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Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors

Published: 01 June 2019 Publication History

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Highlights

Novel indole-2-carbohydrazides (5,6) and indole-2-carboxamides (7,8) were synthesized.
5a and 6b showed antiproliferative properties at nanomolar concentration.
6 g and 6f showed high potential as tubulin polymerization inhibitors.
Binding modes of 6 g and 6f were identified via molecular docking simulations.
Synthesized compounds may serve as scaffolds for novel anticancer chemotherapeutics.

Abstract

A new series of N’-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 μM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.

References

[1]
S.S. Abd El-Karim, M.M. Anwar, N.A. Mohamed, T. Nasr, S.A. Elseginy, Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran–pyrazole derivatives as anticancer agents, Bioorg. Chem. 63 (2015) 1–12,.
[2]
M. Akkurt, İ. Çelik, F.K. Gürbüzel, S. Özkırımlı, O. Büyükgüngör, 5-Chloro-N-{4-oxo-2-[4-(trifluoro­meth­yl)phen­yl]-1,3-thia­zolidin-3-yl}-3-phenyl-1H-indole-2-carboxamide, Acta Crystallogr. Sect. E Struct. Reports 68 (2012) o2969–o2970,. Online.
[3]
G. Bacher, B. Nickel, P. Emig, U. Vanhoefer, S. Seeber, A. Shandra, T. Klenner, T. Beckers, D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity, Cancer Res. 61 (2001) 392–399.
[4]
T.W.H. Backman, Y. Cao, T. Girke, ChemMine tools: an online service for analyzing and clustering small molecules, Nucleic Acids Res. 39 (2011) W486–W491,.
[5]
R.Z. Batran, A.F. Kassem, E.M.H. Abbas, S.A. Elseginy, M.M. Mounier, Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells, Bioorg. Med. Chem. 26 (2018) 3474–3490,.
[6]
S.N. Baytas, N. Inceler, A. Yılmaz, A. Olgac, S. Menevse, E. Banoglu, E. Hamel, R. Bortolozzi, G. Viola, Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors, Bioorg. Med. Chem. 22 (2014) 3096–3104,.
[7]
H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne, The protein data bank, Nucleic Acids Res. 28 (2000) 235–242.
[8]
S. Bommagani, J. Ponder, N.R. Penthala, V. Janganati, C.T. Jordan, M.J. Borrelli, P.A. Crooks, Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells, Eur. J. Med. Chem. 136 (2017) 393–405,.
[9]
G. Borisy, R. Heald, J. Howard, C. Janke, A. Musacchio, E. Nogales, Microtubules: 50 years on from the discovery of tubulin, Nat. Rev. Mol. Cell Biol. 17 (2016) 322–328,.
[10]
M.R. Boyd, K.D. Paull, Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen, Drug Dev. Res. 34 (1995) 91–109,.
[11]
Cai, S.X., Drewe, J.A., Zhang, H.-Z., 2004. Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof. US 6747052B2. (Cytovia Inc).
[12]
G. Cihan-Üstündağ, D. Şatana, G. Özhan, G. Çapan, Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents, J. Enzyme Inhib. Med. Chem. 31 (2016) 369–380,.
[13]
D. Das Mukherjee, N.M. Kumar, M.P. Tantak, A. Das, A. Ganguli, S. Datta, D. Kumar, G. Chakrabarti, Development of novel bis(indolyl)-hydrazide–hydrazone derivatives as potent microtubule-targeting cytotoxic agents against A549 lung cancer cells, Biochemistry 55 (2016) 3020–3035,.
[14]
J.F. de Oliveira, T.S. Lima, D.B. Vendramini-Costa, S.C.B. de Lacerda Pedrosa, E.A. Lafayette, R.M.F. da Silva, S.M.V. de Almeida, R.O. de Moura, A.L.T.G. Ruiz, J.E. de Carvalho, M. de Lima, C.A. do, Thiosemicarbazones and 4-thiazolidinones indole-based derivatives: synthesis, evaluation of antiproliferative activity, cell death mechanisms and topoisomerase inhibition assay, Eur. J. Med. Chem. 136 (2017) 305–314,.
[15]
O. Demir-Ordu, H. Demir-Dundar, S. Ozkirimli, Stereochemical investigations of diastereomeric N-[2-(aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamides by nuclear magnetic resonance spectroscopy (1D and 2D), Int. J. Spectrosc. 2015 (2015),.
[16]
E. Di Cesare, A. Verrico, A. Miele, M. Giubettini, P. Rovella, A. Coluccia, V. Famiglini, G. La Regina, E. Cundari, R. Silvestri, P. Lavia, Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules, Oncotarget 8 (2017) 19738–19759,.
[17]
M. Dong, F. Liu, H. Zhou, S. Zhai, B. Yan, Novel natural product- and privileged scaffold-based tubulin inhibitors targeting the colchicine binding site, Molecules 21 (2016) 1375,.
[18]
C. Dumontet, M.A. Jordan, Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat. Rev. Drug Discov. 9 (2010) 790–803,.
[19]
S.S. El-Nakkady, M.M. Hanna, H.M. Roaiah, I.A.Y. Ghannam, Synthesis, molecular docking study and antitumor activity of novel 2-phenylindole derivatives, Eur. J. Med. Chem. 47 (2012) 387–398,.
[20]
Epik, Epik Version 3.4, Schrödinger, LLC, New York, NY, 2015.
[21]
A. Farce, C. Loge, S. Gallet, N. Lebegue, P. Carato, P. Chavatte, P. Berthelot, D. Lesieur, Docking study of ligands into the colchicine binding site of tubulin, J. Enzyme Inhib. Med. Chem. 19 (2004) 541–547,.
[22]
R. Farid, T. Day, R.A. Friesner, R.A. Pearlstein, New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies, Bioorg. Med. Chem. 14 (2006) 3160–3173,.
[23]
T. Fojo, M. Menefee, Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents, Ann. Oncol. 18 (2007) v3–v8,.
[24]
R.A. Friesner, J.L. Banks, R.B. Murphy, T.A. Halgren, J.J. Klicic, D.T. Mainz, M.P. Repasky, E.H. Knoll, M. Shelley, J.K. Perry, D.E. Shaw, P. Francis, P.S. Shenkin, Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J. Med. Chem. 47 (2004) 1739–1749,.
[25]
R.A. Friesner, R.B. Murphy, M.P. Repasky, L.L. Frye, J.R. Greenwood, T.A. Halgren, P.C. Sanschagrin, D.T. Mainz, Extra precision Glide: docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes, J. Med. Chem. 49 (2006) 6177–6196,.
[26]
R. Gaspari, A.E. Prota, K. Bargsten, A. Cavalli, M.O. Steinmetz, Structural basis of cis- and trans-combretastatin binding to tubulin, Chem 2 (2017) 102–113,.
[27]
B. Gigant, C. Wang, R.B.G. Ravelli, F. Roussi, M.O. Steinmetz, P.A. Curmi, A. Sobel, M. Knossow, Structural basis for the regulation of tubulin by vinblastine, Nature 435 (2005) 519–522,.
[28]
Glide, Glide Version 6.9, Schrödinger, LLC, New York, NY, 2015.
[29]
F. Göktaş, E. Vanderlinden, L. Naesens, N. Cesur, Z. Cesur, Microwave assisted synthesis and anti-influenza virus activity of 1-adamantyl substituted N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives, Bioorg. Med. Chem. 20 (2012) 7155–7159,.
[30]
J.R. Greenwood, D. Calkins, A.P. Sullivan, J.C. Shelley, Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution, J. Comput. Aided Mol. Des. 24 (2010) 591–604,.
[31]
T.A. Halgren, R.B. Murphy, R.A. Friesner, H.S. Beard, L.L. Frye, W.T. Pollard, J.L. Banks, Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening, J. Med. Chem. 47 (2004) 1750–1759,.
[32]
E. Hamel, Evaluation of antimitotic agents by quantitative comparisons of their effects on the polymerization of purified tubulin, Cell Biochem. Biophys. 38 (2003) 1–21,.
[33]
S.P. Hiremath, B.H.M. Mruthyunjayaswamy, M.G. Purohit, Synthesis of substituted 2-aminoindolees and 2-(2’-phenyl-1’, 3’,4’-oxidiazolyl)aminoindoles, Indian J. Chem. 16B (1978) 789–792.
[34]
S.L. Holbeck, J.M. Collins, J.H. Doroshow, Analysis of FDA-approved anti-cancer agents in the NCI60 panel of human tumor cell lines, Mol. Cancer Ther. 9 (2010) 1451–1460,.
[35]
W. Humphrey, A. Dalke, K. Schulten, VMD molecular dynamics, J. Mol. Graph. 14 (1996) 33–38.
[36]
Impact version, Impact Version 5.9, Schrödinger, LLC, New York, NY, 2015.
[37]
M.P. Jacobson, R.A. Friesner, Z. Xiang, B. Honig, On the role of the crystal environment in determining protein side-chain conformations, J. Mol. Biol. 320 (2002) 597–608,.
[38]
M.P. Jacobson, D.L. Pincus, C.S. Rapp, T.J.F. Day, B. Honig, D.E. Shaw, R.A. Friesner, A hierarchical approach to all-atom protein loop prediction, Proteins 55 (2004) 351–367,.
[39]
H.I. Januar, A.S. Dewi, E. Marraskuranto, T. Wikanta, In silico study of fucoxanthin as a tumor cytotoxic agent, J. Pharm. Bioallied Sci. 4 (2012) 56–59,.
[40]
M.M. Kamel, H.I. Ali, M.M. Anwar, N.A. Mohamed, A.M. Soliman, Synthesis, antitumor activity and molecular docking study of novel sulfonamide-Schiff’s bases, thiazolidinones, benzothiazinones and their C-nucleoside derivatives, Eur. J. Med. Chem. 45 (2010) 572–580,.
[41]
R. Kaur, G. Kaur, R.K. Gill, R. Soni, J. Bariwal, Recent developments in tubulin polymerization inhibitors: an overview, Eur. J. Med. Chem. 87 (2014) 89–124,.
[42]
G. La Regina, M.C. Edler, A. Brancale, S. Kandil, A. Coluccia, F. Piscitelli, E. Hamel, G. De Martino, R. Matesanz, J.F. Díaz, A.I. Scovassi, E. Prosperi, A. Lavecchia, E. Novellino, M. Artico, R. Silvestri, Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure−activity relationships and molecular modeling studies, J. Med. Chem. 50 (2007) 2865–2874,.
[43]
G. La Regina, T. Sarkar, R. Bai, M.C. Edler, R. Saletti, A. Coluccia, F. Piscitelli, L. Minelli, V. Gatti, C. Mazzoccoli, V. Palermo, C. Mazzoni, C. Falcone, A.I. Scovassi, V. Giansanti, P. Campiglia, A. Porta, B. Maresca, E. Hamel, A. Brancale, E. Novellino, R. Silvestri, New arylthioindoles and related bioisosteres at the sulfur bridging group. 4. Synthesis, tubulin polymerization, cell growth inhibition, and molecular modeling studies, J. Med. Chem. 52 (2009) 7512–7527,.
[44]
G. La Regina, R. Bai, A. Coluccia, V. Naccarato, V. Famiglini, M. Nalli, D. Masci, A. Verrico, P. Rovella, C. Mazzoccoli, E. Da Pozzo, C. Cavallini, C. Martini, S. Vultaggio, G. Dondio, M. Varasi, C. Mercurio, E. Hamel, P. Lavia, R. Silvestri, New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors, Eur. J. Med. Chem. 152 (2018) 283–297,.
[45]
LigPrep, LigPrep Version 3.6, Schrödinger, LLC, New York, NY, 2015.
[46]
J. Löwe, H. Li, K.H. Downing, E. Nogales, Refined structure of αβ-tubulin at 3.5 Å resolution, J. Mol. Biol. 313 (2001) 1045–1057,.
[47]
Y. Lu, J. Chen, M. Xiao, W. Li, D.D. Miller, An overview of tubulin inhibitors that interact with the colchicine binding site, Pharm. Res. 29 (2012) 2943–2971,.
[48]
G. Madhavi Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman, Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments, J. Comput. Aided Mol. Des. 27 (2013) 221–234,.
[49]
Maestro, Maestro Version 10.4, Schrödinger, LLC, New York, NY, 2015.
[50]
K.A. Mills, S.T. Roach, J.M. Quinn, L. Guo, H.M. Beck, E. Lomonosova, A.R. Ilivicky, C.M. Starks, J.A. Lawrence, A.R. Hagemann, C. McCourt, P.H. Thaker, M.A. Powell, D.G. Mutch, K.C. Fuh, SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth, Gynecol. Oncol. (2018),.
[51]
M.S. Morales-Ríos, J. Espiñeira, P. Joseph-Nathan, 13C NMR spectroscopy of indole derivatives, Magn. Reson. Chem. 25 (1987) 377–395,.
[52]
E. Mukhtar, V.M. Adhami, H. Mukhtar, Targeting microtubules by natural agents for cancer therapy, Mol. Cancer Ther. 13 (2014) 275–284,.
[53]
NCI, NCI-60 Screening Methodology, 2015, (accessed 20 October 2018) https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm.
[54]
T.L. Nguyen, C. McGrath, A.R. Hermone, J.C. Burnett, D.W. Zaharevitz, B.W. Day, P. Wipf, E. Hamel, R. Gussio, A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach, J. Med. Chem. 48 (2005) 6107–6116,.
[55]
M. Niu, J. Qin, C. Tian, X. Yan, F. Dong, Z. Cheng, G. Fida, M. Yang, H. Chen, Y. Gu, Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking, Acta Pharmacol. Sin. 35 (2014) 967–979,.
[56]
E. Nogales, M. Whittaker, R.A. Milligan, K.H. Downing, High-resolution model of the microtubule, Cell 96 (1999) 79–88,.
[57]
M.H.M. Olsson, C.R. Søndergaard, M. Rostkowski, J.H. Jensen, PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions, J. Chem. Theory Comput. 7 (2011) 525–537,.
[58]
S. Oudard, B. Beuselinck, J. Decoene, P. Albers, Sunitinib for the treatment of metastatic renal cell carcinoma, Cancer Treat. Rev. 37 (2011) 178–184,.
[59]
S. Ozkirimli, F. Kazan, Y. Tunali, Synthesis, antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones, J. Enzyme Inhib. Med. Chem. 24 (2009) 447–452,.
[60]
E. Pasquier, M. Kavallaris, Microtubules: a dynamic target in cancer therapy, IUBMB Life 60 (2008) 165–170,.
[61]
Prime, Prime Version 3.2, Schrödinger, LLC, New York, NY, 2015.
[62]
Prime, Prime Version 4.2, Schrödinger, LLC, New York, NY, 2015.
[63]
A.E. Prota, K. Bargsten, D. Zurwerra, J.J. Field, J.F. Díaz, K.-H. Altmann, M.O. Steinmetz, Molecular mechanism of action of microtubule-stabilizing anticancer agents, Science 339 (2013) 587–590,.
[64]
A.E. Prota, F. Danel, F. Bachmann, K. Bargsten, R.M. Buey, J. Pohlmann, S. Reinelt, H. Lane, M.O. Steinmetz, The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization, J. Mol. Biol. 426 (2014) 1848–1860,.
[65]
R.B.G. Ravelli, B. Gigant, P.A. Curmi, I. Jourdain, S. Lachkar, A. Sobel, M. Knossow, Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain, Nature 428 (2004) 198–202,.
[66]
H.M. Roaiah, I.A.Y. Ghannam, I.H. Ali, A.M. El Kerdawy, M.M. Ali, S.E.-S. Abbas, S.S. El-Nakkady, Design, synthesis, and molecular docking of novel indole scaffold‐based VEGFR‐2 inhibitors as targeted anticancer agents, Arch. Pharm. (Weinheim) 351 (2018),.
[67]
Schrödinger Suite, Schrödinger Suite 2015-4 Induced Fit Docking protocol 2015-4, Glide version 6.4, Prime version 3.7, Schrödinger, LLC, New York, NY, 2015.
[68]
J.C. Shelley, A. Cholleti, L.L. Frye, J.R. Greenwood, M.R. Timlin, M. Uchimaya, Epik: a software program for pKa prediction and protonation state generation for drug-like molecules, J. Comput. Aided Mol. Des. 21 (2007) 681–691,.
[69]
W. Sherman, H.S. Beard, R. Farid, Use of an induced fit receptor structure in virtual screening, Chem. Biol. Drug Des. 67 (2006) 83–84,.
[70]
W. Sherman, T. Day, M.P. Jacobson, R.A. Friesner, R. Farid, Novel procedure for modeling ligand/receptor induced fit effects, J. Med. Chem. 49 (2006) 534–553,.
[71]
G. Shi, Y. Wang, Y. Jin, S. Chi, Q. Shi, M. Ge, S. Wang, X. Zhang, S. Xu, Structural insight into the mechanism of epothilone A bound to beta-tubulin and its mutants at Arg282Gln and Thr274Ile, J. Biomol. Struct. Dyn. 30 (2012) 559–573,.
[72]
R.H. Shoemaker, The NCI60 human tumour cell line anticancer drug screen, Nat. Rev. Cancer 6 (2006) 813–823,.
[73]
K. Sweidan, D.A. Sabbah, S. Bardaweel, K.A. Dush, G.A. Sheikha, M.S. Mubarak, Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors, Bioorg. Med. Chem. Lett. 26 (2016) 2685–2690,.
[74]
P. Verdier-Pinard, J.-Y. Lai, H.-D. Yoo, J. Yu, B. Marquez, D.G. Nagle, M. Nambu, J.D. White, J.R. Falck, W.H. Gerwick, B.W. Day, E. Hamel, Structure-activity analysis of the interaction of curacin A, the potent colchicine site antimitotic agent, with tubulin and effects of analogs on the growth of MCF-7 breast cancer cells, Mol. Pharmacol. 53 (1998) 62–76,.
[75]
S. Vogel, D. Kaufmann, M. Pojarová, C. Müller, T. Pfaller, S. Kühne, P.J. Bednarski, Evon Angerer, Aroyl hydrazones of 2-phenylindole-3-carbaldehydes as novel antimitotic agents, Bioorg. Med. Chem. 16 (2008) 6436–6447,.
[76]
S. Wang, Y. Zhao, G. Zhang, Y. Lv, N. Zhang, P. Gong, Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent, Eur. J. Med. Chem. 46 (2011) 3509–3518,.
[77]
H. Yamamoto, S. Inaba, T. Hirohashi, K. Ishizumi, Benzodiazepine, 2. Notiz über ein neues verfahren zur herstellung von 1.4-benzodiazepin-derivaten aus 2-aminomethyl-indol-derivaten, Chem. Ber. 101 (1968) 4245–4247,.
[78]
H.-Z. Zhang, J. Drewe, B. Tseng, S. Kasibhatla, S.X. Cai, Discovery and SAR of indole-2-carboxylic acid benzylidene-hydrazides as a new series of potent apoptosis inducers using a cell-based HTS assay, Bioorg. Med. Chem. 12 (2004) 3649–3655,.

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          cover image Computational Biology and Chemistry
          Computational Biology and Chemistry  Volume 80, Issue C
          Jun 2019
          524 pages

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          Elsevier Science Publishers B. V.

          Netherlands

          Publication History

          Published: 01 June 2019

          Author Tags

          1. Anticancer activity
          2. Indole-2-carbohydrazides
          3. Thiazolidinyl-indole
          4. Tubulin polymerization
          5. Molecular docking

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