Research progress of glutarimide-containing polyketides: Structures, bioactivities and their biosynthesis

Abstract

Glutarimide-containing polyketides (GPs) are an important class of natural products with antifungal, antibacterial, antitumor and other biological activities. Generally, the structures have a six-membered ring of glutarimide (also known as 2,6-piperidinedione) and a polyketide side chain or a ring of varying lengths attached at C4 such as cycloheximide, 9-methylstreptimidone and migrastatin. Currently, at least 65 natural glutarimide antibiotics have been isolated and identified. The novel biosynthetic mechanism of the trans-AT PKS and multifaceted modes of action have promoted the progressive exploration of glutarimide-containing products. However, the related information on the aspects of new structure discovery, biological activity and biosynthesis of GPs is still not available. This review summarizes the current research from the aspects of new structure discovery, biological activity and biosynthesis, aiming to provide a reference for in-depth products mining and structure-activity relationship research. Special emphasis is placed on their potential as drug leads, particularly in cancer therapy, and the role of modern analytical techniques in their discovery and characterization.

Keywords

Glutarimide-containing polyketides / 2,6-Piperidinedione / Trans-AT PKS / Biosynthesis

References

[1] B.E. Leach, J.H. Ford, A.J. Whiffen, Actidione, an antibiotic from Streptomyces griseus, J. Am. Chem. Soc. 69 (1947) 474, https://doi.org/10.1021/ja01194a519.

[2] S.K. Lim, J. Ju, E. Zazopoulos, H. Jiang, J.W. Seo, Y. Chen, Z. Feng, S.R. Rajski, C.M. Farnet, B. Shen, iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL 18993 is governed by a single biosyntheticmachinery featuring an acyltransferase-less type I polyketide synthase, J. Biol. Chem. 284 (2009) 29746-29756, https://doi.org/10.1074/jbc.M109.046805.

[3] T. Sonoda, H. Osada, J. Uzawa, K. Isono, Actiketal, a new member of the glutarimide antibiotics, J. Antibiot. (Tokyo) 44 (1991) 160-163, https://doi.org/10.7164/antibiotics.44.160.

[4] B. Lee, S. Son, J.K. Lee, M. Jang, K.T. Heo, S.K. Ko, D.J. Park, C.S. Park, C.J. Kim, J.S. Ahn, B.Y. Hwang, J.H. Jang, Y.S. Hong, Isolation of new streptimidone derivatives, glutarimide antibiotics from Streptomyces sp. W 3002 using LC-MSguided screening, J. Antibiot. (Tokyo) 73 (2020) 184-188, https://doi.org/10.1038/s41429-019-0264-y.

[5] X.L. Zhao, H. Wang, Z.L. Xue, J.S. Li, H. Qi, H. Zhang, T. Zhao, J.D. Wang, W.S. Xiang,Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780, J. Antibiot. (Tokyo) 72 (2019) 241-245, https://doi.org/10.1038/s41429-019-0143-6.

[6] H. Chen, X. Bai, T. Sun, X. Wang, Y. Zhang, X. Bian, H. Zhou, The genomic-driven discovery of glutarimide-containing derivatives from Burkholderia gladioli, Molecules 28 (2023) 6937, https://doi.org/10.3390/molecules28196937.

[7] I.T. Nakou, M. Jenner, Y. Dashti, I. Romero-Canelon, J. Masschelein, E. Mahenthiralingam, G.L. Challis, Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism, Angew. Chem., Int. Ed. Engl. 59 (2020)23145-23153, https://doi.org/10.1002/anie.202009007.

[8] R.P. Awal, P.A. Haack, C.D. Bader, C.N. Riese, D. Schuler, R. Muller, Sesbanimide R, a novel cytotoxic polyketide produced by Magnetotactic bacteria, mBio 12 (2021) e00591, https://doi.org/10.1128/mBio.00591-21,21.

[9] B.S. Kim, S.S. Moon, B.K. Hwang, Isolation, antifungal activity, and structure elucidation of the glutarimide antibiotic, streptimidone, produced by Micromonospora coerulea, J. Agric. Food Chem. 47 (1999) 3372-3380, https://doi.org/10.1021/jf981259s.

[10] C. Acebal, R. Alcazar, L.M. Canedo, F. de la Calle, P. Rodriguez, F. Romero, J.L. Fernandez Puentes, Two marine Agrobacterium producers of sesbanimide antibiotics, J. Antibiot. (Tokyo) 51 (1998) 64-67, https://doi.org/10.7164/antibiotics.51.64.

[11] D. Kacar, L.M. Cañedo, P. Rodríguez, E.G. Gonzalez, B. Galan, C. Schleissner, S. Leopold-Messer, J. Piel, C. Cuevas, F. de la Calle, J.L. García, Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors, Environ. Microbiol. 23 (2021) 2509-2521,https://doi.org/10.1111/1462-2920.15470.

[12] N. Saito, F. Suzuki, K. Sasaki, N. Ishida, Antiviral and interferon-inducing activity of a new glutarimide antibiotic, 9-methylstreptimidone, Antimicrob. Agents Chemother. 10 (1976) 14-19, https://doi.org/10.1128/AAC.10.1.14.

[13] K. Nakae, Y. Yoshimoto, T. Sawa, Y. Homma, M. Hamada, T. Takeuchi, M. Imoto, Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929-43 F1. Taxonomy, fermentation, isolation and biological activities, J. Antibiot. (Tokyo) 53 (2000) 1130-1136, https://doi.org/10.7164/antibiotics.53.1130.

[14] J.R. Lohman, M. Ma, J. Osipiuk, B. Nocek, Y. Kim, C. Chang, M. Cuff, J. Mack, L. Bigelow, H. Li, M. Endres, G. Babnigg, A. Joachimiak,G.N. Phillips Jr., B. Shen, Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases, Proc. Natl. Acad. Sci. USA 112 (2015) 12693-12698, https://doi.org/10.1073/pnas.1515460112.

[15] E.C. Kornfeld, R.G. Jones, T.V. Parke, The structure and chemistry of actidione, an antibiotic from Streptomyces griseus, J. Am. Chem. Soc. 71 (1949) 150-159,https://doi.org/10.1021/ja01169a041.

[16] F. Johnson, N.A. Starkovsky, W.D. Gurowitz, Glutarimide antibiotics. Vii. The synthesis of DL-neocycloheximide and the determination of the cyclohexanone ring stereochemistry of cycloheximide, its isomers, and inactone, J. Am. Chem. Soc. 87 (1965) 3492-3500, https://doi.org/10.1021/ja01093a038.

[17] R.J. Highet, V. Prelog,Stoffwechselprodukte von actinomyceten.18. Actiphenol, Helv. Chim. Acta 42 (1959) 1523-1526, https://doi.org/10.1002/hlca.19590420514.

[18] M. Yin, Y. Yan, J.R. Lohman, S.X. Huang, M. Ma, G.R. Zhao, L.H. Xu, W. Xiang, B. Shen,Cycloheximide and actiphenol production in Streptomyces sp. YIM56141 governed by single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase, Org. Lett. 16 (2014) 3072-3075, https://doi.org/10.1021/ol501179w.

[19] J.Q. Hu, A. Zhang, H. Wang, L. Niu, Q.X. Wang, L.L. Zhu, Y.Z. Li, C. Wu, Discovery and biosynthesis of glycosylated cycloheximide from a millipede-associated Actinomycete, J. Nat. Prod. 86 (2023) 340-345, https://doi.org/10.1021/acs.jnatprod.2c00951.

[20] D.H. Yan, M.Q. Zhou, A. Adduri, Y.H. Zhuang, M. Guler, S.T. Liu, H. Shin, T. Kovach, G. Oh, X. Liu, Y.T. Deng, X.F. Wang, L. Cao, D.H. Sherman, P.J. Schultz, R.D. Kersten, J.A. Clement, A. Tripathi, B. Behsaz, H. Mohimani, Discovering type I cis-AT polyketides through computational mass spectrometry and genome mining with Seq2PKS, Nat. Commun. 15 (2024) 5356, https://doi.org/10.1038/S41467-024-49587-1.

[21] D. Sun, W. Sun, Y. Yu, Z. Li, Z. Deng, S. Lin, A new glutarimide derivative from marine sponge-derived Streptomyces anulatus S71, Nat. Prod. Res. 28 (2014) 1602-1606, https://doi.org/10.1080/14786419.2014.928877.

[22] J. Hua, Y. Xie, The isolation and structure of antibiotics Nongkang 101-F and G, Hua Hsueh Hsueh Pao 38 (1980) 275-282, https://doi.org/10.7164/antibiotics.50.449.

[23] T.E. Eble, M.E. Bergy, C.M. Large, R.R. Herr, W.G. Jackson, Isolation, purification, and properties of streptovitacins A and B, Antibiot, Annu. 6 (1958) 555-559.

[24] D. Zhang, W. Yi, H. Ge, Z. Zhang, B. Wu, Bioactive streptoglutarimides A-J from the marine-derived Streptomyces sp, ZZ741, J. Nat. Prod. 82 (2019) 2800-2808, https://doi.org/10.1021/acs.jnatprod.9b00481.

[25] T. Sonoda, K. Kobayashi, M. Ubukata, H. Osada, K. Isono, Absolute configuration of epiderstatin, a new glutarimide antibiotic produced by Streptomyces pulveraceus, J. Antibiot. (Tokyo) 45 (1992) 1963-1965, https://doi.org/10.7164/antibiotics.45.1963.

[26] H. Osada, T. Sonoda, H. Kusakabe, K. Isono, Epiderstatin, a new inhibitor of the mitogenic activity induced by epidermal growth factor. I. Taxonomy, fermentation, isolation and characterization, J. Antibiot. (Tokyo) 42 (1989) 1599-1606, https://doi.org/10.7164/antibiotics.42.1599.

[27] T. Sonoda, H. Osada, M. Uramoto, J. Uzawa, K. Isono, Epiderstatin, a new inhibitor of the mitogenic activity induced by epidermal growth factor. II. Structure elucidation, J. Antibiot. (Tokyo) 42 (1989) 1607-1609, https://doi.org/10.7164/antibiotics.42.1607.

[28] T. Fukuda, A. Matsumoto, Y. Takahashi, H. Tomoda, S. Omura, Phenatic acids A and B, new potentiators of antifungal miconazole activity produced by Streptomyces sp. K03-0132, J. Antibiot. (Tokyo) 58 (2005) 252-259, https://doi.org/10.1038/ja.2005.29.

[29] H. Kondo, T. Oritani, K. Yamashita,Synthetic studies on glutarimide antibiotics.2. syntheses and biological-activities of ( þ/-)-streptovitacin A and E-73, Agr. Biol. Chem. Tokyo 54 (1990) 1531-1536, https://doi.org/10.1080/00021369.1990.10870139.

[30] R.P. Frohardt, H.W. Dion, Z.L. Jakubowski, A. Ryder, J.C. French, Q.R. Bartz, Chemistry of streptimidone, a new antibiotic, J. Am. Chem. Soc. 81 (1959)5500-5506, https://doi.org/10.1021/Ja01529a059.

[31] N. Saito, F. Kitame, M. Kikuchi, N. Ishida, Studies on a new antiviral antibiotic, 9-methylstreptimidone.1. physicochemical and biological properties, J. Antibiot. (Tokyo) 27 (1974) 206-214, https://doi.org/10.7164/antibiotics.27.206.

[32] A.M. Becker, R.W. Rickards, The absolute configuration of the glutarimide antibiotics streptimiodone and 9-methylstreptimidone, Helv. Chim. Acta 59 (1976) 2393-2401, https://doi.org/10.1002/hlca.19760590713.

[33] T. Otani, Y. Minami, H. Matsumoto, T. Marunaka, Z.X. Lou, Q.W. Yu, New glutarimide antibiotics, S-632-B1 and B2. II. Isolation, physico-chemical properties and chemical structure, J. Antibiot. (Tokyo) 42 (1989) 654-961,https://doi.org/10.7164/antibiotics.42.654.

[34] T. Otani, T. Sasaki, Y. Minami, T. Marunaka, Q.W. Yu, New glutarimide antibiotics, S-632-B1 and B2. I. Taxonomy of producing strain, fermentation and biological properties, J. Antibiot. (Tokyo) 42 (1989) 647-653, https://doi.org/10.7164/antibiotics.42.647.

[35] C.L. Cheng, Q.Y. Liu, L.H. Chen, W.Z. Jin, S.Y. Si, D.D. Li, Isolation, structure determination and biological activity of a new glutarimide antibiotic, S632A3, J. Asian Nat. Prod. Res. 8 (2006) 55-60, https://doi.org/10.1080/10286020500382884.

[36] A. Urakawa, T. Otani, K. Yoshida, M. Nakayama, K. Suzukake-Tsuchiya, M. Hori, Isolation, structure determination and biological activities of a novel antifungal antibiotic, S-632-C, closely related to glutarimide antibiotics, J. Antibiot. (Tokyo) 46 (1993) 1827-1833, https://doi.org/10.7164/antibiotics.46.1827.

[37] S. Chatterjee, E.K. Vijayakumar, S. Chatterjee, J. Blumbach, B.N. Ganguli, 5-Hydroxy-9-methylstreptimidone, a new glutarimide from a Streptomyces sp, HIL Y-9065403, J. Antibiot (Tokyo) 48 (1995) 271-273, https://doi.org/10.7164/antibiotics.48.271.

[38] L.F. Tang, W.L. Jihuo, P.D. Shi, C.X. Mei, Z.K. Zhao, Y. Chen, Y.T. Di, X.J. Hao, M. Cao, Y. Zhao, Y.Y. Che,Cytotoxic glutarimide-containing polyketides isolated from Streptomyces sp. JCM 4793, J. Antibiot. (Tokyo) 77 (2024) 627-633, https://doi.org/10.1038/s41429-024-00743-1.

[39] S.P. Niehs, J. Kumpfmuller, B. Dose, R.F. Little, K. Ishida, L.V. Florez, M. Kaltenpoth, C. Hertweck, Insect-associated bacteria assemble the antifungal butenolide gladiofungin by non-canonical polyketide chain termination, Angew. Chem., Int. Ed. Engl. 59 (2020) 23122-23126, https://doi.org/10.1002/anie.202005711.

[40] K. Nakae, Y. Yoshimoto, M. Ueda, T. Sawa, Y. Takahashi, H. Naganawa, T. Takeuchi, M. Imoto, Migrastatin, a novel 14-membered lactone from

Streptomyces sp. MK929- 43 F1, J. Antibiot. (Tokyo) 53 (2000) 1228-1230, https://doi.org/10.7164/antibiotics.53.1228.

[41] E.J. Woo, C.M. Starks, J.R. Carney, R. Arslanian, L. Cadapan, S. Zavala, P. Licari, Migrastatin and a new compound, isomigrastatin, from Streptomyces platensis, J. Antibiot. (Tokyo) 55 (2002) 141-146, https://doi.org/10.7164/antibiotics.55.141.

[42] J. Ju, S.K. Lim, H. Jiang, B. Shen, Migrastatin and dorrigocins are shunt metabolites of iso-migrastatin, J. Am. Chem. Soc. 127 (2005) 1622-1623, https://doi.org/10.1021/ja043808i.

[43] Z. Feng, L. Wang, S.R. Rajski, Z. Xu, M.F. Coeffet-LeGal, B. Shen, Engineered production of iso-migrastatin in heterologous Streptomyces hosts, Bioorg. Med. Chem. 17 (2009) 2147-2153, https://doi.org/10.1016/j.bmc.2008.10.074.

[44] K. Sugawara, Y. Nishiyama, S. Toda, N. Komiyama, M. Hatori, T. Moriyama, Y. Sawada, H. Kamei, M. Konishi, T. Oki, Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity, J. Antibiot. (Tokyo) 45 (1992) 1433-1441, https://doi.org/10.7164/antibiotics.45.1433.

[45] Y. Takayasu, K. Tsuchiya, T. Aoyama, Y. Sukenaga,NK30424A and B, novel inhibitors of lipopolysaccharide-induced tumour necrosis factor alpha production, produced by Streptomyces sp. NA30424, J. Antibiot. (Tokyo) 54 (2001)1111-1115, https://doi.org/10.7164/antibiotics.54.1111.

[46] J. Ju, J.W. Seo, Y. Her, S.K. Lim, B. Shen, New lactimidomycin congeners shed insight into lactimidomycin biosynthesis in Streptomyces amphibiosporus, Org. Lett. 9 (2007) 5183-5186, https://doi.org/10.1021/ol702249g.

[47] J. Ju, S.K. Lim, H. Jiang, J.W. Seo, B. Shen, Iso-migrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK30424 scaffolds, J. Am. Chem. Soc. 127 (2005) 11930-11931, https://doi.org/10.1021/ja053118u.

[48] D. Zhang, W. Yi, H. Ge, Z. Zhang, B. Wu, Bioactive streptoglutarimides A-J from the marine-derived Streptomyces sp, ZZ741, J. Nat. Prod. 82 (2019) 2800-2808,https://doi.org/10.1021/acs.jnatprod.9b00481.

[49] H.L. Kim, I.H. Krakoff, R.A. Newman, Isolation of sesbanimide from the seed of Sesbania vesicaria, Gen. Pharmacol. 23 (1992) 701-703, https://doi.org/10.1016/0306-3623(92)90151-9.

[50] R.G. Powell, R.D. Plattner, M. Suffness, Occurrence of sesbanimide in seeds of toxic Sesbania species, Weed Sci. 38 (1990) 148-152, https://doi.org/10.1017/S0043174500056290.

[51] R.G. P, R.S. C, D. W, Sesbanimide A and related tumor inhibitors from Sesbania drummondii: structure and chemistry, Phytochemistry 23 (1984) 2789-2796,https://doi.org/10.1016/0031-9422(84)83017-4.

[52] D. Kačar, L.M. Cañedo, P. Rodríguez, E.G. Gonzalez, B. Galan, C. Schleissner, S. Leopold-Messer, J. Piel, C. Cuevas, F. de la Calle, J.L. García, Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors, Environ. Microbiol. 23 (2021) 2509-2521,https://doi.org/10.1111/1462-2920.15470.

[53] R.P. Awal, P.A. Haack, C.D. Bader, C.N. Riese, D. Schüler, R. Müller, W. Zhang, A. Komeili, R. Sesbanimide, A novel cytotoxic polyketide produced by Magnetotactic bacteria, mBio 12 (2021), https://doi.org/10.1128/mBio.00591-21.

[54] D. Michalska, B. Morzyk, D.C. Bienko, W. Wojciechowski,Glutarimide: a carrier transporting drug through cell membranes, Med. Hypotheses 54 (2000) 472-474,https://doi.org/10.1054/mehy.1999.0879.

[55] J. Spizek, I. Malek, J. Suchy, M. Vondracek, Z. Vanek, Metabolites of Streptomyces noursei. V. Relation of the production of cycloheximide and actiphenol to the production of fungicidin, Folia Microbiol. 10 (1965) 263-266, https://doi.org/10.1007/BF02871023.

[56] T. Schneider-Poetsch, J. Ju, D.E. Eyler, Y. Dang, S. Bhat, W.C. Merrick, R. Green, B. Shen, J.O. Liu, Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin, Nat. Chem. Biol. 6 (2010) 209-217, https://doi.org/10.1038/nchembio.304.

[57] N. Stern-Ginossar, B. Weisburd, A. Michalski, V.T. Le, M.Y. Hein, S.X. Huang, M. Ma, B. Shen, S.B. Qian, H. Hengel, M. Mann, N.T. Ingolia, J.S. Weissman, Decoding human cytomegalovirus, Science 338 (2012) 1088-1093, https://doi.org/10.1126/science.1227919.

[58] G. Huifang, L. Yuhuan, T. Peizhen, Y. Hong, W. Shuqin, H. Weiying, J. Jiandong, L. Zhuorong, Antiviral activities of cycloheximide and its derivatives, Acta Pharm. Sin. 45 (2010) 268-273.

[59] H.-f. Guo, Y.-h. Li, P.-z. Tao, H. Yi, S.-q. Wang, W.-y. He, J.-d. Jiang, Z.-r. Li, Antiviral activities of cycloheximide and its derivatives, Yao Xue Xue Bao 45(2010) 268-273.

[60] H. Ge, D. Zhang, M. Shi, X. Lian, Z. Zhang, Antiproliferative activity and potential mechanism of marine-sourced streptoglutarimide H against lung cancer cells, Mar. Drugs 19 (2021) 79, https://doi.org/10.3390/md19020079.

[61] H. Osada, K. Kikuchi, F. Makishima, K. Isono, Inhibitory action of epiderstatin on EGF-stimulated growth of mouse epidermal. BALB/MK cells without direct effect on protein kinase activities, Oncol. Res. 6 (1994) 11-17.

[62] M.R. Siegel, H.D. Sisler, F. Johnson, Relationship of structure to fungitoxicity of cycloheximide and related glutarimide derivatives, Biochem. Pharmacol. 15 (1966) 1213-1223, https://doi.org/10.1016/0006-2952(66)90286-3.

[63] T. Umenai, F. Suzuki, N. Ishida, Effect of an interferon inducer, 9-methylstreptimidone, on Candida albicans infection in mice, Antimicrob. Agents Chemother. 13(1978) 939-943, https://doi.org/10.1128/AAC.13.6.939.

[64] H.B. Deng, N. Zhang, Y. Wang, J.J. Chen, J.J. Shen, Z. Wang, R. Xu, J.P. Zhang, D.G. Song, D.S. Li, S632A3, a new glutarimide antibiotic, suppresses lipopolysaccharide-induced pro-inflammatory responses via inhibiting the activation of glycogen synthase kinase 3β Exp. Cell Res. 318 (2012) 2592-2603,https://doi.org/10.1016/j.yexcr.2012.08.008.

[65] Y. Ishikawa, M. Tachibana, C. Matsui, R. Obata, K. Umezawa, S. Nishiyama, Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-κB, Bioorg. Med. Chem. Lett. 19 (2009) 1726-1728, https://doi.org/10.1016/j.bmcl.2009.01.107.

[66] J. Ju, S.R. Rajski, S.K. Lim, J.W. Seo, N.R. Peters, F.M. Hoffmann, B. Shen, Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration, J. Am. Chem. Soc. 131 (2009) 1370-1371, https://doi.org/10.1021/ja808462p.

[67] K. Majchrzak, D. Lo Re, M. Gajewska, M. Bulkowska, A. Homa, K. Pawlowski, T. Motyl, P.V. Murphy, M. Krol, Migrastatin analogues inhibit canine mammary cancer cell migration and invasion, PLoS One 8 (2013) e76789, https://doi.org/10.1371/journal.pone.0076789.

[68] J. Ju, S.R. Rajski, S.K. Lim, J.W. Seo, N.R. Peters, F.M. Hoffmann, B. Shen, Evaluation of new migrastatin and dorrigocin congeners unveils cell migration inhibitors with dramatically improved potency, Bioorg. Med. Chem. Lett. 18 (2008) 5951-5954, https://doi.org/10.1016/j.bmcl.2008.07.072.

[69] D. Shan, L. Chen, J.T. Njardarson, C. Gaul, X. Ma, S.J. Danishefsky, X.Y. Huang,Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice, Proc. Natl. Acad. Sci. USA 102 (2005) 3772-3776, https://doi.org/10.1073/pnas.0500658102.

[70] G. Anquetin, S.L. Rawe, K. McMahon, E.P. Murphy, P.V. Murphy, Synthesis of novel migrastatin and dorrigocin A analogues from D-glucal, Chemistry 14 (2008) 1592-1600, https://doi.org/10.1002/chem.200701033.

[71] N. Lecomte, J.T. Njardarson, P. Nagorny, G. Yang, R. Downey, O. Ouerfelli, M.A. Moore, S.J. Danishefsky,Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin, Proc. Natl. Acad. Sci. USA 108 (2011) 15074-15078, https://doi.org/10.1073/pnas.1015247108.

[72] L. Chen, S. Yang, J. Jakoncic, J.J. Zhang, X.Y. Huang, Migrastatin analogues target fascin to block tumour metastasis, Nature 464 (2010) 1062-1066, https://doi.org/10.1038/nature08978.

[73] P. Nagorny, I. Krauss, J.T. Njardarson, L. Perez, C. Gaul, G. Yang, O. Ouerfelli, S.J. Danishefsky, Confirmation of the structures of synthetic derivatives of migrastatin in the light of recently disclosed crystallographically based claims, Tetrahedron Lett. 51 (2010) 3873-3875, https://doi.org/10.1016/j.tetlet.2010.05.056.

[74] T. Oskarsson, P. Nagorny, I.J. Krauss, L. Perez, M. Mandal, G. Yang, O. Ouerfelli, D. Xiao, M.A. Moore, J. Massague, S.J. Danishefsky, Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: in vivo and mechanistic studies on the migrastatin core ether analog, J. Am. Chem. Soc. 132 (2010) 3224-3228, https://doi.org/10.1021/ja9101503.

[75] Y. Takayasu, K. Tsuchiya, Y. Sukenaga, Oxidative modification of NK30424A and B enhance inhibitory effect on lipopolysaccharide-induced tumour necrosis factoralpha promoter activity, J. Antibiot. (Tokyo) 55 (2002) 337-340, https://doi.org/10.7164/antibiotics.55.337.

[76] B.J. Larsen, Z. Sun, E. Lachacz, Y. Khomutnyk, M.B. Soellner, P. Nagorny, Synthesis and biological evaluation of lactimidomycin and its analogues, Chemistry 21 (2015) 19159-19167, https://doi.org/10.1002/chem.201503527.

[77] M. Carocci, P.L. Yang, Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses, Antivir. Res. 128 (2016) 57-62, https://doi.org/10.1016/j.antiviral.2016.02.005.

[78] C.P. Gorstallman, P.S. Steyn, R. Vleggaar, N. Grobbelaar, Structure elucidation of sesbanimide using high-field Nmr-spectroscopy, J. Chem. Soc. Perk T 1 (1984) 1311-1314, https://doi.org/10.1039/P19840001311.

[79] R.G. Powell, C.R. Smith, D. Weisleder, G.K. Matsumoto, J. Clardy, J. Kozlowski, Sesbanimide, a potent anti-tumor substance from Sesbania-Drummondii seed, J. Am. Chem. Soc. 105 (1983) 3739-3741, https://doi.org/10.1021/Ja00349a081.

[80] A.T. Keatinge-Clay, The structures of type I polyketide synthases, Nat. Prod. Rep. 29 (2012) 1050, https://doi.org/10.1039/c2np20019h.

[81] T. Bretschneider, J.B. Heim, D. Heine, R. Winkler, B. Busch, B. Kusebauch, T. Stehle, G. Zocher, C. Hertweck, Vinylogous chain branching catalysed by a dedicated polyketide synthase module, Nature 502 (2013) 124-128, https://doi.org/10.1038/nature12588.

[82] M. Yin, Y. Yan, J.R. Lohman, S.-X. Huang, M. Ma, G.-R. Zhao, L.-H. Xu, W. Xiang, B. Shen,Cycloheximide and actiphenol production in Streptomyces sp. YIM56141 governed by single biosynthetic machinery featuring an acyltransferase-less Type I polyketide synthase, Org. Lett. 16 (2014) 3072-3075, https://doi.org/10.1021/ol501179w.

[83] J. Tang, X. Guo, J. Yang, Y.-J. Wang, J. Luo, M. Yin, Y. Yan, S.-X. Huang, Uncovering the parallel biosynthetic pathways of the cyclohexanone and phenol rings in cycloheximide and actiphenol by tailoring redox enzymes, ACS Catal. 14 (2024) 13148-13155, https://doi.org/10.1021/acscatal.4c03332.

[84] B. Wang, Y. Song, M. Luo, Q. Chen, J. Ma, H. Huang, J. Ju, Biosynthesis of 9-methylstreptimidone involves a new decarboxylative step for polyketide terminal diene formation, Org. Lett. 15 (2013) 1278-1281, https://doi.org/10.1021/ol400224n.

[85] I.T. Nakou, M. Jenner, Y. Dashti, I. Romero-Canelon, J. Masschelein, E. Mahenthiralingam, G.L. Challis, Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism, Angew. Chem., Int. Ed. Engl. 59 (2020) 23145-23153, https://doi.org/10.1002/anie.202009007.

[86] S.P. Niehs, J. Kumpfmuller, B. Dose, R.F. Little, K. Ishida, L.V. Florez, M. Kaltenpoth, C. Hertweck, Insect-associated bacteria assemble the antifungal butenolide gladiofungin by non-canonical polyketide chain termination, Angew. Chem., Int. Ed. Engl. 59 (2020) 23122-23126, https://doi.org/10.1002/anie.202005711.

[87] M. Ma, T. Kwong, S.-K. Lim, J. Ju, J.R. Lohman, B. Shen, Post-polyketide synthase steps in iso-migrastatin biosynthesis, featuring tailoring enzymes with broad substrate specificity, J. Am. Chem. Soc. 135 (2013) 2489-2492, https://doi.org/10.1021/ja4002635.

[88] J. Ju, S.K. Lim, H. Jiang, J.W. Seo, B. Shen, Iso-migrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK30424 scaffolds, J. Am. Chem. Soc. 127 (2005) 11930-11931, https://doi.org/10.1021/ja053118u.

[89] B. Zhang, Z. Xu, Q. Teng, G. Pan, M. Ma, B. Shen, A long-range acting dehydratase domain as the missing link for C17-dehydration in iso-migrastatin biosynthesis, Angew. Chem., Int. Ed. Engl. 56 (2017) 7247-7251, https://doi.org/10.1002/anie.201703588.

[90] A.D. Steele, H. Jiang, G. Pan, S.K. Lim, E. Kalkreuter, T. Kwong, J. Ju, S. Rajski, B. Shen, Discrete acyltransferases and thioesterases in iso-migrastatin and lactimidomycin biosynthesis, Biochem 63 (2024) 563-575, https://doi.org/10.1021/acs.biochem.3c00672.

[91] E. Ota, M. Takeiri, M. Tachibana, Y. Ishikawa, K. Umezawa, S. Nishiyama, Synthesis and biological evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide, Bioorg. Med. Chem. Lett. 22 (2012) 164-167, https://doi.org/10.1016/j.bmcl.2011.11.045.

[92] M. Krasavin, M. Adamchik, A. Bubyrev, C. Heim, S. Maiwald, D. Zhukovsky, P. Zhmurov, A. Bunev, M.D. Hartmann, Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): investigation of their binding mode and antiproliferative effects against myeloma cell lines, Eur. J. Med. Chem. 246 (2023) 114990, https://doi.org/10.1016/j.ejmech.2022.114990.

[93] Y.I. Bolgova, A.I. Emel'yanov, O.M. Trofimova, A.A. Ivanova, A.I. Albanov, N.P. Kuznetsova, T.A. Semenova, A.S. Pozdnyakov, Synthesis, characterization, and application prospects of novel soluble polysilsesquioxane bearing glutarimide side-chain groups, Polymers 16 (2024), https://doi.org/10.3390/polym16233235.

[94] X.Y. Ji, Z.J. Zhong, S.T. Xue, S. Meng, W.Y. He, R.M. Gao, Y.H. Li, Z.R. Li, Synthesis and antiviral activities of synthetic glutarimide derivatives, Chem. Pharm. Bull. (Tokyo) 58 (2010) 1436-1441, https://doi.org/10.1248/cpb.58.1436.

[95] H.F. Guo, Y.H. Li, H. Yi, T. Zhang, S.Q. Wang, P.Z. Tao, Z.R. Li, Synthesis, structures and anti-HBV activities of derivatives of the glutarimide antibiotic cycloheximide, J. Antibiot. (Tokyo) 62 (2009) 639-642, https://doi.org/10.1038/ja.2009.87.

[96] J. Piel,A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles, Proc. Natl. Acad. Sci. USA 99 (2002) 14002-14007, https://doi.org/10.1073/pnas.222481399.

[97] Y.Q. Cheng, G.L. Tang, B. Shen,Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis, Proc. Natl. Acad. Sci. USA 100 (2003) 3149-3154, https://doi.org/10.1073/pnas.0537286100.

[98] Y.Q. Cheng, J.M. Coughlin, S.K. Lim, B. Shen, Type I polyketide synthases that require discrete acyltransferases, Methods Enzymol. 459 (2009) 165-186, https://doi.org/10.1016/S0076-6879(09)04608-4.

[99] M. Hildebrand, L.E. Waggoner, H. Liu, S. Sudek, S. Allen, C. Anderson, D.H. Sherman, M. Haygood, bryA: an unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina, Chem. Biol. 11 (2004) 1543-1552, https://doi.org/10.1016/j.chembiol.2004.08.018.

[100] H. Irschik, M. Kopp, K.J. Weissman, K. Buntin, J. Piel, R. Muller, Analysis of the sorangicin gene cluster reinforces the utility of a combined phylogenetic/retrobiosynthetic analysis for deciphering natural product assembly by trans-AT PKS, Chembiochem 11 (2010) 1840-1849, https://doi.org/10.1002/cbic.201000313.

[101] S.Y. Son, D.W. Bae, E. Kim, B.G. Jeong, M.Y. Kim, S.Y. Youn, S. Yi, G. Kim, J.S. Hahn, N.K. Lee, Y.J. Yoon, S.S. Cha, Structural investigation of the docking domain assembly from trans-AT polyketide synthases, Structure 32 (2024)1477-1487, https://doi.org/10.1016/j.str.2024.05.017.

[102] M.F.J. Mabesoone, S. Leopold-Messer, H.A. Minas, C. Chepkirui, P. Chawengrum, S. Reiter, R.A. Meoded, S. Wolf, F. Genz, N. Magnus, B. Piechulla, A.S. Walker, J. Piel, Evolution-guided engineering of trans-acyltransferase polyketide synthases, Science 383 (2024) 1312-1317, https://doi.org/10.1126/science.adj7621.