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Synthesis 2019; 51(23): 4443-4451
DOI: 10.1055/s-0039-1690198
DOI: 10.1055/s-0039-1690198
paper
The Synthesis and Biological Evaluation of Indolactam Alkaloids
This research was financially supported by start-up funds granted by the College of Natural Sciences and Mathematics at California State University, Fullerton. Instrumentation support was provided by the National Science Foundation MRI (CHE-1726903) for acquisition of a UPLC-MS system.Further Information
Publication History
Received: 17 July 2019
Accepted after revision: 13 August 2019
Publication Date:
30 August 2019 (online)
Abstract
In this work, we execute a general synthetic strategy to access novel indolactam alkaloids, which are agonists of protein kinase C. This protocol allowed for the most efficient reported syntheses of indolactam V (ILV) stereoisomers, while also affording the large-scale production of natural product (–)-ILV. Structure–activity studies were conducted with these compounds to elucidate the elements necessary to promote PKC-mediated cellular response. EC50 measurements in leukemia and lymphoma cell lines, as well as molecular docking analyses with the PKCδ C1B domain, provided the foundation for these studies. A distinct correlation between in vitro activity and the conformation of the macrocyclic lactam ring was discovered, which can guide design efforts for therapeutics that target the PKC regulatory domain.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690198.
- Supporting Information
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References
- 1 Protein Kinase C . Dekker LV. Springer; New York: 2004
- 2a Whiteside CI, Dlugosz JA. Am. J. Physiol. 2002; 282: F975
- 2b Vlahos CJ, McDowell SA, Clerk A. Nat. Rev. Drug Discovery 2003; 2: 99
- 2c Greenberg DA. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 7943
- 2d Etcheberrigaray R, Tan M, Dewachter I, Kuiperi C, Van der Auwera I, Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, Van Leuven F, Alkon DL. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11141
- 3 Griner EM, Kazanietz MG. Nat. Rev. Cancer 2007; 7: 281
- 4a Carter CA, Kane CJ. M. Curr. Med. Chem. 2004; 11: 2883
- 4b O’Brian CA, Ward NE, Stewart JR, Chu F. Cancer Metastasis Rev. 2001; 20: 95
- 4c Battaini F. Pharmacol. Res. 2001; 44: 353
- 4d Ma D. Curr. Med. Chem. 2001; 8: 191
- 4e Marquez VE, Blumberg PM. Acc. Chem. Res. 2003; 36: 434
- 5a Endo Y, Takehana S, Ohno M, Driedger PE, Stabel S, Mizutani MY, Tomioka N, Itai A, Shudo K. J. Med. Chem. 1998; 41: 1476
- 5b Wender PA, Koehler KF, Sharkey NA, Dell’Aquila ML, Blumberg PM. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 4214
- 6 Fujiki H, Sugimura T. Adv. Cancer Res. 1987; 49: 223
- 7a Endo Y, Shudo K, Furuhata K, Ogura H, Sakai S, Aimi N, Hitotsuyanagi Y, Koyama Y. Chem. Pharm. Bull. 1984; 32: 358
- 7b Endo Y, Shudo K, Itai A, Hasegawa M, Sakai S. Tetrahedron 1986; 42: 5905
- 7c de Laszlo SE, Ley SV, Porter RA. J. Chem. Soc., Chem. Commun. 1986; 344
- 7d Mascal M, Moody CJ. J. Chem. Soc., Chem. Commun. 1988; 589
- 7e Masuda T, Nakatsuka S, Goto T. Agric. Biol. Chem. 1989; 53: 2257
- 7f Kogan TP, Somers TC, Venuti MC. Tetrahedron 1990; 46: 6623
- 7g Mascal M, Moody CJ, Slawin AM. Z, Williams D. J. Chem. Soc., Perkin Trans. 1 1992; 823
- 7h Semmelhack MF, Rhee HA. Tetrahedron Lett. 1993; 34: 1395
- 7i Quick J, Saha B, Driedger PE. Tetrahedron Lett. 1994; 35: 8549
- 7j Bronner SM, Goetz AE, Garg NK. J. Am. Chem. Soc. 2011; 133: 3832
- 7k Xu Z, Zhang F, Zhang L, Jia Y. Org. Biomol. Chem. 2011; 9: 2512
- 7l Nathel NF. F, Shah TK, Bronner SM, Garg NK. Chem. Sci. 2014; 5: 2184
- 7m Noji T, Okano K, Tokuyama H. Tetrahedron 2015; 71: 3833
- 7n Haynes-Smith J, Diaz I, Billingsley KL. Org. Lett. 2016; 18: 2008
- 7o Nakamura H, Yasui K, Kanda Y, Baran PS. J. Am. Chem. Soc. 2019; 141: 1494
- 8 Fujiki H, Suganuma M, Nakayasu M, Tahira T, Endo Y, Shudo K, Sugimura T. Gann 1984; 75: 866
- 9a Endo Y, Shudo K, Okamoto T. Chem. Pharm. Bull. 1982; 30: 3457
- 9b Nakatsuka S.-i, Masuda T, Sakai K, Goto T. Tetrahedron Lett. 1986; 27: 5735
- 9c Mari M, Bartoccini F, Piersanti G. J. Org. Chem. 2013; 78: 7727
- 10 Choi DW, Hartley DM. US5292765A, 1994
- 11 Kawai T, Ichinose T, Endo Y, Shudo K, Itai A. J. Med. Chem. 1992; 35: 2248
- 12 Mendoza M, Rao N, Tran U, Castaneda C, Billingsley KL. Tetrahedron 2019; 75: 4337
- 13 Angelini E, Balsamini C, Bartoccini F, Lucarini S, Piersanti G. J. Org. Chem. 2008; 73: 5654
- 14a Kortmansky J, Schwartz GK. Cancer Invest. 2003; 21: 924
- 14b Kollár P, Rajchard J, Balounová Z, Pazourek J. Pharm. Biol. 2014; 52: 237
- 15 Nakagawa Y, Irie K, Yanagita RC, Ohigashi H, Tsuda K. J. Am. Chem. Soc. 2005; 127: 5746
- 16 Irie K, Isaka T, Iwata Y, Yanai Y, Nakamura Y, Koizumi F, Ohigashi H, Wender PA, Satomi Y, Nishino H. J. Am. Chem. Soc. 1996; 118: 10733
- 17 Kawai T, Ichinose T, Takeda M, Tomioka N, Endo Y, Yamaguchi K, Shudo K, Itai A. J. Org. Chem. 1992; 57: 6150
- 18 Hesek D, Lee M, Noll BC, Fisher JF, Mobashery S. J. Org. Chem. 2009; 74: 2567