Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
3. Materials and Methods
3.1. General Information
3.2. Compound Synthesis
3.2.1. Tert-Butyl [(2S)-1-(Thynylamino)-4-methyl-1-oxopentan-2-yl]carbamate (4)
3.2.2. Boc-Leu-NHCH2-triazole-(CH2)3NH2 (6a, b)
3.2.3. Boc-Leu-NHCH2-triazole-(CH2)3NHMe (7)
3.2.4. Boc-Leu-NHCH2-triazole-(CH2)3NHMe-wortmannin (9)
3.2.5. Leu-NHCH2-triazole-(CH2)3NHMe-wortmannin (10)
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Chang, L.; Graham, P.H.; Ni, J.; Hao, J.; Bucci, J.; Cozzi, P.J.; Li, Y. Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. Crit. Rev. Oncol. Hematol. 2015, 96, 507–517. [Google Scholar] [CrossRef] [PubMed]
- Sarker, D.; Reid, A.H.M.; Yap, T.A.; de Bono, J.S. Targeting the PI3K/AKT Pathway for the Treatment of Prostate Cancer. Clin. Cancer Res. 2009, 15, 4799–4805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toren, P.; Zoubeidi, A. Targeting the PI3K/Akt pathway in prostate cancer: Challenges and opportunitie. Int. J. Oncol. 2014, 45, 1793–1801. [Google Scholar] [CrossRef] [PubMed]
- Uzoh, C.C.; Perks, C.M.; Bahl, A.; Holly, J.M.P.; Sugiono, M.; Persad, R.A. PTEN-mediated pathways and their association with treatment-resistant prostate cancer. BJU Int. 2009, 104, 556–561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; et al. Gerald, Integrative Genomic Profiling of Human Prostate Cancer. Cancer Cell. 2010, 18, 11–22. [Google Scholar] [CrossRef] [PubMed]
- Ma, X.; Hu, Y. Targeting PI3K/Akt/mTOR Cascade: The Medicinal Potential, Updated Research Highlights and Challenges Ahead. Curr. Med. Chem. 2013, 20, 2991–3010. [Google Scholar] [CrossRef] [PubMed]
- Asif, K.Q.; Aashiq, H.; Abid, H.; Yasrib, Q.; Rabiya, M.; Mudassier, A.; Rauf, A.N.; Javeed, A.B.; Shashank, K.S.; Mohmmad, A.Z.; et al. Recent Development in Targeting PI3K-Akt-mTOR Signaling for Anticancer Therapeutic Strategies. Anti-cancer Agent. Med. Chem. 2013, 13, 1552–1564. [Google Scholar]
- Baiz, D.; Pinder, T.A.; Hassan, S.; Karpova, Y.; Salsbury, F.; Welker, M.E.; Kulik, G. Synthesis and Characterization of a Novel Prostate Cancer-Targeted Phosphatidylinositol-3-kinase Inhibitor Prodrug. J. Med. Chem. 2012, 55, 8038–8046. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wipf, P.; Minion, D.J.; Halter, R.J.; Berggren, M.I.; Ho, C.B.; Chiang, G.G.; Kirkpatrick, L.; Abraham, R.; Powis, G. Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin. Org. Biomol. Chem. 2004, 2, 1911–1920. [Google Scholar] [CrossRef] [PubMed]
- Yuan, H.; Luo, J.; Weissleder, R.; Cantley, L.; Josephson, L. Wortmannin-C20 conjugates generate wortmannin. J. Med. Chem. 2006, 49, 740–747. [Google Scholar] [CrossRef] [PubMed]
- Lebreton, L.; Jost, E.; Carboni, B.; Annat, J.; Vaultier, M.; Dutartre, P.; Renaut, P. Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety. J. Med. Chem. 1999, 42, 4749–4763. [Google Scholar] [CrossRef] [PubMed]
- Singh, M.S.; Chowdhury, S.; Koley, S. Advances of azide-alkyne cycloaddition-click chemistry over the recent decade. Tetrahedron 2016, 72, 5257–5283. [Google Scholar] [CrossRef]
- Bayascas, J.R.; Alessi, D.R. Regulation of Akt/PKB Ser473 Phosphorylation. Mol. Cell 2005, 18, 143–145. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors. |
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Cantrell, W.; Huang, Y.; Menchaca, A.A.; Kulik, G.; Welker, M.E. Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative. Molecules 2018, 23, 1791. https://doi.org/10.3390/molecules23071791
Cantrell W, Huang Y, Menchaca AA, Kulik G, Welker ME. Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative. Molecules. 2018; 23(7):1791. https://doi.org/10.3390/molecules23071791
Chicago/Turabian StyleCantrell, William, Yue Huang, Antonio A. Menchaca, George Kulik, and Mark E. Welker. 2018. "Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative" Molecules 23, no. 7: 1791. https://doi.org/10.3390/molecules23071791