Concise Synthesis of 1,1-Diarylvinyl Sulfones and Investigations on their Antiproliferative Activity via Tubulin Inhibition

Author(s): Lavanya Reddy, Suja T. Dharmabalan*, Kanakaraju Manupati, Ragini Yeeravalli, Lakshmi D. Vijay, Kavitha Donthiboina, Vadithe Lakshma Naik, Amitava Das

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 12 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Discovery of small molecules that inhibit tubulin polymerization is an attractive strategy for the development of new and improved anti-proliferative agents.

Objective: A series of novel 2-sulfonyl-1,1-diarylethenes were designed towards this end keeping in view the favorable chemical and pharmacological virtues of unsaturated sulfones.

Methods: Rapid, convenient and efficient two-step assembly of the designed molecules was achieved by the vicinal iodo-sulfonylation-Suzuki coupling sequence.

Results: As hypothesized, these compounds showed good anti-proliferative activity against different tissuespecific cancer cell lines: MCF-7, DU-145, A-549, HepG2, and HeLa. The most active compound, pnitrophenyl ring-bearing analog, exhibited an IC50 value of 0.90μM against A-549 cells. Flow cytometry studies on this derivative revealed that it arrests the cell cycle of A-549 cells at the G2/M phase. This compound exhibited molecular binding to tubulin as well as tubulin polymerization inhibition comparable to that of colchicine.

Conclusion: A new class of potent, tubulin binding anticancer agents based on 1,1,-diarylvinyl sulfone scaffold has been designed and synthesized.

Keywords: Tubulin polymerization inhibitor, vinyl sulfone, diarylethenes, ceric ammonium nitrate, Suzuki-Miyaura coupling, antiproliferative activity.

[1]
(a)Hadfield, J.A.; Ducki, S.; Hirst, N.; McGown, A.T. Tubulin and microtubules as targets for anticancer drugs. Prog. Cell Cycle Res., 2003, 5, 309-325.
[PMID: 14593726]
(b)Kingston, D.G.I. Tubulin-interactive natural products as anticancer agents. J. Nat. Prod, 2009, 72(3), 507-515.
[http://dx.doi.org/10.1021/np800568j] [PMID: 19125622]
(c)Butler, M.S. Natural products to drugs: Natural product-derived compounds in clinical trials. Nat. Prod. Rep., 2008, 25(3), 475-516.
[http://dx.doi.org/10.1039/b514294f] [PMID: 18497896]
(d)Arora, S.; Wang, X.I.; Keenan, S.M.; Andaya, C.; Zhang, Q.; Peng, Y.; Welsh, W.J. Novel microtubule polymerization inhibitor with potent antiproliferative and antitumor activity. Cancer Res., 2009, 69(5), 1910-1915.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0877] [PMID: 19223556]
(e)Kamal, A.; Kumar, G.B.; Vishnuvardhan, M.V.P.S.; Shaik, A.B.; Reddy, V.S.; Mahesh, R.; Sayeeda, I.B.; Kapure, J.S. Synthesis of phenstatin/isocombretastatin-chalcone conjugates as potent tubulin polymerization inhibitors and mitochondrial apoptotic inducers. Org. Biomol. Chem., 2015, 13(13), 3963-3981.
[http://dx.doi.org/10.1039/C4OB02606C] [PMID: 25721862]
[2]
(a)Newman, D.J.; Cragg, G.M.; Holbeck, S.; Sausville, E.A. Natural products and derivatives as leads to cell cycle pathway targets in cancer chemotherapy. Curr. Cancer Drug Targets, 2002, 2(4), 279-308.
[http://dx.doi.org/10.2174/1568009023333791] [PMID: 12470208]
(b)Hamel, E.; Covell, D.G. Antimitotic peptides and depsipeptides. Curr. Med. Chem. Anticancer Agents, 2002, 2(1), 19-53.
[http://dx.doi.org/10.2174/1568011023354263] [PMID: 12678750]
(c)Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. Med. Res. Rev., 2008, 28(1), 155-183.
[http://dx.doi.org/10.1002/med.20097] [PMID: 17464966]
[3]
(a)Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F. Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6(1a). J. Med. Chem., 1995, 38(10), 1666-1672.
[http://dx.doi.org/10.1021/jm00010a011] [PMID: 7752190]
(b)Siemann, D.W.; Chaplin, D.J.; Walicke, P.A. A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin. Investig. Drugs, 2009, 18(2), 189-197.
[http://dx.doi.org/10.1517/13543780802691068] [PMID: 19236265]
[4]
(a)Tron, G.C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A.A. Medicinal chemistry of combretastatin A4: Present and future directions. J. Med. Chem., 2006, 49(11), 3033-3044.
[http://dx.doi.org/10.1021/jm0512903] [PMID: 16722619]
(b)Chaplin, D.J.; Horsman, M.R.; Siemann, D.W. Current development status of small-molecule vascular disrupting agents. Curr. Opin. Investig. Drugs, 2006, 7(6), 522-528.
[PMID: 16784022]
[5]
(a)Cushman, M.; Nagarathnam, D.; Gopal, D.; He, H.M.; Lin, C.M.; Hamel, E. Synthesis and evaluation of analogues of (Z)-1-(4- methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents. J. Med. Chem., 1992, 35(12), 2293-2306.
[http://dx.doi.org/10.1021/jm00090a021] [PMID: 1613753]
(b)Pettit, G.R.; Toki, B.; Herald, D.L.; Verdier-Pinard, P.; Boyd, M.R.; Hamel, E.; Pettit, R.K. Antineoplastic agents. 379. Synthesis of phenstatin phosphate. J. Med. Chem., 1998, 41(10), 1688-1695.
[http://dx.doi.org/10.1021/jm970644q] [PMID: 9572894]
(c)Pettit, G.R.; Grealish, M.P.; Herald, D.L.; Boyd, M.R.; Hamel, E.; Pettit, R.K. Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug. J. Med. Chem., 2000, 43(14), 2731-2737.
[http://dx.doi.org/10.1021/jm000045a] [PMID: 10893310]
[6]
(a)Cullen, M.D.; Sarkar, T.; Hamel, E.; Hartman, T.L.; Watson, K.M.; Buckheit, R.W., Jr; Pannecouque, C.; De Clercq, E.; Cushman, M. Inhibition of tubulin polymerization by select alkenyldiarylmethanes. Bioorg. Med. Chem. Lett., 2008, 18(2), 469-473.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.114] [PMID: 18083556]
(b)Álvarez, R.; Álvarez, C.; Mollinedo, F.; Sierra, B.G.; Medarde, M.; Peláez, R. Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds. Bioorg. Med. Chem., 2009, 17(17), 6422-6431.
[http://dx.doi.org/10.1016/j.bmc.2009.07.012] [PMID: 19647439]
[7]
(a)Zhang, L-H.; Wu, L.; Raymon, H.K.; Chen, R.S.; Corral, L.; Shirley, M.A.; Narla, R.K.; Gamez, J.; Muller, G.W.; Stirling, D.I.; Bartlett, J.B.; Schafer, P.H.; Payvandi, F. The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-α production with antitumor activity. Cancer Res., 2006, 66(2), 951-959.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-2083] [PMID: 16424030]
(b)Ruchelman, A.L.; Man, H-W.; Chen, R.; Liu, W.; Lu, L.; Cedzik, D.; Zhang, L.; Leisten, J.; Collette, A.; Narla, R.K.; Raymon, H.K.; Muller, G.W. 1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4. Bioorg. Med. Chem., 2011, 19(21), 6356-6374.
[http://dx.doi.org/10.1016/j.bmc.2011.08.068] [PMID: 21955454]
[8]
For a review, see:; Meadows, D.C.; Gervay-Hague, J. Vinyl sulfones:synthetic preparations and medicinal chemistry applications. Med. Res. Rev., 2006, 26, 793-814.For recent synthetic applications of unsaturated sulfones, see .
(a)Undeela, S.; Ravikumar, G.; Nanubolu, J.B. The facile synthesis of 1-benzoazepine derivatives via gold-catalyzed regioselective cycloisomerization reactions of N-(o-alkynylaryl)-N-vinyl sulfonamides. Chem. Commun., 2016, 52, 4824-4827.
(b)Undeela, S.; Thadkapally, S.; Nanubolu, J.B. Catalystcontrolled divergence in cycloisomerisation reactions of Npropargyl-N-vinyl sulfonamides: Gold-catalysed synthesis of 2-sulfonylmethyl pyrroles and dihydropyridines. Chem. Commun., 2015, 51, 13748-13751.
(c)Kumar, A.; Thadkapally, S.; Menon, R.S Base-Mediated cyclocondensation of salicylaldehydes and 2-bromoallyl sulfones for the synthesis of 3-sulfonylchromene derivatives and their regioselective Friedel–Crafts heteroarylation reactions. J. Org. Chem, 2015, 80, 11048-11056.
(d)Thadkapally, S.; Kunjachan, A.; Menon, R.S. Facile synthesis of 4H-chromene derivatives via base-mediated annulation of orthohydroxychalcones and 2-bromoallyl sulfones. Beilstein J. Org. Chem, 2016, 12, 16-21.
(e)Joshi, P.R.; Undeela, S.; Reddy, D.D Regioselective synthesis of substituted arenes via aerobic oxidative [3 + 3] benzannulation reactions of α,β-unsaturated aldehydes and ketones. Org. Lett., 2015, 17, 1449-1452.
[9]
(a)Roush, W.R.; Gwaltney, S.L., II; Cheng, J.; Scheidt, K.A.; McKerrow, J.H.; Hansell, E. Vinyl sulfonate esters and vinyl sulfonamides: potent, irreversible inhibitors of cysteine proteases. J. Am. Chem. Soc., 1998, 120, 10994-10995.
[http://dx.doi.org/10.1021/ja981792o]
(b)Palmer, J.T.; Rasnick, D.; Klaus, J.L.; Brömme, D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J. Med. Chem., 1995, 38(17), 3193-3196.
[http://dx.doi.org/10.1021/jm00017a002] [PMID: 7650671]
(c)Frankel, B.A.; Bentley, M.; Kruger, R.G.; McCafferty, D.G. Vinyl sulfones: Inhibitors of SrtA, a transpeptidase required for cell wall protein anchoring and virulence in Staphylococcus aureus. J. Am. Chem. Soc., 2004, 126(11), 3404-3405.
[http://dx.doi.org/10.1021/ja0390294] [PMID: 15025450]
[10]
Nair, V.; Augustine, A.; Suja, T.D. CAN mediated reaction of aryl sulfinates with alkenes and alkynes: synthesis of vinyl sulfones, β-iodovinyl sulfones and acetylenic sulfones. Synthesis, 2002, 2259-2265.
[http://dx.doi.org/10.1055/s-2002-34838]]
[11]
Gogoi, P.; Bezboruah, P.; Boruah, R.C. Ligand‐free suzuki cross‐coupling reactions: Application to β‐halo‐α,β‐unsaturated aldehydes. Eur. J. Org. Chem., 2013, 23, 5032-5035.
[http://dx.doi.org/10.1002/ejoc.201300491]
[12]
Taniguchi, N. Aerobic copper-catalyzed synthesis of (E)-alkenyl sulfones and (E)-b-halo-alkenyl sulfones via addition of sodium sulfinates to alkynes. Tetrahedron, 2014, 70, 1984-1990.
[http://dx.doi.org/10.1016/j.tet.2014.01.071]]
[13]
(a)Manupati, K.; Dhoke, N.R.; Debnath, T.; Yeeravalli, R.; Guguloth, K.; Saeidpour, S.; De, U.C.; Debnath, S.; Das, A. Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal-epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs. FEBS J., 2017, 284(12), 1830-1854.
[http://dx.doi.org/10.1111/febs.14084] [PMID: 28398698]
(b)Lin, D.W.; Chung, B.P.; Kaiser, P. S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1. J. Cell Sci., 2014, 127(Pt 1), 50-59.
[http://dx.doi.org/10.1242/jcs.127811] [PMID: 24155332]
[14]
(a)Manupati, K.; Debnath, S.; Goswami, K.; Bhoj, P.S.; Chandak, H.S.; Bahekar, S.P.; Das, A. Glutathione S-transferase omega 1 inhibition activates JNK-mediated apoptotic response in breast cancer stem cells. FEBS J., 2019, 286(11), 2167-2192.
[http://dx.doi.org/10.1111/febs.14813] [PMID: 30873742 ]
(b)Jafari, R.; Almqvist, H.; Axelsson, H.; Ignatushchenko, M.; Lundbäck, T.; Nordlund, P.; Martinez Molina, D. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat. Protoc., 2014, 9(9), 2100-2122.
[http://dx.doi.org/10.1038/nprot.2014.138] [PMID: 25101824]
[15]
Yang, J.; Yan, W.; Yu, Y.; Wang, Y.; Yang, T.; Xue, L.; Yuan, X.; Long, C.; Liu, Z.; Chen, X.; Hu, M.; Zheng, L.; Qiu, Q.; Pei, H.; Li, D.; Wang, F.; Bai, P.; Wen, J.; Ye, H.; Chen, L. The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in β-tubulin. J. Biol. Chem., 2018, 293(24), 9461-9472.
[http://dx.doi.org/10.1074/jbc.RA117.001658] [PMID: 29691282]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 12
Year: 2020
Published on: 07 September, 2020
Page: [1469 - 1474]
Pages: 6
DOI: 10.2174/1871520620666200423075630
Price: $65

Article Metrics

PDF: 31
HTML: 2
EPUB: 1
PRC: 1