Synthesis of a 5,6-Dihydropyran-2-one Derivative with Dual Anti-Cell-Migration and Anticancer Activity

Abstract

The 5,6-dihydropyran-2-one scaffold is found in several biologically active compounds. In this study, we synthesized a new derivative, named PY801. This compound (1 mM) was shown to suppress the migration of lung cancer cells. Furthermore, in cancer cell line panel experiments, PY801 showed cytotoxicity against several specific cell lines. The IC50 values of PY801 against colorectal cancer cells HCT116 and breast cancer cells MCF7 were determined to be 8.9 and 9.3 mM, respectively; these values are lower than those of the anticancer drug cisplatin. Compared with the IC50 against peripheral blood mononuclear cells (PBMC) from a healthy donor, the selectivity index was determined to be >7. This study showed PY801 might be a new lead compound for anti-cell-migration and anticancer drugs.

Key words

dihydropyran-2-ones - anti-cell-migration activity - anticancer drugs

Publication History

Received: 27 February 2025

Accepted after revision: 28 April 2025

Accepted Manuscript online:
28 April 2025

Article published online:
16 June 2025

• References and Notes

• 1 Current address: College of Pharmacy, University of Florida, FL, USA
• 2 Eskandari K, Rafieian-Kopaei M. Chem. Heterocycl. Compd. 2016; 52: 158
• 3 Meragelman TL, Scudiero DA, Davis RE, Staudt LM, McCloud TG, Cardellina JH. II, Shoemaker RH. J. Nat. Prod. 2009; 72: 336
• 4 Grover A, Agrawal V, Shandilya A, Bisaria VS, Sundar DI. BMC Bioinf. 2011; 12 (Suppl. 13) S22
• 5 BouzBouz S, Cossy J. Org. Lett. 2003; 5: 1995
• 6 Sassa T, Kato H, Kajiura H. Tetrahedron Lett. 1986; 27: 2121
• 7 Goswami A, Saikia PP, Saikia B, Chaturvedi D, Barua NC. Tetrahedron Lett. 2011; 52: 5133
• 8 Smith TE, Djang M, Velander AJ, Downey CW, Carroll KA, van Alphen S. Org. Lett. 2004; 6: 2317
• 9 Wang F.-D, Yue J.-M. Synlett 2005; 2077
• 10 Yadav J, Ather H, Rao NV, Reddy MS, Prasad A. Synlett 2010; 1205
• 11 Carré G, Carreyre H, Ouedraogo M, Becq F, Bois P, Thibaudeau S, Vandebrouck C, Bescond J. Eur. J. Pharmacol. 2014; 728: 119
• 12 Li H, Tatlock J, Linton A, Gonzalez J, Jewell T, Patel L, Ludlum S, Drowns M, Rahavendran SV, Skor H, Hunter R, Shi ST, Herlihy KJ, Parge H, Hickey M, Yu X, Chau F, Nonomiya J, Lewis C. J. Med. Chem. 2009; 52: 1255
• 13 Gan W, He M, Huang Y, Dai Z, Yu M, Lu Y, Wang Y, Han X, Zeng X. Org. Lett. 2024; 26: 10114
• 14 Hamdy AK, Sakamoto T, Toma T, Sakamoto M, Abourehab MA. S, Otsuka M, Fujita M, Tateishi H, Radwan MO. Pharmaceuticals 2022; 15: 1579
• 15 Avula SK, Das B, Csuk R, Al-Rawahi A, Al-Harrasi A. Molecules 2020; 25: 1905
• 16 Marco JA, Carda M, Murga J, Falomir E. Tetrahedron 2007; 63: 2929
• 17 Neumaier J, Maier ME. Synlett 2011; 187
• 18 Wender PA, Baryza JL, Brenner SE, DeChristopher BA, Loy BA, Schrier AJ, Verma VA. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 6721
• 19 Shinde DB, Kanth BS, Satyakumar A, Kamble V, Das B. Lett. Org. Chem. 2013; 10: 317
• 20 Ding F, Jennings MP. J. Org. Chem. 2008; 73: 5965
• 21 Pardo LM, Tellitu I, Domínguez E. Tetrahedron 2010; 66: 5811
• 22 Kamo M, Ito M, Toma T, Gotoh H, Shimozono R, Nakagawa R, Koga R, Monde K, Tateishi H, Misumi S, Otsuka M, Fujita M. Bioorg. Chem. 2021; 107: 104627
• 23 https://dtp.cancer.gov/discovery_development/nci-60/methodology.htm (accessed 8 December 2024).
• 24 Sakamoto M, Kai S, Tateishi H, Biswas T, Sakamoto T, Teshima M, Iwanaga M, Nishikawa A, Sakamoto A, Shimozono R. Synlett. in press, DOI:
• 25 Toma T, Tateishi H, Kawakami K, Ali TF, Kamo M, Monde K, Nakashima Y, Fujita M, Otsuka M. Int. J. Mol. Sci. 2022; 23: 5047
• 26 Benzyl 2-[(2R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]ethyl Propane-1,3-diylbiscarbamate (PY801) Amine 11 (406 mg, 1.95 mmol) was added to a solution of carbonate 8 (400 mg, 1.30 mmol) in DMSO (5 mL), and the mixture was stirred for 5 h under argon. H₂O (30 mL) was then added, and the mixture was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic phase was dried (Na₂SO₄) and concentrated under a vacuum. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (8:2)] to give white powder; yield: 411 mg (84%). ¹H NMR (600 MHz, CDCl₃): = 7.31–7.23 (m, 5 H), 6.83–6.79 (m, 1 H), 5.96 (dd, J = 9.7, 1.3 Hz, 1 H), 5.10 (d, J = 20.3 Hz, 2 H), 5.03 (s, 2 H), 4.50 (dt, J = 12.0, 4.6 Hz, 1 H), 4.22–4.12 (m, 2 H), 3.20–3.12 (m, 4 H), 2.34–2.25 (m, 2 H), 2.02 (dd, J = 13.9, 7.7 Hz, 1 H), 1.92 (dd, J = 13.0, 5.7 Hz, 1 H), 1.78–1.31 (m, 2 H). ¹³C NMR (150 MHz, CDCl₃): = 164.01, 156.93, 156.66, 144.80, 136.55, 128.54, 128.14, 128.03, 121.52, 74.92, 66.75, 60.46, 37.66, 37.56, 34.46, 30.42, 29.37. HRMS (FAB): m/z [M + Na]⁺ calcd for C₁₉H₂₄N₂NaO₆: 399.1532; found: 399.1537.