecks, Andrea Schöler, Arndt Borkhardt, Sanil Bhatia, and et al. 2022. "Synthesis, Antiplasmodial, and Antileukemia Activity of Dihydroartemisinin–HDAC Inhibitor Hybrids as Multitarget Drugs" Pharmaceuticals 15, no. 3: 333. https://doi.org/10.3390/ph15030333