Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century
Abstract
:1. Introduction
2. SAR Studies 2001–2009
2.1. FAA Analogues
2.2. DMXAA Analogues
2.3. Miscellaneous
3. Targeted SAR Studies 2013–2021
3.1. Recently Developed FAA Derivatives
3.2. Recently Developed DMXAA Derivatives
3.3. DMXAA Combinations/Hybrids
4. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
- Yoo, S.Y.; Kwon, S.M. Angiogenesis and its therapeutic opportunities. Mediat. Inflamm. 2013, 2013, 127170. [Google Scholar] [CrossRef] [Green Version]
- Fallah, A.; Sadeghinia, A.; Kahroba, H.; Samadi, A.; Heidari, H.R.; Bradaran, B.; Zeinali, S.; Molavi, O. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed. Pharmacother. 2019, 110, 775–785. [Google Scholar] [CrossRef]
- Goel, S.; Duda, D.G.; Xu, L.; Munn, L.L.; Boucher, Y.; Fukumura, D.; Jain, R.K. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 2011, 91, 1071–1121. [Google Scholar] [CrossRef]
- Eales, K.L.; Hollinshead, K.E.; Tennant, D.A. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis 2016, 5, e190. [Google Scholar] [CrossRef] [Green Version]
- De Palma, M.; Hanahan, D. The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities. Mol. Oncol. 2012, 6, 111–127. [Google Scholar] [CrossRef] [PubMed]
- Smolarczyk, R.; Czapla, J.; Jarosz-Biej, M.; Czerwinski, K.; Cichoń, T. Vascular disrupting agents in cancer therapy. Eur. J. Pharmacol. 2021, 891, 173692. [Google Scholar] [CrossRef]
- Porcù, E.; Bortolozzi, R.; Basso, G.; Viola, G. Recent advances in vascular disrupting agents in cancer therapy. Future Med. Chem. 2014, 6, 1485–1498. [Google Scholar] [CrossRef] [PubMed]
- Atassi, G.; Briet, P.; Berthelon, J.J.; Collonges, F. Synthesis and antitumor activity of some 8-substituted-4-oxo-4H-1-benzopyrans. Eur. J. Med. Chem. Chim. Ther. 1985, 20, 10. [Google Scholar]
- Rewcastle, G.W.; Atwell, G.J.; Baguley, B.C.; Calveley, S.B.; Denny, W.A. Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo. J. Med. Chem. 1989, 32, 793–799. [Google Scholar] [CrossRef] [PubMed]
- Rewcastle, G.W.; Atwell, G.J.; Li, Z.A.; Baguley, B.C.; Denny, W.A. Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids. J. Med. Chem. 1991, 34, 217–222. [Google Scholar] [CrossRef]
- Baguley, B.C. Antivascular therapy of cancer: DMXAA. Lancet Oncol. 2003, 4, 141–148. [Google Scholar] [CrossRef]
- Daei Farshchi Adli, A.; Jahanban-Esfahlan, R.; Seidi, K.; Samandari-Rad, S.; Zarghami, N. An overview on Vadimezan (DMXAA): The vascular disrupting agent. Chem. Biol. Drug Des. 2018, 91, 996–1006. [Google Scholar] [CrossRef] [PubMed]
- Prantner, D.; Perkins, D.J.; Lai, W.; Williams, M.S.; Sharma, S.; Fitzgerald, K.A.; Vogel, S.N. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J. Biol. Chem. 2012, 287, 39776–39788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Corrales, L.; Glickman, L.H.; McWhirter, S.M.; Kanne, D.B.; Sivick, K.E.; Katibah, G.E.; Woo, S.R.; Lemmens, E.; Banda, T.; Leong, J.J.; et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015, 11, 1018–1030. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Sun, Z.; Pei, J.; Luo, Q.; Zeng, X.; Li, Q.; Yang, Z.; Quan, J. Identification of α-Mangostin as an Agonist of Human STING. ChemMedChem 2018, 13, 2057–2064. [Google Scholar] [CrossRef]
- Gobbi, S.; Rampa, A.; Bisi, A.; Belluti, F.; Piazzi, L.; Valenti, P.; Caputo, A.; Zampiron, A.; Carrara, M. Synthesis and biological evaluation of 3-alkoxy analogues of flavone-8-acetic acid. J. Med. Chem. 2003, 46, 3662–3669. [Google Scholar] [CrossRef]
- Valenti, P.; Bisi, A.; Rampa, A.; Gobbi, S.; Belluti, F.; Da Re, P.; Cima, L.; Carrara, M. Synthesis of flavone-2′-carboxylic acid analogues as potential antitumor agents. Anticancer Drug Des. 1998, 13, 881–892. [Google Scholar] [PubMed]
- Carrara, M.; Zampiron, A.; Barbera, M.; Caputo, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Piazzi, L.; Rampa, A.; Valenti, P. Mono- or di-fluorinated analogues of flavone-8-acetic acid: Synthesis and in vitro biological activity. Anticancer Res. 2005, 25, 1179–1185. [Google Scholar]
- Valenti, P.; Fabbri, G.; Rampa, A.; Bisi, A.; Gobbi, S.; Da Re, P.; Carrara, M.; Sgevano, A.; Cima, L. Synthesis and antitumor activity of some analogues of flavone acetic acid. Anticancer Drug Des. 1996, 11, 243–252. [Google Scholar] [PubMed]
- Barbera, M.; Caputo, A.; Zampiron, A.; Gobbi, S.; Rampa, A.; Bisi, A.; Carrara, M. The ability of coumarin-, flavanon- and flavonol-analogues of flavone acetic acid to stimulate human monocytes. Oncol. Rep. 2008, 19, 187–196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gobbi, S.; Rampa, A.; Bisi, A.; Belluti, F.; Valenti, P.; Caputo, A.; Zampiron, A.; Carrara, M. Synthesis and antitumor activity of new derivatives of xanthen-9-one-4-acetic acid. J. Med. Chem. 2002, 45, 4931–4939. [Google Scholar] [CrossRef] [PubMed]
- Thomsen, L.L.; Ching, L.M.; Zhuang, L.; Gavin, J.B.; Baguley, B.C. Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice. Cancer Res. 1991, 51, 77–81. [Google Scholar]
- Gobbi, S.; Belluti, F.; Bisi, A.; Piazzi, L.; Rampa, A.; Zampiron, A.; Barbera, M.; Caputo, A.; Carrara, M. New derivatives of xanthenone-4-acetic acid: Synthesis, pharmacological profile and effect on TNF-alpha and NO production by human immune cells. Bioorg. Med. Chem. 2006, 14, 4101–4109. [Google Scholar] [CrossRef]
- Barbera, M.; Kettunen, M.I.; Caputo, A.; Hu, D.E.; Gobbi, S.; Brindle, K.M.; Carrara, M. Immune-modulating and anti-vascular activities of two xanthenone acetic acid analogues: A comparative study to DMXAA. Int. J. Oncol. 2009, 34, 273–279. [Google Scholar] [CrossRef] [Green Version]
- Wang, L.C.; Reddy, C.B.; Baguley, B.C.; Kestell, P.; Sutherland, R.; Ching, L.M. Induction of tumour necrosis factor and interferon-gamma in cultured murine splenocytes by the antivascular agent DMXAA and its metabolites. Biochem. Pharmacol. 2004, 67, 937–945. [Google Scholar] [CrossRef]
- Engelmann, H.; Holtmann, H.; Brakebusch, C.; Avni, Y.S.; Sarov, I.; Nophar, Y.; Hadas, E.; Leitner, O.; Wallach, D. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J. Biol. Chem. 1990, 265, 14497–14504. [Google Scholar] [CrossRef]
- Philpott, M.; Ching, L.M.; Baguley, B.C. The antitumour agent 5,6-dimethylxanthenone-4-acetic acid acts in vitro on human mononuclear cells as a co-stimulator with other inducers of tumour necrosis factor. Eur. J. Cancer 2001, 37, 1930–1937. [Google Scholar] [CrossRef]
- Bauvois, B.; Puiffe, M.L.; Bongui, J.B.; Paillat, S.; Monneret, C.; Dauzonne, D. Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. J. Med. Chem. 2003, 46, 3900–3913. [Google Scholar] [CrossRef] [PubMed]
- Malolanarasimhan, K.; Lai, C.C.; Kelley, J.A.; Iaccarino, L.; Reynolds, D.; Young, H.A.; Marquez, V.E. Synthesis and biological study of a flavone acetic acid analogue containing an azido reporting group designed as a multifunctional binding site probe. Bioorg. Med. Chem. 2005, 13, 2717–2722. [Google Scholar] [CrossRef] [PubMed]
- Palmer, B.D.; Henare, K.; Woon, S.T.; Sutherland, R.; Reddy, C.; Wang, L.C.; Kieda, C.; Ching, L.M. Synthesis and biological activity of azido analogues of 5,6-dimethylxanthenone-4-acetic acid for use in photoaffinity labeling. J. Med. Chem. 2007, 50, 3757–3764. [Google Scholar] [CrossRef]
- Li, A.; Yi, M.; Qin, S.; Song, Y.; Chu, Q.; Wu, K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy. J. Hematol. Oncol. 2019, 12, 35. [Google Scholar] [CrossRef]
- Zhou, Z.Z.; Gu, C.P.; Deng, Y.H.; Yan, G.H.; Li, X.F.; Yu, L.; Chen, W.H.; Liu, S.W. Synthesis, selective cytotoxicities and probable mechanism of action of 7-methoxy-3-arylflavone-8-acetic acids. Bioorg. Med. Chem. 2014, 22, 1539–1547. [Google Scholar] [CrossRef] [PubMed]
- Yan, G.H.; Li, X.F.; Ge, B.C.; Shi, X.D.; Chen, Y.F.; Yang, X.M.; Xu, J.P.; Liu, S.W.; Zhao, P.L.; Zhou, Z.Z.; et al. Synthesis and anticancer activities of 3-arylflavone-8-acetic acid derivatives. Eur. J. Med. Chem. 2015, 90, 251–257. [Google Scholar] [CrossRef]
- Pham, M.H.; Dauzonne, D.; Chabot, G.G. Not flavone-8-acetic acid (FAA) but its murine metabolite 6-OH-FAA exhibits remarkable antivascular activities in vitro. Anticancer Drugs 2016, 27, 398–406. [Google Scholar] [CrossRef] [PubMed]
- Tijono, S.M.; Guo, K.; Henare, K.; Palmer, B.D.; Wang, L.C.; Albelda, S.M.; Ching, L.M. Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Br. J. Cancer 2013, 108, 1306–1315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, S.-J.; Ding, Z.-S.; Jiang, F.-S.; Ge, Q.-F.; Guo, D.-W.; Li, H.-B.; Hu, W.-X. Synthesis, anticancer evaluation and docking study of Vadimezan derivatives with carboxyl substitution. Med. Chem. Commun. 2014, 5, 9. [Google Scholar] [CrossRef]
- Zhang, S.-J.; Xu, F.; Ge, Q.-F.; Li, H.-B.; Hu, W.-X. Synthesis, structural characterization and cancer cell cytotoxic activity of Vadimezan hydrazones. Pharm. Chem. J. 2016, 50, 5. [Google Scholar] [CrossRef]
- Hwang, J.; Kang, T.; Lee, J.; Choi, B.S.; Han, S. Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists. Org. Biomol. Chem. 2019, 17, 1869–1874. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Zhang, J.; Wang, H.; Liu, Z.; Zhang, C.; Jiang, Z.; Chen, H. Synthesis of xanthone derivatives and studies on the inhibition against cancer cells growth and synergistic combinations of them. Eur. J. Med. Chem. 2017, 133, 50–61. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Zhou, F.; Zhang, L.; Wang, H.; Zhang, J.; Zhang, C.; Jiang, Z.; Li, Y.; Liu, Z.; Chen, H. DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions. Eur. J. Med. Chem. 2018, 143, 1768–1778. [Google Scholar] [CrossRef]
- Zhang, H.; Qian, D.Z.; Tan, Y.S.; Lee, K.; Gao, P.; Ren, Y.R.; Rey, S.; Hammers, H.; Chang, D.; Pili, R.; et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA 2008, 105, 19579–19586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Smolarczyk, R.; Cichoń, T.; Pilny, E.; Jarosz-Biej, M.; Poczkaj, A.; Kułach, N.; Szala, S. Combination of anti-vascular agent—DMXAA and HIF-1α inhibitor—Digoxin inhibits the growth of melanoma tumors. Sci. Rep. 2018, 8, 7355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Gobbi, S.; Belluti, F.; Rampa, A.; Bisi, A. Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century. Molecules 2021, 26, 4228. https://doi.org/10.3390/molecules26144228
Gobbi S, Belluti F, Rampa A, Bisi A. Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century. Molecules. 2021; 26(14):4228. https://doi.org/10.3390/molecules26144228
Chicago/Turabian StyleGobbi, Silvia, Federica Belluti, Angela Rampa, and Alessandra Bisi. 2021. "Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century" Molecules 26, no. 14: 4228. https://doi.org/10.3390/molecules26144228