Source: https://pubs.rsc.org/en/content/articlehtml/2013/md/c2md20172k
Timestamp: 2019-04-26 09:53:35+00:00

Document:
The sesquiterpene lactone class of natural products displays a diverse array of biological activities due to the presence of the α-methylene-γ-lactone motif. However, clinical translation of this class has been hampered by poor aqueous solubility and non-selective binding as a Michael acceptor at undesired targets. A prodrug approach has been developed to overcome these problems in which an amine is added into the α-methylene-γ-lactone to mask this group from nucleophiles and increase solubility. The medicinal chemistry of amino-derivatives of the sesquiterpene lactones is described, beginning with synthetic development, moving into pharmacological applications, and finishing with clinical translation.
Download mol file of compoundwater solubility, and the α-methylene-γ-lactone can exhibit non-selective binding as a Michael acceptor with undesired targets.2 Therefore, an amino-prodrug strategy has been developed in which the reactive α,β-unsaturated enone is masked; additionally, it can enhance aqueous solubility, improve the pharmacokinetic profile, and maintain or even augment the biological activity of the parent molecule. The last characteristic has been hypothesized to occur by elimination of the amine, potentially through bioactivation, to regenerate the α,β-unsaturated enone at the site of action. This prodrug approach has enabled the first successful clinical translation of a member of the sesquiterpene lactones. In this review, a concise description of the medicinal chemistry of amino-derivatives of the sesquiterpene lactones is presented, beginning from its early development in synthesis, moving into its applications in medicinal chemistry, and finishing with its translation into a clinical candidate.
Fig. 1 Conversion of α-methylene-γ-lactones into amino-derivatives.
Originally, the conversion of an α-methylene-γ-lactone into its amino-derivative was used as a method to protect the α,β-unsaturation from a subsequent hydrogenation. In 1968, the sesquiterpene lactone dehydrocostus lactone (1) was transformed into its dimethylamino-adduct to enable selective reduction of two other alkenes (Fig. 2).4N-Alkylation and subsequent pyrolysis reformed the conjugated α-methylene-γ-lactone. Although biological evaluation of the novel derivatives was not conducted, these studies were the first successful application of this strategy to the sesquiterpene lactones.
Fig. 2 Synthesis of amino-derivative of dehydrocostus lactone (1) as a protection strategy for the α,β-unsaturated enone.
Download mol file of compoundhelenalin (2).
Fig. 4 Mechanism of action of α-methylene-γ-lactones by thiol trapping.
Download mol file of compoundpiperidine analogue 8 manifested antiproliferative activity most similar to the parent compound 6 across the majority of the cell lines. For example, biological activities for 6–8 in lung cancer (NCI-H522), melanoma (LOX-IMVI), and breast cancer (MCF7) cells are nearly identical. Additionally, there was a substantial increase in the aqueous solubilities of the amine hydrochlorides 7 and 8, but the exact levels of aqueous solubility were not quantified.
Fig. 5 Structures of ambrosin (6) and its amino-derivatives 7–8 along with antiproliferative assay data.
Fig. 6 Conversion of the ambrosin prodrug 8 into ambrosin 6.
Download mol file of compoundcostunolide (9) and saussureamines A–E (10–14).
Download mol file of compoundEtOH-induced lesions. c Inhibition of nitric oxide production in LPS-activated mouse macrophages.
Download mol file of compoundcostunolide (9) and antiproliferative activities.
Download mol file of compoundalantolactone (20) and isoalantolactone (21).
Download mol file of compoundParthenolide and its amino-prodrugs 25–29 with anti-HCV effects in cellular assays.
Fig. 11 Antiproliferative activity of parthenolide 24 and aminoparthenolide 30.
a Anti-leukemic activity at 10 μM dose. b Concentration causing death of 50% of the population of primary AML cells.
Fig. 12 Fluorinated aminoparthenolide 31.
Download mol file of compoundglutathione.
Download mol file of compoundwater solubility, improve the pharmacokinetic profile, and maintain (or enhance) the biological activity of an enone-containing lead compound; however, a series of amino-analogues must be prepared to ensure identification of the best candidate. This approach is a substantial innovation, especially as new biologically active molecules with key α,β-unsaturated enones continue to be identified.34,35 Future efforts to expand the application of this type of amino-prodrug strategy will likely be directed toward establishing that the amino-derivatives display fewer effects from non-selective binding than the parent enones. Also, validating the mechanism of biological activation for the amino-derivatives in a living system would be a substantial advancement.
Download mol file of compoundβ-amino-ethyl ketone for irreversible binding at active site.
Download mol file of compound3-aminopropanamide inhibitor of EGFR.
R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew. Chem., Int. Ed., 2009, 48, 9426–9451 CrossRef CAS.
A. Ghantous, H. Gali-Muhtasib, H. Vuorela, N. A. Saliba and N. Darwiche, Drug Discovery Today, 2010, 15, 668–678 CrossRef CAS.
C. Avonto, O. Taglialatela-Scafati, F. Pollastro, A. Minassi, V. Di Marzo, L. De Petrocellis and G. Appendino, Angew. Chem., Int. Ed., 2011, 50, 467–471 CrossRef CAS.
N. R. Unde, S. V. Hiremath, G. H. Kulkarni and G. R. Kelkar, Tetrahedron Lett., 1968, 9, 4861–4862 CrossRef.
K.-H. Lee, H. Furukawa and E.-S. Huang, J. Med. Chem., 1972, 15, 609–611 CrossRef CAS.
K.-H. Lee, S.-H. Kim, H. Furukawa, C. Piantadosi and E.-S. Huang, J. Med. Chem., 1975, 18, 59–63 CrossRef CAS.
K.-H. Lee, T. Ibuka, E.-C. Mar and I. H. Hall, J. Med. Chem., 1978, 21, 698–701 CrossRef CAS.
T. J. Schmidt, Bioorg. Med. Chem., 1997, 5, 645–653 CrossRef CAS.
R. Hoffmann, K. von Schwarzenberg, N. López-Antón, A. Rudy, G. Wanner, V. M. Dirsch and A. M. Vollmar, Biochem. Pharmacol., 2011, 82, 453–463 CrossRef CAS.
E. Hejchman, R. D. Haugwitz and M. Cushman, J. Med. Chem., 1995, 38, 3407–3410 CrossRef CAS.
V. M. Dirsch, H. Stuppner, E. P. Ellmerer-Müller and A. M. Vollmar, Bioorg. Med. Chem., 2000, 8, 2747–2753 CrossRef CAS.
M. Yoshikawa, S. Hatakeyama, Y. Inoue and J. Yamahara, Chem. Pharm. Bull., 1993, 41, 214–216 CrossRef CAS.
H. Matsuda, T. Kageura, Y. Inoue, T. Morikawa and M. Yoshikawa, Tetrahedron, 2000, 56, 7763–7777 CrossRef CAS.
H. Matsuda, I. Toguchida, K. Ninomiya, T. Kageura, T. Morikawa and M. Yoshikawa, Bioorg. Med. Chem., 2003, 11, 709–715 CrossRef CAS.
C.-M. Sun, W. Syu, Jr, M.-J. Don, J.-J. Lu and G.-H. Lee, J. Nat. Prod., 2003, 66, 1175–1180 CrossRef CAS.
S. K. Srivastava, A. Abraham, B. Bhat, M. Jaggi, A. T. Singh, V. K. Sanna, G. Singh, S. K. Agarwal, R. Mukherjee and A. C. Burman, Bioorg. Med. Chem. Lett., 2006, 16, 4195–4199 CrossRef CAS.
M. Duvvuri, S. Konkar, K. H. Hong, B. S. J. Blagg and J. P. Krise, ACS Chem. Biol., 2006, 1, 309–315 CrossRef CAS.
N. J. Lawrence, A. T. McGown, J. Nduka, J. A. Hadfield and R. G. Pritchard, Bioorg. Med. Chem. Lett., 2001, 11, 429–431 CrossRef CAS.
M. L. Guzman, R. M. Rossi, L. Karnischky, X. Li, D. R. Peterson, D. S. Howard and C. T. Jordan, Blood, 2005, 105, 4163–4169 CrossRef CAS.
D.-R. Hwang, Y.-S. Wu, C.-W. Chang, T.-W. Lien, W.-C. Chen, U.-K. Tan, J. T. A. Hsu and H.-P. Hsieh, Bioorg. Med. Chem., 2006, 14, 83–91 CrossRef CAS.
S. Nasim and P. A. Crooks, Bioorg. Med. Chem. Lett., 2008, 18, 3870–3873 CrossRef CAS.
S. Neelakantan, S. Nasim, M. L. Guzman, C. T. Jordan and P. A. Crooks, Bioorg. Med. Chem. Lett., 2009, 19, 4346–4349 CrossRef CAS.
M. L. Guzman, R. M. Rossi, S. Neelakantan, X. Li, C. A. Corbett, D. C. Hassane, M. W. Becker, J. M. Bennett, E. Sullivan, J. L. Lachowicz, A. Vaughan, C. J. Sweeney, W. Matthews, M. Carroll, J. L. Liesveld, P. A. Crooks and C. T. Jordan, Blood, 2007, 110, 4427–4435 CrossRef CAS.
D. C. Hassane, S. Sen, M. Minhajuddin, R. M. Rossi, C. A. Corbett, M. Balys, L. Wei, P. A. Crooks, M. L. Guzman and C. T. Jordan, Blood, 2010, 116, 5983–5990 CrossRef CAS.
S. Hewamana, T. T. Lin, C. Jenkins, A. K. Burnett, C. T. Jordan, C. Fegan, P. Brennan, C. Rowntree and C. Pepper, Clin. Cancer Res., 2008, 14, 8102–8111 CrossRef CAS.
R. Shanmugam, P. Kusumanchi, L. Cheng, P. Crooks, S. Neelakantan, W. Matthews, H. Nakshatri and C. J. Sweeney, Prostate, 2010, 70, 1074–1086 CrossRef CAS.
B. H. B. Kwok, B. Koh, M. I. Ndubuisi, M. Elofsson and C. M. Crews, Chem. Biol., 2001, 8, 759–766 CrossRef CAS.
E. A. Curry III, D. J. Murry, C. Yoder, K. Fife, V. Armstrong, H. Nakshatri, M. O'Connell and C. J. Sweeney, Invest. New Drugs, 2004, 22, 299–305 CrossRef.
S. Wagner, F. Kratz and I. Merfort, Planta Med., 2004, 70, 227–233 CrossRef CAS.
J. R. Woods, H. Mo, A. A. Bieberich, T. Alavanja and D. A. Colby, J. Med. Chem., 2011, 54, 7934–7941 CrossRef CAS.
H. Mo, K. M. Balko and D. A. Colby, Bioorg. Med. Chem. Lett., 2010, 20, 6712–6715 CrossRef CAS.
A. W. Maresso, R. Wu, J. W. Kern, R. Zhang, D. Janik, D. M. Missiakas, M.-E. Duban, A. Joachimiak and O. Schneewind, J. Biol. Chem., 2007, 282, 23129–23139 CrossRef CAS.
C. Carmi, E. Galvani, F. Vacondio, S. Rivara, A. Lodola, S. Russo, S. Aiello, F. Bordi, G. Costantino, A. Cavazzoni, R. R. Alfieri, A. Ardizzoni, P. G. Petronini and M. Mor, J. Med. Chem., 2012, 55, 2251–2264 CrossRef CAS.
J. K. Hexum, R. Tello-Aburto, N. B. Struntz, A. M. Harned and D. A. Harki, ACS Med. Chem. Lett., 2012, 3, 459–464 CrossRef CAS.
M. V. Riofski, J. P. John, M. M. Zheng, J. Kirshner and D. A. Colby, J. Org. Chem., 2011, 76, 3676–3683 CrossRef CAS.

References: V. 
 V. 
 V. 

V. 
 V. 
 V. 
 V.