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DOI: 10.1055/a-2564-5063
DOI: 10.1055/a-2564-5063
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Small Molecules in Medicinal Chemistry
Indolactam Alkaloids: Syntheses and Emerging Therapeutic Applications
This research was supported by funds granted by the College of Arts and Sciences at Loyola University Chicago.
Abstract
Protein kinase C (PKC) enzymes play critical regulatory roles in maintaining cellular homeostasis. In turn, specific isoforms have emerged as targets for therapeutic intervention, and recent studies have highlighted the importance of PKC activation in preventing cancer cell proliferation. The indolactam alkaloids are a family of natural products that potently activate conventional and novel PKC isozymes. Importantly, this activity offers new opportunities for drug design and the development of novel chemotherapeutics. In this review, we describe our recent synthetic studies aimed at accessing numerous members of this natural product family. We also detail various approaches to prepare focused libraries of indolactam-based analogues. These efforts have facilitated medicinal chemistry studies of the indolactam scaffold and importantly provided a preclinical platform for evaluating PKC activation as a therapeutic strategy in multiple cancer models.
1 Introduction
2 Total Syntheses of Indolactam Alkaloids
3 Biological Studies of Indolactam Alkaloids
4 Conclusions and Outlook
Publikationsverlauf
Eingereicht: 26. Februar 2025
Angenommen nach Revision: 21. März 2025
Accepted Manuscript online:
21. März 2025
Artikel online veröffentlicht:
29. April 2025
© 2025. Thieme. All rights reserved
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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References
- 1 Newton AC. Crit. Rev. Biochem. Mol. Biol. 2018; 53: 208
- 2 Jaken S. Curr. Opin. Cell Biol. 1996; 8: 168
- 3 Black AR, Black JD. Front. Immunol. 2012; 3: 423
- 4 Nam KY, Morino A, Kimura S, Fujiki H, Imanishi Y. Biochem. J. 1990; 268: 169
- 5 Livneh E, Fishman DD. Eur. J. Biochem. 1997; 248: 1
- 6 Giese KP, Mizuno K. Learn. Mem. 2013; 20: 540
- 7 Callender JA, Newton AC. Neuronal Signaling. NS20160005, 2017 1(2).
- 8 Aksoy E, Goldman M, Willems F. Int. J. Biochem. Cell Biol. 2004; 36: 183
- 9 Aquino A, Bianchi N, Terrazzan A, Franzese O. Biology 2023; 12: 1047
- 10 Geraldes P, King GL. Circ. Res. 2010; 106: 1319
- 11 Changkakoti L, Das JM, Borah R, Rajabalaya R, David SR, Balaraman AK, Pramanik S, Haldar PK, Bala A. Endocr., Metab. Immune Disord.: Drug Targets 2024; 24: 777
- 12 Naruse K, King GL. Circ. Res. 2000; 86: 1104
- 13 Palaniyandi SS, Sun L, Ferreira JC, Mochly-Rosen D. Cardiovasc. Res. 2009; 82: 229
- 14 Zhou Z, Chen F, Zhong S, Zhou Y, Zhang R, Kang K, Zhang X, Xu Y, Zhao M, Zhao C. Aging 2020; 12: 21798
- 15 Salzer E, Santos-Valente E, Keller B, Warnatz K, Boztug K. J. Clin. Immunol. 2016; 36: 631
- 16 Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, Trotter EW, Gallegos LL, Miller CJ, Furnari FB, Hunter T, Brognard J, Newton AC. Cell 2015; 160: 489
- 17 Isakov N. Semin. Cancer Biol. 2018; 48: 36
- 18 He S, Li Q, Huang Q, Cheng J. Cancers 2022; 14: 3832
- 19 Kikkawa U, Takai Y, Tanaka Y, Miyake R, Nishizuka Y. J. Biol. Chem. 1983; 258: 11442
- 20 Kraft AS, Smith JB, Berkow RL. Proc. Natl. Acad. Sci. USA 1986; 83: 1334
- 21 Wender PA, Cribbs CM, Koehler KF, Sharkey NA, Herald CL, Kamano Y, Pettit GR, Blumberg PM. Proc. Natl. Acad. Sci. USA 1988; 85: 7197
- 22 de Vries DJ, Herald CL, Pettit GR, Blumberg PM. Biochem. Pharmacol. 1988; 37: 4069
- 23 Arcoleo JP, Weinstein IB. Carcinogenesis 1985; 6: 213
- 24 Kikumori M, Yanagita RC, Tokuda H, Suzuki N, Nagai H, Suenaga K, Irie K. J. Med. Chem. 2012; 55: 5614
- 25 Sekido T, Yamamoto K, Yanagita RC, Kawamani Y, Hanaki Y, Irie K. Bioorg. Med. Chem. 2022; 73: 116988
- 26 Hanaki Y, Shikata Y, Kikumori M, Okamura M, Dan S, Imoto M, Irie K. Biochem. Biophys. Res. Commun. 2023; 675: 19
- 27 DeChristopher BA, Loy BA, Marsden MD, Schrier AJ, Zack JA, Wender PA. Nat. Chem. 2012; 4: 705
- 28 Wender PA, Baryza JL, Brenner SE, DeChristopher BA, Loy BA, Schrier AJ, Verma VA. Proc. Natl. Acad. Sci. USA 2011; 108: 6721
- 29 Trost BM, Yang H, Thiel OR, Frontier AJ, Brindle CS. J. Am. Chem. Soc. 2007; 129: 2206
- 30 Wender PA, Sloane JL, Luu-Nguyen QH, Ogawa Y, Shimizu AJ, Ryckbosch SM, Tyler JH, Hardman C. J. Org. Chem. 2020; 85: 15116
- 31 Newton AC. Semin. Cancer Biol. 2018; 48: 18
- 32 Pearson LA, Karuso P, Neilan BA. Alkaloids: Chem. Biol. 2024; 92: 1
- 33 Endo Y, Shudo K, Okamoto T. Chem. Pharm. Bull. 1982; 30: 3457
- 34 Endo Y, Shudo K, Itai A, Hasegawa M, Sakai S. Tetrahedron 1986; 42: 5905
- 35 Irie K, Hirota M, Hagiwara N, Koshimizu K, Hayashi H, Murao S, Tokuda H, Ito Y. Agric. Biol. Chem. 1984; 48: 1269
- 36 Irie K, Kajiyama S, Koshimizu K, Hayashia H, Arai M. Tetrahedron Lett. 1990; 31: 7337
- 37 Hagiwara N, Irie K, Funaki A, Hayashi H, Arai M, Koshimizu K. Agric. Biol. Chem. 1987; 52: 641
- 38 Irie K, Hagiwara N, Kurome T, Hayashi H, Arai M, Koshimizu K. Agric. Biol. Chem. 1987; 51: 285
- 39 Irie K, Hagiwara N, Funaki A, Hayashi H, Arai M, Koshimizi K. Agric. Biol. Chem. 1987; 51: 1733
- 40 Aimi N, Odaka H, Sakai S, Fujiki H, Suganuma M, Moore RE, Patterson GM. J. Nat. Prod. 1990; 53: 1593
- 41 Sun HH, White CB, Dedinas J, Cooper R, Sedlock DM. J. Nat. Prod. 1991; 54: 1440
- 42 Yamashita T, Imoto M, Isshiki K, Saw T, Naganawa H, Kurasawa S, Zhu B, Umezawa K. J. Nat. Prod. 1988; 51: 1184
- 43 Irie K, Kajiyama S, Okuno S, Kondo M, Koshimizu K, Hayashi H, Arai M, Nishino H, Iwashima A. J. Nat. Prod. 1994; 57: 363
- 44 Cardellina JH, Marner FJ, Moore RE. Science 1979; 204: 193
- 45 Sakai S, Hitotsuyanagi Y, Aimi N, Fujiki H, Suganuma M, Sugimura T, Endo Y, Shudo K. Tetrahedron Lett. 1986; 27: 5219
- 46 Izumikawa M, Khan ST, Komaki H, Takagi M, Shin-Ya K. J. Antibiot. 2010; 63: 33
- 47 Jiang W, Tan S, Hanaki Y, Irie K, Uchida H, Watanabe R, Suzuki T, Sakamoto B, Kamio M, Nagai H. Mar. Drugs 2014; 12: 5788
- 48 Youssef DT, Shaala LA, Mohamed GA, Ibrahim SR, Banjar ZM, Badr JM, McPhail KL, Risinger AL, Mooberry SL. Nat. Prod. Res. 2015; 29: 703
- 49 Kumagai H, Iijima M, Dobashi K, Naganawa H, Sawa T, Hamada M, Ishizuka M, Takeuchi T. J. Antibiot. 1991; 44: 1029
- 50 Irie K, Funaki A, Koshimizu K, Hayashi H, Arai M. Tetrahedron Lett. 1989; 30: 2113
- 51 Ichiyanagi Y, Fujiki H, Suganuma M, Aimi N, Sakai S, Endo Y, Sugimura T. Chem. Pharm. Bull. 1984; 32: 4233
- 52 Hitotsuyanagi Y, Yamaguchi K, Ogata K, Aimi N, Sakai S, Koyama Y, Endo Y, Shudo K, Itai A, Iitaka Y. Chem. Pharm. Bull. 1984; 32: 3774
- 53 Sakai S, Aimi N, Yamaguchi K, Hitotsuyanagi Y, Watanabe C, Yokose K, Koyama Y, Shudo K, Itai A. Chem. Pharm. Bull. 1984; 32: 354
- 54 Sakai S, Hitotsuyanagi Y, Yamaguchi K, Aimi N, Ogata K, Kuramochi T, Seki H, Hara R, Fujiki H, Suganuma M. Chem. Pharm. Bull. 1986; 34: 4883
- 55 Kozikowski AP, Shum PW, Basu A, Lazo JS. J. Med. Chem. 1991; 34: 2420
- 56 Jiang W, Zhou W, Uchida H, Kikumori M, Irie K, Watanabe R, Suzuki T, Sakamoto B, Kamio M, Nagai H. Mar. Drugs 2014; 12: 2748
- 57 Endo Y, Takehana S, Ohno M, Driedger PE, Stabel S, Mizutani MY, Tomioka N, Itai A, Shudo K. J. Med. Chem. 1998; 41: 1476
- 58 Huang H, Yao Y, He Z, Yang T, Ma J, Tian X, Li Y, Huang C, Chen X, Li W, Zhang S, Zhang C, Ju J. J. Nat. Prod. 2011; 74: 2122
- 59 Kajiyama S, lrie K, Kido T, Koshimizu K, Hayashi H, Arai M. Tetrahedron 1991; 47: 5453
- 60 Nakagawa Y, Irie K, Ohigashi H, Hayashi H, Wender PA. Bioorg. Med. Chem. Lett. 2000; 10: 2087
- 61 Hirota M, Suganuma M, Yoshizawa S, Horiuchi T, Nakayasu M, Hasegawa M, Endo Y, Shudo K, Fujiki H. Jpn. J. Cancer Res. 1987; 78: 577
- 62 Endo Y, Ohno M, Hirano M, Itai A, Shudo K. J. Am. Chem. Soc. 1996; 118: 1841
- 63 Endo Y, Hasegawa M, Itai A, Shudo K. Tetrahedron 1987; 43: 3695
- 64 Fujiki H, Mori M, Nakayasu M, Terada M, Sugimura T. Biochem. Biophys. Res. Commun. 1979; 90: 976
- 65 Tsai JY, Redei D, Hohmann J, Wu CC. Int. J. Mol. Sci. 2020; 21: 7579
- 66 Irie K, Yanagita RC. Chem. Rec. 2014; 14: 251
- 67 Quick J, Saha B, Driedger PE. Tetrahedron Lett. 1994; 35: 8549
- 68 Nakatsuka S, Masuda T, Sakai K, Goto T. Tetrahedron Lett. 1986; 27: 5735
- 69 de Laszlo SE, Ley SV, Porter RA. J. Chem. Soc., Chem. Commun. 1986; 344
- 70 Kogan TP, Somers TC, Venuti MC. Tetrahedron 1990; 46: 6623
- 71 Semmelhack MF, Rhee H. Tetrahedron Lett. 1993; 34: 1395
- 72 Xu Z, Zhang F, Zhang L, Jia Y. Org. Biomol. Chem. 2011; 9: 2512
- 73 Bronner SM, Goetz AE, Garg NK. J. Am. Chem. Soc. 2011; 133: 3832
- 74 Nathel NF, Shah TK, Bronner SM, Garg NK. Chem. Sci. 2014; 5: 2184
- 75 Mascal M, Moody CJ. J. Chem. Soc., Chem. Commun. 1988; 565
- 76 Noji T, Okano K, Tokuyama H. Tetrahedron 2015; 71: 3833
- 77 Nakamura H, Yasui K, Kanda Y, Baran PS. J. Am. Chem. Soc. 2019; 141: 1494
- 78 Haynes-Smith J, Diaz I, Billingsley KL. Org. Lett. 2016; 18: 2008
- 79 Thomas C, Wu M, Billingsley KL. J. Org. Chem. 2016; 81: 330
- 80 Mendoza M, Rao N, Tran U, Castaneda C, Billingsley KL. Tetrahedron 2019; 75: 4337
- 81 Mendoza M, Eomb R, Salasa C, Haynes-Smith J, Billingsley KL. Synthesis 2019; 51: 4443
- 82 Yanagita RC, Torii K, Nakagawa Y, Irie K. Heterocycles 2007; 73: 289
- 83 Meseguer B, Alonso-Diaz D, Griebenow N, Herget T, Waldmann H. Angew. Chem. Int. Ed. 1999; 38: 2902
- 84 Okabe K, Muratake H, Natsume M. Tetrahedron 1990; 46: 5113
- 85 Moreno OA, Kishi Y. Bioorg. Med. Chem. 1998; 6: 1243
- 86 Yang Y, Buchwald SL. J. Am. Chem. Soc. 2013; 135: 10642
- 87 Mendoza M, Tran U, Zhang GC, Leister J, To K, Malepeai-Tofaeono T, Ondrus AE, Billingsley KL. ACS Med. Chem. Lett. 2022; 13: 1036
- 88 Muratake H, Natsume M. Tetrahedron Lett. 1987; 28: 2265
- 89 MacQueen J, Wilber C, Faiq S, Billingsley KL. J. Org. Chem. 2025; 90: 1214
- 90 Takashima M, Sakai H, Mori R, Arima K. Agric. Biol. Chem. 1962; 26: 660
- 91 Irie K, Hagiwara N, Koshimizu K, Tokuda H, Ito Y, Hayashi H, Murao S. Agric. Biol. Chem. 1985; 49: 1441
- 92 Irie K, Tokudo H, Hagiwara N, Koshimizu K, Hayashi H, Murao S, Ito Y. Int. J. Cancer 1985; 36: 485
- 93 Fujiki H, Suganuma M, Nakayasu M, Tahira T, Endo Y, Shudo K, Sugimura T. Jpn. J. Cancer Res. 1984; 75: 866
- 94 Choi, D. W.; Hartley, D. M. Neuroprotection by Indolactam V and Derivatives Thereof. U.S. Patent WO 5292765, March 8, 1994.
- 95 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
- 96 Igumenova TI. Biochemistry 2015; 54: 4953
- 97 Nakagawa Y, Irie K, Nakamura Y, Ohigashi H, Hayashi H. Biosci., Biotechnol., Biochem. 1998; 62: 1568
- 98 Irie K, Okuno S, Kajiyama S, Koshimizu K, Nishino H, Iwashima A. Carcinogenesis 1991; 12: 1883
- 99 Fürstenberger G, Berry DL, Sorg B, Marks F. Proc. Natl. Acad. Sci. USA 1981; 78: 7722
- 100 Blumberg PM, Jaken S, Konig B, Sharkey NA, Leach KL, Jeng AY, Yeh E. Biochem. Pharmacol. 1984; 33: 933
- 101 Hennings H, Blumberg PM, Pettit GR, Herald CL, Shores R, Yuspa SH. Carcinogenesis 1987; 8: 1343
- 102 Wu R, Chen H, Chang N, Xu Y, Jiao J, Zhang H. Chem. Eur. J. 2020; 26: 1166
- 103 Kollar P, Rajchard J, Balounova Z, Pazourek J. Pharm. Biol. 2014; 52: 237
- 104 Mochly-Rosen D, Das K, Grimes KV. Nat. Rev. Drug Discovery 2012; 11: 937
- 105 Sanders JL, Stern PH. J. Bone Miner. Res. 1996; 11: 1862
- 106 Jaken S, Armen H, Tashjian J, Blumberg PM. Cancer Res. 1981; 41: 2175
- 107 Szallasi Z, Krsmanovic L, Blumberg PM. Cancer Res. 1993; 53: 2507
- 108 Nakagawa Y, Yanagita RC, Hamada N, Murakami A, Takahashi H, Saito N, Nagai H, Irie K. J. Am. Chem. Soc. 2009; 131: 7573
- 109 Kamachi H, Tanaka K, Yanagita RC, Murakami A, Murakami K, Tokuda H, Suzuki N, Nakagawa Y, Irie K. Bioorg. Med. Chem. 2013; 21: 2695
- 110 Kedei N, Lubart E, Lewin NE, Telek A, Lim L, Mannan P, Garfield SH, Kraft MB, Keck GE, Kolusheva S, Jelinek R, Blumberg PM. ChemBioChem 2011; 12: 1242
- 111 Kozikowski AP, Nowak I, Petukhov PA, Etcheberrigaray R, Mohamed A, Tan M, Lewin N, Hennings H, Pearce LL, Blumberg PM. J. Med. Chem. 2003; 46: 364
- 112 Tran U, Billingsley KL. Bioorg. Med. Chem. Lett. 2024; 97: 129570
- 113 Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. Bosnian J. Basic Med. Sci. 2018; 18: 8
- 114 Lauth M, Bergstrom A, Toftgard R. Oncogene 2007; 26: 5163
- 115 Riobo NA, Haines GM, Emerson CP. Jr. Cancer Res. 2006; 66: 839
- 116 Hom ME, Ondrus AE, Sakata-Kato T, Rack PG, Chen JK. ChemMedChem 2020; 15: 1044
- 117 Nakatsuka S, Masuda T, Goto T. Tetrahedron Lett. 1987; 28: 3671
- 118 Okabe K, Muratake H, Natsume M. Tetrahedron 1991; 47: 8559
