Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Colley, H.E.; Muthana, M.; Danson, S.J.; Jackson, L.V.; Brett, M.L.; Harrison, J.; Coole, S.F.; Mason, D.P.; Jennings, L.R.; Wong, M.; Tulasi, V.; Norman, D.; Lockey, P.M.; Williams, L.; Dossetter, A.G.; Griffen, E.J.; Thompson, M.J. (2015)
Publisher: American Chemical Society
Languages: English
Types: Article
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • (1) Nitika, V.; Kapil, K. Microtubule targeting agents: a benchmark in cancer therapy. Curr. Drug Ther. 2014, 8, 189−196.
    • (2) Risinger, A. L.; Giles, F. J.; Mooberry, S. L. Microtubule dynamics as a target in oncology. Cancer Treat. Rev. 2009, 35, 255−261.
    • (3) Stanton, R. A.; Gernert, K. M.; Nettles, J. H.; Aneja, R. Drugs that target dynamic microtubules: a new molecular perspective. Med. Res.
    • Rev. 2011, 31, 443−481.
    • (4) Barbier, P.; Tsvetkov, P. O.; Breuzard, G.; Devred, F. Deciphering the molecular mechanisms of anti-tubulin plant derived drugs.
    • Phytochem. Rev. 2014, 13, 157−169.
    • (5) Rohena, C. C.; Mooberry, S. L. Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities. Nat.
    • Prod. Rep. 2014, 31, 335−355.
    • (6) Jordan, M. A.; Horwitz, S. B.; Lobert, S.; Correia, J. J. Exploring the mechanisms of action of the novel microtubule inhibitor vinflunine. Semin. Oncol. 2008, 35, S6−S12.
    • (7) Field, J. J.; Kanakkanthara, A.; Miller, J. H. Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function. Bioorg. Med. Chem. 2014, 22, 5050−5059.
    • (8) Zasadil, L. M.; Andersen, K. A.; Yeum, D.; Rocque, G. B.; Wilke, L. G.; Tevaarwerk, A. J.; Raines, R. T.; Burkard, M. E.; Weaver, B. A.
    • Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci. Transl. Med. 2014, 6, 229ra43.
    • (9) Ogden, A.; Rida, P. C. G.; Reid, M. D.; Aneja, R. Interphase microtubules: chief casualties in the war on cancer? Drug Discovery Today 2014, 19, 824−829.
    • (10) Fürst, R.; Vollmar, A. M. A new perspective on old drugs: nonmitotic actions of tubulin-binding drugs play a major role in cancer treatment. Pharmazie 2013, 68, 478−483.
    • (11) Mitchison, T. J. The proliferation rate paradox in antimitotic chemotherapy. Mol. Biol. Cell 2012, 23, 1−6.
    • (12) Seligmann, J.; Twelves, C. Tubulin: an example of targeted chemotherapy. Future Med. Chem. 2013, 5, 339−352.
    • (13) Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nat. Rev. Cancer 2010, 10, 194−204.
    • (14) Katsetos, C. D.; Draber, P. Tubulins as therapeutic targets in cancer: from bench to bedside. Curr. Pharm. Des. 2012, 18, 2778− 2792.
    • (15) Murray, S.; Briasoulis, E.; Linardou, H.; Bafaloukos, D.; Papadimitriou, C. Taxane resistance in breast cancer: mechanisms, predictive biomarkers and circumvention strategies. Cancer Treat. Rev.
    • (16) Gan, P. P.; Kavallaris, M. Tubulin-targeted drug action: functional significance of class II and class IVb β-tubulin in Vinca alkaloid sensitivity. Cancer Res. 2008, 68, 9817−9824.
    • (17) Carlson, K.; Ocean, A. J. Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach.
    • Clin. Breast Cancer 2011, 11, 73−81.
    • (18) Canta, A.; Chiorazzi, A.; Cavaletti, G. Tubulin: a target for antineoplastic drugs into the cancer cells but also in the peripheral nervous system. Curr. Med. Chem. 2009, 16, 1315−1324.
    • (19) Dumontet, C.; Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discovery 2010, 9, 790−803.
    • (20) Kingston, D. G. I.; Snyder, J. P. The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent. Acc. Chem. Res.
    • (21) Gerullis, H.; Ecke, T.; Eimer, C.; Wishahi, M.; Otto, T.
    • Vinflunine as second-line treatment in platin-resistant metastatic urothelial carcinoma: a review. Anti-Cancer Drugs 2011, 22, 9−17.
    • (22) Gourmelon, C.; Frenel, J. S.; Campone, M. Eribulin mesylate for the treatment of late-stage breast cancer. Expert Opin. Pharmacother.
    • (23) Preston, J. N.; Trivedi, M. V. Eribulin: a novel cytotoxic chemotherapy agent. Ann. Pharmacother. 2012, 46, 802−811.
    • (24) Cortes, J.; Montero, A. J.; Glück, S. Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treat.
    • Rev. 2012, 38, 143−151.
    • (25) Brogdon, C. F.; Lee, F. Y.; Canetta, R. M. Development of other microtubule-stabilizer families: the epothilones and their derivatives.
    • Anti-Cancer Drugs 2014, 25, 599−609.
    • (26) Edelman, M. J.; Shvartsbeyn, M. Epothilones in development for non-small-cell lung cancer: novel anti-tubulin agents with the potential to overcome taxane resistance. Clin. Lung Cancer 2012, 13, 171−180.
    • (27) Sadeghi, S.; Olevsky, O.; Hurvitz, S. A. Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine. Pharmacogenomics Pers. Med. 2014, 7, 329−338.
    • (28) Coen van Hasselt, J. G.; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H. M.; Huitema, A. D. R. Population pharmacokineticpharmacodynamic analysis for eribulin mesylate-associated neutropenia. Br. J. Clin. Pharmacol. 2013, 76, 412−424.
    • (29) Valero, V. Managing ixabepilone adverse events with dose reduction. Clin. Breast Cancer 2013, 13, 1−6.
    • (30) Ebenezer, G. J.; Carlson, K.; Donovan, D.; Cobham, M.; Chuang, E.; Moore, A.; Cigler, T.; Ward, M.; Lane, M. E.; Ramnarain, A.; Vahdat, L. T.; Polydefkis, M. Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients. Ann. Clin. Transl.
    • Neurol. 2014, 1, 639−649.
    • (31) Vahdat, L. T.; Garcia, A. A.; Vogel, C.; Pellegrino, C.; Lindquist, D. L.; Iannotti, N.; Gopalakrishna, P.; Sparano, J. A. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res. Treat. 2013, 140, 341−351.
    • (32) Wozniak, K. M.; Nomoto, K.; Lapidus, R. G.; Wu, Y.; Carozzi, V.; Cavaletti, G.; Hayakawa, K.; Hosokawa, S.; Towle, M. J.; Littlefield, B. A.; Slusher, B. S. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel and ixabepilone in mice. Cancer Res. 2011, 71, 3952−3962.
    • (33) LaPointe, N. E.; Morfini, G.; Brady, S. T.; Feinstein, S. C.; Wilson, L.; Jordan, M. A. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy.
    • NeuroToxicology 2013, 37, 231−239.
    • (34) Polastro, L.; Aftimos, P. G.; Awada, A. Eribulin mesylate in the management of metastatic breast cancer and other solid cancers: a drug review. Expert Rev. Anticancer Ther. 2014, 14, 649−665.
    • (35) Laughney, A. M.; Kim, E.; Sprachman, M. M.; Miller, M. A.; Kohler, R. H.; Yang, K. S.; Orth, J. D.; Mitchison, T. J.; Weissleder, R.
    • Transl. Med. 2014, 6, 261ra152.
    • (36) Lu, Y.; Chen, J.; Xiao, M.; Li, W.; Miller, D. D. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm.
    • Res. 2012, 29, 2943−2971.
    • (37) Patil, S. A.; Patil, R.; Miller, D. D. Indole molecules as inhibitors of tubulin polymerization: potential new anticancer agents. Future Med. Chem. 2012, 4, 2085−2115.
    • (38) Kaur, R.; Kaur, G.; Gill, R. K.; Soni, R.; Bariwal, J. Recent developments in tubulin polymerization inhibitors: an overview. Eur. J.
    • Med. Chem. 2014, 87, 89−124.
    • (39) Liu, Y.-M.; Chen, H.-L.; Lee, H.-Y.; Liou, J.-P. Tubulin inhibitors: a patent review. Expert Opin. Ther. Pat. 2014, 24, 69−88.
    • (40) Wienecke, A.; Bacher, G. Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin. Cancer Res. 2009, 69, 171−177.
    • (41) Desai, A.; Ratain, M. J.; Moshier, K.; Tipton, M.; Dooley, W.; Hocknell, K.; Dahl, T.; Sherman, M.; Limentani, S. A phase I, doseescalation trial of STA-5312, a microtubule inhibitor with a novel binding site, in advanced or metastatic solid malignancies. J. Clin.
    • Oncol. 2006, 24, 13040, 2006 ASCO Annual Meeting Proceedings Part I.
    • (42) (a) STA-5312 administered on alternate weekdays every two weeks to patients with hematologic malignancies and patients with solid tumors, NCT00088101. www.clinicaltrials.gov (accessed December 30, 2014). (b) A phase I study of STA-5312 in subjects with advanced or metastatic solid tumors, NCT00276913. www.
    • clinicaltrials.gov (accessed December 30, 2014).
    • (43) Bacher, G.; Nickel, B.; Emig, P.; Vanhoefer, U.; Seeber, S.; Shandra, A.; Klenner, T.; Beckers, T. 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. 2001, 61, 392−399.
    • (44) Kuppens, I. E. L. M.; Witteveen, P. O.; Schot, M.; Schuessler, V.
    • M.; Daehling, A.; Beijnen, J. H.; Voest, E. E.; Schellens, J. H. M. Phase I dose-finding and pharmacokinetic trial of orally administered Indibulin (D-24851) to patients with solid tumors. Invest. New Drugs 2007, 25, 227−235.
    • (45) Oostendorp, R. L.; Witteveen, P. O.; Schwartz, B.; Vainchtein, L. D.; Schot, M.; Nol, A.; Rosing, H.; Beijnen, B. H.; Voest, E. E.; Schellens, J. H. M. Dose-finding and pharmacokinetic study of orally administered Indibulin (D-24851) to patients with advanced solid tumors. Invest. New Drugs 2010, 28, 163−170.
    • (46) Semenova, M. N.; Kiselyov, A. S.; Titov, I. Y.; Raihstat, M. M.; Molodtsov, M.; Grishchuk, E.; Spiridonov, I.; Semenov, V. V. In vivo evaluation of indolyl glyoxylamides in the phenotypic sea urchin embryo assay. Chem. Biol. Drug Des. 2007, 70, 485−490.
    • (47) (a) Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability − are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011−1020.
    • (b) Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. Drug Discovery Today 2011, 16, 164−171.
    • (48) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J.
    • Med. Chem. 2009, 52, 6752−6756.
    • (49) Ishikawa, M.; Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem. 2011, 54, 1539−1554.
    • (50) Mok, N. Y.; Maxe, S.; Brenk, R. Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries. J. Chem. Inf. Model.
    • (51) Hennemann, B. Palliative chemotherapy of head and neck cancer: present status and future development. Laryngorhinootologie 2006, 85, 172−178.
    • (52) Cullen, K. J.; Schumaker, L.; Nikitakis, N.; Goloubeva, O.; Tan, M.; Sarlis, M. J.; Haddad, R. I.; Posner, M. R. β-Tubulin-II expression strongly predicts outcome in patients receiving induction chemotherapy for locally advanced squamous carcinoma of the head and neck: a companion analysis of the TAX 324 trial. J. Clin. Oncol. 2009, 27, 6222−6228.
    • (53) Schena, M.; Barone, C.; Birocco, N.; Dongiovanni, D.; Numico, G.; Colantonio, I.; Bertetto, O. Weekly cisplatin paclitaxel and continuous infusion fluorouracil in patients with recurrent and/or metastatic head and neck squamous cell carcinoma: a phase II study.
    • Cancer Chemother. Pharmacol. 2005, 55, 271−276.
    • (54) Pointreau, Y.; Garaud, P.; Chapet, S.; Sire, C.; Tuchais, C.; Tortochaux, J.; Faivre, S.; Guerrif, S.; Alfonsi, M.; Calais, G.
    • Randomized trial of induction chemotherapy with cisplatin and 5- fluorouracil with or without docetaxel for larynx preservation. J. Natl.
    • Cancer Inst. 2009, 101, 498−506.
    • (55) Paccagnella, A.; Ghi, M. G.; Loreggian, L.; Buffoli, A.; Koussis, H.; Mione, C. A.; Bonetti, A.; Campostrini, F.; Gardani, G.; Ardizzoia, A.; Dondi, D.; Guaraldi, M.; Cavallo, R.; Tomio, L.; Gava, A.
    • Concomintant chemoradiotherapy versus induction docetaxel, cisplatin and 5-fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann. Oncol. 2010, 21, 1515−1522.
    • (56) Theile, D.; Ketabi-Kiyanvash, N.; Herold-Mende, C.; Dyckhoff, G.; Efferth, T.; Bertholet, V.; Haefeli, W. E.; Weiss, J. Evaluation of drug transporters' significance in for multidrug resistance in head and neck squamous cell carcinoma. Head Neck 2011, 33, 959−968.
    • (57) (a) Jacobs, C.; Lyman, G.; Velez-Garcia, E.; Sridhar, K. S.; Knight, W.; Hochster, H.; Goodnough, L. T.; Mortimer, J. E.; Einhorn, L. H.; Schacter, L. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J. Clin. Oncol. 1992, 10, 257−263. (b) Forastiere, A. A.; Metch, B.; Schuller, D. E.; Ensley, J. F.; Hutchins, L. F.; Triozzi, P.; Kish, J. A.; McClure, S.; VonFeldt, E.; Williamson, S. K. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J. Clin. Oncol. 1992, 10, 1245−1251.
    • (58) Lee, J.; Moon, C. Current status of experimental therapeutics for head and neck cancer. Exp. Biol. Med. 2011, 236, 375−389.
    • (59) Machiels, J. P.; Schmitz, S. New advances in targeted therapies for squamous cell carcinoma of the head and neck. Anti-Cancer Drugs 2011, 22, 626−633.
    • (60) Matta, A.; Ralhan, R. Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma.
    • Head Neck Oncol. 2009, 1, 6.
    • (61) Raza, S.; Kornblum, N.; Kancharla, V. P.; Baig, M. A.; Singh, A.
    • Anti-Cancer Drug Discovery 2011, 6, 246−257.
    • (62) Denaro, N.; Russi, E. G.; Colantonio, I.; Adamo, V.; Merlano, M. C. The role of antiangiogenic agents in the treatment of head and neck cancer. Oncology 2012, 83, 108−116.
    • (63) (a) Faller, B.; Ertl, P. Computational approaches to determine drug solubility. Adv. Drug Delivery Rev. 2007, 59, 533−545.
    • (b) Delaney, J. S. Predicting aqueous solubility from structure. Drug Discovery Today 2005, 10, 289−295.
    • (64) (a) Tetko, I. V.; Tanchuk, V. Y.; Kasheva, T. N.; Villa, A. E.
    • Estimation of aqueous solubility of chemical compounds using E-state indices. J. Chem. Inf. Model. 2001, 41, 1488−1493. (b) Tetko, I. V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl, P.; Palyulin, V. A.; Radchenko, E. V.; Zefirov, N. S.; Makarenko, A. S.; Tanchuk, V. Y.; Prokopenko, V. V. Virtual computational chemistry laboratory − design and description. J. Comput.-Aided Mol. Des. 2005, 19, 453−463. (c) VCCLAB; Virtual Computational Chemistry Laboratory; http://www.vcclab.org, (accessed October 17, 2015).
    • (65) Tetko, I. V.; Tanchuk, V. Y.; Kasheva, T. N.; Villa, A. E. P.
    • Internet software for the calculation of the lipophilicity and aqeuous solubility of chemical compounds. J. Chem. Inf. Model. 2001, 41, 246− 252.
    • (66) (a) Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.; Wood, J. M.; Colclough, N.; Law, B. Matched molecular pairs as a guide in the optimization of pharmaceutical properties: a study of aqueous solubility, plasma protein binding and oral exposure. J. Med. Chem. 2006, 49, 6672−6682. (b) Gleeson, P.; Bravi, G.; Modi, S.; Lowe, D. ADMET rules of thumb II: a comparison of the effects of common substituents on a range of ADMET parameters. Bioorg. Med. Chem. 2009, 17, 5906−5919. (c) Griffen, E.; Leach, A. G.; Robb, G. R.; Warner, D. J. Matched molecular pairs as a medicinal chemistry tool. J. Med. Chem. 2011, 54, 7739−7750.
    • (67) Fishburn, C. S. Attenuating attrition. SciBX 2013, 6(26), doi:10.1038/scibx.2013.647.
    • (68) Hussain, J.; Rea, C. Computationally efficient algorithm to identify matched molecular pairs (MMPs) in large data sets. J. Chem.
    • Inf. Model. 2010, 50, 339−348.
    • (69) Warner, D. J.; Griffen, E.; St-Gallay, S. A. WizePairZ: a novel algorithm to identify, encode, and exploit matched molecular pairs with unspecified cores in medicinal chemistry. J. Chem. Inf. Model.
    • (70) Papadatos, G.; Alkarouri, M.; Gillet, V. J.; Willett, P.; Kadirkamanathan, V.; Luscombe, C. N.; Bravi, G.; Richmond, N. J.; Pickett, S. D.; Hussain, J.; Pritchard, J. M.; Cooper, A. W. J.; Macdonald, S. J. F. Lead optimization using matched molecular pairs: inclusion of contextual information for enchanced prediction of hERG inhibition, solubility and lipophilicity. J. Chem. Inf. Model. 2010, 50, 1872−1886.
    • (71) Thompson, M. J.; Louth, J. C.; Ferrara, S.; Jackson, M. P.; Sorrell, F. J.; Cochrane, E. J.; Gever, J.; Baxendale, S.; Silber, M. B.; Roehl, H. H.; Chen, B. Discovery of 6-substituted indole-3- glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity. Eur. J. Med. Chem.
    • (72) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell, N. A.; Kadow, J. F.; Wang, T. An effective procedure for the acylation of azaindoles at C-3. J. Org. Chem. 2002, 67, 6226−6227.
    • (73) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]- dec-5-ene (TBD) under solvent-free conditions. Tetrahedron Lett.
    • (74) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. N-Cyclopropylation of indoles and cyclic amides with copper(II) reagent. Org. Lett. 2008, 10, 1653−1655.
    • (75) Nguyen, T. M.; Duong, H. A.; Richard, J.-A.; Johannes, C. W.; Pincheng, F.; Ye, D. K. J.; Shuying, E. L. Cascade fluorofunctionalisatdon of 2,3-unsubstituted indoles by means of electrophilic fluorination. Chem. Commun. 2013, 49, 10602−10604.
    • (76) (a) Conner, S. E.; Gossett, L. S.; Green, J. E.; Jones, W. D., Jr.; Mantlo, N. B.; Matthews, D. P.; Mayhugh, D. R.; Smith, D. L.; Vance, J. A.; Wang, X.; Warshawsky, A. M.; Winneroski, L. L., Jr.; Xu, Y.; Zhu, G. Preparation of sulfonamide derivatives, in particular N,N-benzo[b]thiophene sulfonamides, as PPAR modulators, especially PPAR agonists. (Eli Lilly & Co., USA) WO 2004073606 A2, September 2, 2004; SciFinder Scholar AN 2004:718289;. (b) Wilson, D.; Fanning, L.
    • (Vertex Pharmaceuticals Inc., USA) WO 2007075892 A2, July 5, 2007; SciFinder Scholar AN 2007:730896.
    • (77) Yeom, C.-E.; Kim, M. J.; Kim, B. M. 1,8-Diazabycyclo[5.4.0]- undec-7-ene (DBU)-promoted efficient and versatile aza-Michael reaction. Tetrahedron 2007, 63, 904−909.
    • (78) Amato, G.; Roeloffs, R.; Rigdon, G. C.; Antonio, B.; Mersch, T.; McNaughton-Smith, G.; Wickenden, A. G.; Fritch, P.; Suto, M. J. NPyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy. ACS Med. Chem. Lett. 2011, 2, 481−484.
    • (79) Kel'in, A. V.; Sromek, A. W.; Gevorgyan, V. A novel Cu-assisted cycloisomerization of alkynyl imines: efficient synthesis of pyrroles and pyrrole-containing heterocycles. J. Am. Chem. Soc. 2001, 123, 2074− 2075.
    • (80) Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L.
    • Development of a practical synthesis of STA-5312, a novel indolizine oxalylamide microtubule inhibitor. Org. Process Res. Dev. 2007, 11, 246−250.
    • (81) Debnar, T.; Dreisigacker, S.; Menche, D. Highly regioselective opening of zirconacyclopentadienes by remote coordination: concise synthesis of the furan core of the leupyrrins. Chem. Commun. 2013, 49, 725−727.
    • (82) Chen, Y.-J.; Huang, W.-C.; Wei, Y.-L.; Hsu, S.-C.; Yuan, P.; Lin, H. Y.; Wistuba, I. I.; Lee, J. J.; Yen, C.-J.; Su, W.-C.; Chang, K.-Y.; Chang, W.-C.; Chou, T.-C.; Chou, C.-K.; Tsai, C.-H.; Hung, M.-C.
    • Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells. PLoS One 2011, 6, e21428.
    • (83) (a) Shelanski, M. L.; Gaskin, F.; Cantor, C. R. Microtubule assembly in the absence of added nucleotides. Proc. Natl. Acad. Sci. U.
    • S. A. 1973, 70, 765−768. (b) Lee, J. C.; Timasheff, S. N. In vitro reconstitution of calf brain microtubules: effects of solution variables.
    • Biochemistry 1977, 16, 1754−1764.
    • (84) Bonne, D.; Heusel̀e, C.; Simon, C.; Pantaloni, D. 4′,6- Diamidino-2-phenylindole, a fluorescent probe for tubulin and microtubules. J. Biol. Chem. 1985, 260, 2819−2825.
    • (85) Cortese, F.; Bhattacharyya, B.; Wolff, J. Podophyllotoxin as a probe for the colchicine binding site of tubulin. J. Biol. Chem. 1977, 252, 1134−1140.
    • (86) Wallner, B. P.; Schwartz, B. E.; Komarnitsky, P. B.; Bacher, G.; Kutscher, B.; Raab, G. Use of indolyl-3-glyoxylic acid derivatives including indibulin, alone or in combination with further agents for treating cancer. (Ziopharm Oncology Inc., USA) WO 2008066807 A1, Jun 5, 2008; SciFinder Scholar AN 2008:673085.
    • (87) Yamada, H. Y.; Gorbsky, G. J. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol. Cancer Ther. 2006, 5, 2963−2969.
    • (88) Harker, W. G.; Sikic, B. I. Multidrug (pleiotropic) resistance in doxorubicin-selected variants of the human sarcoma cell line MES-SA.
    • Cancer Res. 1985, 45, 4091−4096.
    • (89) Chen, G.; Jaffreźou, J.-P.; Fleming, W. H.; Durań, G. E.; Sikic, B.
    • I. Prevalence of multidrug resistance related to activation of the Mdr1 gene in human sarcoma mutants derived by single-step doxorubicin selection. Cancer Res. 1994, 54, 4980−4987.
    • (90) Nakamura, T.; Sakaeda, T.; Ohmoto, N.; Tamura, T.; Aoyama, N.; Shirakawa, T.; Nakamura, T.; Kim, K. I.; Kim, S. R.; Kuroda, Y.; Matsuo, M.; Kasuga, M.; Okumura, K. Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2 and CYP3AmRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas. Drug Metab. Dispos. 2002, 30, 4−6.
    • (91) Gutmann, H.; Fricker, G.; Török, M.; Michael, S.; Beglinger, C.; Drewe, J. Evidence for different ABC-transporters in Caco-2 cells modulating drug uptake. Pharm. Res. 1999, 16, 402−407.
    • (92) Xia, C. Q.; Liu, N.; Yang, D.; Miwa, G.; Gan, L.-S. Expression, localization and functional characteristics of breast cancer resistance protein in Caco-2 cells. Drug Metab. Dispos. 2005, 33, 637−643.
    • (93) Breslin, S.; O'Driscoll, L. Three-dimensional cell culture: the missing link in drug discovery. Drug Discovery Today 2013, 18, 240− 249.
    • (94) Hirschhaeuser, F.; Menne, H.; Dittfeld, C.; West, J.; MuellerKlieser, W.; Kunz-Schughart, L. A. Multicellular tumor spheroids: an underestimated tool is catching up again. J. Biotechnol. 2010, 148, 3− 15.
    • (95) Colley, H. E.; Hearnden, V.; Avila-Olias, M.; Cecchin, D.; Canton, I.; Madsen, J.; MacNeil, S.; Warren, N.; Hu, K.; McKeating, J.
    • Polymersome-mediated delivery of combination anticancer therapy to head and neck cancer cells: 2D and 3D in vitro evaluation. Mol.
    • Pharmaceutics 2014, 11, 1176−1188.
    • (96) (a) Kadletz, L.; Heiduschka, G.; Domayer, J.; Schmid, R.; Enzenhofer, E.; Thurnher, D. Evaluation of spheroid head and neck squamous cell carcinoma cell models in comparison to monolayer cultures. Oncol. Lett. 2015, 10, 1281−1286. (b) Tupper, J.; Greco, O.; Tozer, G. M.; Dachs, G. U. Analysis of the horseradish peroxidase/ indole-3-acetic acid combination in a three-dimensional tumor model.
    • Cancer Gene Ther. 2004, 11, 508−513.
    • (97) Huang, T.-H.; Chiu, S.-J.; Chiang, P.-H.; Chiou, S.-H.; Li, W.-T.; Chen, C.-T.; Chang, C. A.; Chen, J.-C.; Lee, Y.-J. Antiproliferative effects of N-heterocyclic indole glyoxylamide derivatives on human lung cancer cells. Anticancer Res. 2011, 31, 3407−3416.
    • (98) Li, W.-T.; Yeh, T.-K.; Song, J.-S.; Yang, Y.-N.; Chen, T.-W.; Lin, C.-H.; Chen, C.-P.; Shen, C.-C.; Hsieh, C.-C.; Lin, H.-L.; Chao, Y.-S.; Chen, C.-T. BPR0C305, and orally active microtubule-disrupting anticancer agent. Anti-Cancer Drugs 2013, 24, 1047−1057.
    • (99) Hu, C.-B.; Chen, C.-P.; Yeh, T.-K.; Song, J.-S.; Chang, C.-Y.; Chuu, J.-J.; Tung, F.-F.; Ho, P.-Y.; Chen, T.-W.; Lin, C.-H.; Wang, M.- H.; Chang, K.-Y.; Huang, C.-L.; Lin, H.-L.; Li, W.-T.; Hwang, D.-R.; Chern, J.-H.; Hwang, L.-L.; Chang, J.-Y.; Chao, Y.-S.; Chen, C.-T.
    • BPR0C261 is a novel orally active antitumor agent with antimitotic and anti-angiogenic activities. Cancer Sci. 2011, 102, 182−191.
    • (100) Li, W.-T.; Hwang, D.-R.; Chen, C.-P.; Shen, C.-W.; Huang, C.- L.; Chen, T.-W.; Lin, C.-H.; Chang, Y.-L.; Chang, Y.-Y.; Lo, Y.-K.; Tseng, H.-Y.; Lin, C.-C.; Song, J.-S.; Chen, H.-C.; Chen, S.-J.; Wu, S.- H.; Chen, C.-T. Synthesis and biological evaluation of N-heterocyclic indolyl glyoxylamides as orally active anticancer agents. J. Med. Chem.
    • (101) Thompson, M. J.; Louth, J. C.; Ferrara, S.; Sorrell, F. J.; Irving, B. J.; Cochrane, E. J.; Meijer, A. J. H. M.; Chen, B. Structure−activity relationship refinement and further assessment of indole-3-glyoxylamides as a lead series against prion disease. ChemMedChem 2011, 6, 115−130.
    • (102) Baell, J. B. Screening-based translation of public research encounters painful problems. ACS Med. Chem. Lett. 2015, 6, 229−234.
    • (103) Fitton, A. O.; Hill, J.; Jane, D. E.; Millar, R. Synthesis of simple oxetanes carrying reactive 2-sustituents. Synthesis 1987, 1987, 1140− 1142.
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
  • No similar publications.

Share - Bookmark

Cite this article