Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

A New Synthetic Spiroketal: Studies on Antitumor Activity on Murine Melanoma Model In Vivo and Mechanism of Action In Vitro

Author(s): Maria P. Fuggetta*, Pietro Spanu*, Fausta Ulgheri, Francesco Deligia, Paola Carta, Alberto Mannu, Veronica Trotta, Rosanna De Cicco, Adriano Barra, Enrica Zona and Franco Morelli*

Volume 19, Issue 4, 2019

Page: [567 - 578] Pages: 12

DOI: 10.2174/1871520619666190131141400

Price: $65

Abstract

Background: In a previous study, we synthesised a new spiroketal derivative, inspired to natural products, that has shown high antiproliferative activity, potent telomerase inhibition and proapoptotic activity on several human cell lines.

Objective: This work focused on the study of in vivo antitumor effect of this synthetic spiroketal on a murine melanoma model. In order to shed additional light on the origin of the antitumor effect, in vitro studies were performed.

Methods: Spiroketal was administered to B16F10 melanoma mice at a dose of 5 mg/Kg body weight via intraperitoneum at alternate days for 15 days. Tumor volume measures were made every 2 days starting after 12 days from cells injection. The effects of the spiroketal on tumor growth inhibition, apoptosis induction, and cell cycle modification were investigated in vitro on B16 cells. HIF1α gene expression, the inhibition of cells migration and the changes induced in cytoskeleton conformation were evaluated.

Results: Spiroketal displayed proapoptotic activity and high antitumor activity in B16 cells with nanomolar IC50. Moreover it has shown to inhibit cell migration, to strongly reduce the HIF1α expression and to induce strongly deterioration of cytoskeleton structure. A potent dose-dependent antitumor efficacy in syngenic B16/C57BL/6J murine model of melanoma was observed with the suppression of tumor growth by an average of 90% at a dose of 5 mg/kg.

Conclusion: The synthesized spiroketal shows high antitumor activity in the B16 cells in vitro at nM concentration and a dose-dependent antitumor efficacy in syngenic B16/C57BL/6J mice. The results suggest that this natural product inspired spiroketal may have a potential application in melanoma therapy.

Keywords: Spiroketals, anticancer, melanoma, apoptosis, HIF1α, cell migration.

« Previous
Graphical Abstract

[1]
Perron, F.; Albizati, K.F. Chemistry of spiroketals. Chem. Rev., 1989, 89, 1617-1661.
[2]
Aho, J.E.; Pihko, P.M.; Rissa, T.K. Nonanomeric spiroketals in Natural products: Structures, sources, and synthetic strategies. Chem. Rev., 2005, 105, 4406-4440.
[3]
Raju, B.R.; Saikia, A.K. Asymmetric synthesis of naturally occuring spiroketals. Molecules, 2008, 13, 1942-2038.
[4]
Brasholz, M.; Sörge, S.; Azap, C.; Reißig, H.U. Rubromycins: Structurally intriguing, biologically valuable, synthetically challenging antitumour antibiotics. Eur. J. Org. Chem., 2007, 23, 3801-3814.
[5]
Booth, Y.K.; Kitching, W.; De Voss, J.J. Biosynthesis of insect spiroacetals. Nat. Prod. Rep., 2009, 26, 490-525.
[6]
Zinzalla, G.; Milroy, L.G.; Ley, S.V. Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives. Org. Biomol. Chem., 2006, 4, 1977-2002.
[7]
Zheng, Y.; Tice, C.M.; Singh, S.B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett., 2014, 24, 3673-3682.
[8]
Rizvi, S.A.; Liu, S.; Chen, Z.; Skau, C.; Pytynia, M.; Kovar, D.R.; Chmura, S.J.; Kozmin, S.A. Rationally simplified bistramide analog reversibly targets actin polymerization and inhibits cancer progression In Vitro and In Vivo. J. Am. Chem. Soc., 2010, 132, 7288-7290.
[9]
Choi, K.W.; Brimble, M.A. Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds. Org. Biomol. Chem., 2009, 7, 1424-1436.
[10]
Fuggetta, M.P.; De-Mico, A.; Cottarelli, A.; Morelli, F.; Zonfrillo, M.; Ulgheri, F.; Peluso, P.; Mannu, A.; Deligia, F.; Marchetti, M.; Roviello, G.; Reyes Romero, A.; Dömling, A.; Spanu, P. Synthesis and enantiomeric separation of a novel spiroketal derivative: A potent human telomerase inhibitor with High In Vitro anticancer activity. J. Med. Chem., 2016, 59, 9140-9149.
[11]
De-Mico, A.; Cottarelli, A.; Fuggetta, M.P.; Lanzilli, G.; Tricarico, M. Dioxaspiroketal derivatives, process for their preparation and uses thereof. Patent WO2007/132496, 2007: US Patent 20100227919, 2010.
[12]
Uckun, F.M.; Mao, C.; Vassilev, A.O.; Huang, H.; Jan, S.T. Structure-based design of a novel synthetic spiroketal pyran as a pharmacophore for the marine natural product spongistatin 1. Bioorg. Med. Chem. Lett., 2000, 10, 541-545.
[13]
Barun, O.; Kumar, K.; Sommer, S.; Langerak, A.; Mayer, T.U.; Müller, O.; Waldmann, H. Natural product-guided synthesis of a spiroacetal collection reveals modulators of tubulin cytoskeleton integrity. Eur. J. Org. Chem., 2005, 11, 4773-4788.
[14]
Mitsuhashi, S.; Shima, H.; Kawamura, T.; Kikuchi, K.; Oikawah, M.; Ichiharab, A.; Oikawa, H. The spiroketals containing a benzyloxymethyl moiety at C8 position showed the most potent apoptosis-inducing activity. Bioorg. Med. Chem. Lett., 1999, 9(14), 2007-2012.
[15]
Scheepstra, M.; Andrei, S.A.; Unver, M.Y.; Hirsch, A.K.H.; Leysen, S.; Ottmann, C.; Brunsveld, L.; Milroy, L.G. Designed spiroketal protein modulation. Angew. Chem. Int. Ed. Engl., 2017, 56, 5480-5484.
[16]
Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.Y.; Ahn, K.H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Discovery of tofogliflozin, a novel c-arylglucoside with an o-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2012, 55, 7828-7840.
[17]
Lv, B.; Feng, Y.; Dong, J.; Xu, M.; Xu, B.; Zhang, W.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Conformationally constrained spiro c-arylglucosides as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. ChemMedChem, 2010, 5, 827-831.
[18]
Milroy, L.G.; Zinzalla, G.; Loiseau, F.; Qian, Z.; Prencipe, G.; Pepper, C.; Fegan, C.; Ley, S.V. Natural-product-like spiroketals and fused bicyclic acetals as potential therapeutic agents for b-cell chronic lymphocytic leukaemia. ChemMedChem, 2008, 3, 1922-1935.
[19]
Dimitrov, I.; Furkert, D.P.; Fraser, J.D.; Radcliff, F.J.; Fincha, O.; Brimble, M.A. Synthesis and anti-helicobacter pylori activity of analogues of spirolaxine methyl ether. MedChemComm, 2012, 3, 938-943.
[20]
Loftus, S.K.; Baxter, L.L.; Cronin, J.C.; Fufa, T.D.; Pavan, W.J.; Barnabas, B.B. Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis. Pigment Cell Melanoma Res., 2017, 30, 339-352.
[21]
Lambrechts, A.; Van-Troys, M.; Ampe, C. The actin cytoskeleton in normal and pathological cell motility. Int. J. Biochem. Cell Biol., 2004, 36, 1890-1909.
[22]
Yamaguchi, H.; Condeelis, J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim. Biophys. Acta, 2007, 5, 642-652.
[23]
Ki, H.H.; Poudel, B.; Lee, J.H.; Lee, Y.M.; Kim, D.K. In Vitro and In Vivo anti-cancer activity of dichloromethane fraction of Triticum aestivum sprouts. Biomed. Pharmacother., 2017, 96, 120-128.
[24]
Li, Z.; Qin, B.; Qi, X.; Mao, J.; Wu, D. Isoalantolactone induces apoptosis in human breast cancer cells via ROS-mediated mitochondrial pathway and downregulation of SIRT1. Arch. Pharm. Res., 2016, 39, 1441-1453.
[25]
Del-Bufalo, D.; Rizzo, A.; Trisciuoglio, D.; Cardinali, G.; Torrisi, M.R.; Zangemeister-Wittke, U.; Zupi, G.; Biroccio, A. Involvemen of hTERT in apoptosis induced by interference with Bcl-2 expression and function. Cell Death Differ., 2005, 12, 1429-1438.
[26]
Kitai, Y.; Zhang, X.; Hayashida, Y.; Kakehi, Y.; Tamura, H. Induction of G2/M arrest and apoptosis through mitochondria pathway by a dimer sesquiterpene lactone from Smallanthus sonchifolius in HeLa cells. J. Food Drug Anal., 2017, 25(3), 619-627.
[27]
Semenza, G.L. Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life, 2008, 60(9), 591-597.
[28]
Masoud, G.N.; Li, W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin., 2015, 5, 378-389.
[29]
Keith, B.; Johnson, R.S.; Simon, M.C. HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer, 2011, 12(1), 9-22.
[30]
Cai, F.; Xu, C.; Pan, X.; Cai, L.; Lin, X.Y.; Chen, S.; Biskup, E. Prognostic value of plasma levels of HIF-1α and PGC-1α in breast cancer. Oncotarget, 2016, 7, 77793-77806.
[31]
Tatè, R.; Zona, E.; De-Cicco, R.; Trotta, V.; Urciuoli, M.; Morelli, A.; Baiano, S.; Carnuccio, R.; Fuggetta, M.P.; Morelli, F. Simvastatin inhibits the expression of stemness-related genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton. Int. J. Oncol., 2017, 51, 1851-1859.

Rights & Permissions Print Cite
Article Metrics
46
5
© 2024 Bentham Science Publishers | Privacy Policy