Synthesis, Structural Characterisation, and Preliminary Evaluation of Non-Indolin-2-one-based Angiogenesis Inhibitors Related to Sunitinib (Sutent®)
Pichit Sudta A F , Nicholas Kirk B F , Anna Bezos C , Anthony Gurlica B , Rhys Mitchell B , Thomas Weber B , Anthony C. Willis D , Samran Prabpai E , Palangpon Kongsaeree E , Christopher R. Parish C , Sunit Suksamrarn A and Michael J. Kelso B G
+ Author Affiliations
- Author Affiliations
A Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand.
B School of Chemistry, Faculty of Science, University of Wollongong, Wollongong, NSW 2522, Australia.
C Cancer and Vascular Biology Group, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia.
D Single-crystal X-ray Diffraction Unit, Research School of Chemistry, Australian National University, Canberra, ACT 2600, Australia.
E Centre for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
F These authors contributed equally to this work.
G Corresponding author. Email: mkelso@uow.edu.au
Australian Journal of Chemistry 66(8) 864-873 https://doi.org/10.1071/CH13219
Submitted: 29 April 2013 Accepted: 24 May 2013 Published: 20 June 2013
Abstract
The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent®) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.
References
[1] D. Hanahan, J. Folkman, Cell 1996, 86, 353.| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK28XltVSks7s%3D&md5=b6d8ce23650310ea2a6b7879d67bf4a6CAS | 8756718PubMed |
[2] P. Carmeliet, Nat. Med. 2003, 9, 653.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXktFOntbY%3D&md5=e57ec771c6d3c05cdf236728b1062b7eCAS | 12778163PubMed |
[3] B. R. Zetter, Annu. Rev. Med. 1998, 49, 407.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXhtFKqt70%3D&md5=1df3b945417dc58c15c70088e90f4c1fCAS | 9509272PubMed |
[4] F. Shojaei, Cancer Lett. 2012, 320, 130.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XltVamtLY%3D&md5=4e90c33f44976d52e451f80dcd7abd7aCAS | 22425960PubMed |
[5] H. Hurwitz, L. Fehrenbacher, W. Novotny, T. Cartwright, J. Hainsworth, W. Heim, J. Berlin, A. Baron, S. Griffing, E. Holmgren, N. Ferrara, G. Fyfe, B. Rogers, R. Ross, F. Kabbinavar, N. Engl. J. Med. 2004, 350, 2335.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXks1Gjt74%3D&md5=3ea3aab794bf23bff823dd1abbaa78bdCAS | 15175435PubMed |
[6] A. Sandler, R. Gray, M. C. Perry, J. Brahmer, J. H. Schiller, A. Dowlati, R. Lilenbaum, D. H. Johnson, N. Engl. J. Med. 2006, 355, 2542.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtlWqsbzI&md5=72de2058bee27278d15b9f9f3725a365CAS | 17167137PubMed |
[7] K. Miller, M. Wang, J. Gralow, M. Dickler, M. Cobleigh, E. A. Perez, T. Shenkier, D. Cella, N. E. Davidson, N. Engl. J. Med. 2007, 357, 2666.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXisVOnsg%3D%3D&md5=2d4e666af26e827c4442e9d32102265bCAS | 18160686PubMed |
[8] J. Holash, S. Davis, N. Papadopoulos, S. D. Croll, L. Ho, M. Russell, P. Boland, R. Leidich, D. Hylton, E. Burova, E. Ioffe, T. Huang, C. Radziejewski, K. Bailey, J. P. Fandl, T. Daly, S. J. Wiegand, G. D. Yancopoulos, J. S. Rudge, Proc. Natl. Acad. Sci. USA 2002, 99, 11393.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XmslSmu7s%3D&md5=cbeb536a7ef5ff7ad7b2f9cdb6b5e2d8CAS | 12177445PubMed |
[9] A.-M. O’Farrell, T. J. Abrams, H. A. Yuen, T. J. Ngai, S. G. Louie, K. W. H. Yee, L. M. Wong, W. Hong, L. B. Lee, A. Town, B. D. Smolich, W. C. Manning, L. J. Murray, M. C. Heinrich, J. M. Cherrington, Blood 2003, 101, 3597.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXjs1aqtrs%3D&md5=c79371c34373d5760b2011a7db7e5bc6CAS | 12531805PubMed |
[10] W. T. A. van der Graaf, J.-Y. Blay, S. P. Chawla, D.-W. Kim, B. Bui-Nguyen, P. G. Casali, P. Schöffski, M. Aglietta, A. P. Staddon, Y. Beppu, A. Le Cesne, H. Gelderblom, I. R. Judson, N. Araki, M. Ouali, S. Marreaud, R. Hodge, M. R. Dewji, C. Coens, G. D. Demetri, C. D. Fletcher, A. P. Dei Tos, P. Hohenberger, Lancet 2012, 379, 1879.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xnt1CltLo%3D&md5=5053eaa7b8017b383cdcc70507e5367dCAS |
[11] P. Kupsch, B. F. Henning, K. Passarge, H. Richly, K. Wiesemann, R. A. Hilger, M. E. Scheulen, O. Christensen, E. Brendel, B. Schwartz, E. Hofstra, R. Voigtmann, S. Seeber, D. Strumberg, Clin. Colorectal Cancer 2005, 5, 188.
| Crossref | GoogleScholarGoogle Scholar | 16197622PubMed |
[12] X. Wu, Y. Jin, I. H. Cui, Z. Xu, Y. Zhang, X. Zhang, C. Tang, Y. Gong, J. Chen, Anticancer Drugs 2012, 23, 731.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XptFWhtL8%3D&md5=77137b57715b53f786a3972c2fe8dd79CAS | 22700001PubMed |
[13] L. Wood, Expert Opin. Pharmacother. 2012, 13, 1323.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XnsFGntL8%3D&md5=cb9d08d4f62b9bf939d714ed3388dba8CAS | 22607009PubMed |
[14] V. P. Koshenkov, S. E. Rodgers, Curr. Opin. Oncol. 2012, 24, 414.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XotFGktbs%3D&md5=d6253e2dfd53ab72d746f1db6a459326CAS | 22572723PubMed |
[15] C. Zhou, J. Zhang, Y. Zheng, Z. Zhu, Int. J. Cancer 2012, 131, 1013.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XlsFynsbg%3D&md5=edbf2ecdb5170364f74474205a235af0CAS | 22437917PubMed |
[16] R. Roskoski, Biochem. Biophys. Res. Commun. 2007, 356, 323.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXjsVGisLo%3D&md5=dea119572c30d4cdbb6e7ee2b5c4e978CAS | 17367763PubMed |
[17] C. R. Prakash, S. Raja, Mini Rev. Med. Chem. 2012, 12, 98.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XivFSqtbY%3D&md5=f9dbea975dc1d63bf26b526faf7e03eeCAS | 22372601PubMed |
[18] L. Sun, C. Liang, S. Shirazian, Y. Zhou, T. Miller, J. Cui, J. Y. Fukuda, J.-Y. Chu, A. Nematalla, X. Wang, H. Chen, A. Sistla, T. C. Luu, F. Tang, J. Wei, C. Tang, J. Med. Chem. 2003, 46, 1116.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXhslSlsbg%3D&md5=6b0c2fb4cb8edee086fb1d078c1eee96CAS | 12646019PubMed |
[19] A. D. Abell, B. K. Nabbs, A. R. Battersby, J. Am. Chem. Soc. 1998, 120, 1741.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXhsVektL0%3D&md5=a5c7ef7edbb3e4cdd61b87e1011b7b62CAS |
[20] J.-R. Schauder, S. Jendrezejewski, A. Abell, G. J. Hart, A. R. Battersby, J. Chem. Soc. Chem. Commun. 1987, 436.
| Crossref | GoogleScholarGoogle Scholar |
[21] E. Arunan, G. R. Desiraju, R. A. Klein, J. Sadlej, S. Scheiner, I. Alkorta, D. C. Clary, R. H. Crabtree, J. J. Dannenberg, P. Hobza, H. G. Kjaergaard, A. C. Legon, B. Mennucci, D. J. Nesbitt, Pure Appl. Chem. 2011, 83, 1637.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhs1Orsb7F&md5=a52a39a9b090bc7be16676410f86de28CAS |
[22] L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. McMahon, C. Tang, J. Med. Chem. 1998, 41, 2588.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXkt12jtrw%3D&md5=754f9f3559aa406e6e2188c4f279a666CAS | 9651163PubMed |
[23] K. J. Brown, S. F. Maynes, A. Bezos, D. J. Maguire, M. D. Ford, C. R. Parish, Lab. Invest. 1996, 75, 539.
| 1:CAS:528:DyaK28XmvFWms70%3D&md5=32f439df52342acb5507ae6f575e22a2CAS | 8874385PubMed |
[24] C. R. Parish, C. Freeman, K. J. Brown, D. J. Francis, W. B. Cowden, Cancer Res. 1999, 59, 3433.
| 1:CAS:528:DyaK1MXks1OmsLs%3D&md5=a1ed647559dcb68ef8356c702f140a3cCAS | 10416607PubMed |
[25] P.-J. Chen, S. Chang, Medigen Biotechnology Corporation, A Phase III Study of PI-88 in the Adjuvant Treatment of Subjects with Hepatitis Virus Related Hepatocellular Carcinoma After Surgical Resection. Available at http://www.cancer.gov/clinicaltrials/search/view?cdrid=706994&version=HealthProfessional&protocolsearchid=11780342 (accessed 5 June 2013).
[26] Z. Otwinowski, W. Minor, in Methods in Enzymology:Macromolecular Crystallography, Part A (Eds C. W. Carter Jr, R. M. Sweet) 1997, Vol. 276, pp. 307–326 (Academic: New York, NY).
[27] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, J. Appl. Cryst. 1994, 27, 435.
[28] P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout, D. J. Watkin, J. Appl. Cryst. 2003, 36, 1487.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXptFekt78%3D&md5=27ab58411389a62e3ab495bba39187feCAS |
[29] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J. Appl. Cryst. 1999, 32, 115.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhsFOrsbo%3D&md5=55cf028ec17bfae20ae728ca395b451cCAS |
[30] G. M. Sheldrick, Acta Crystallogr. A 2008, 64, 112.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsVGhurzO&md5=c16dcfe329fce2375df65b1474a83185CAS | 18156677PubMed |
