An Efficient Synthesis of 3-Aryl-2H-chromene Derivatives as Potential Bone Anabolic Agents

Abstract

In a quest to identify new osteogenic agents, a new series of 3-aryl-2H-chromene derivatives were rationally designed based on natural isoflavonoids and synthesized through ring transformation of 2H-pyran-2-ones with 3-acetyl-2H-chromene derivatives. From primary screening, five compounds were found to be active in osteoblast differentiation. Among these, the most active compound, 3-(7-methoxy-2H-chromen-3-yl)-5-piperidin-1-ylbiphenyl-4-carbonitrile, showed significantly enhanced calcium nodule formation at 1 pM and 100 pM, and increased osteoblast cell viability. Western blotting experiments indicate that this chromene upregulated osteogenic marker genes such as RUNX2, BMP2, and Type 1 col at the transcriptional and translational levels at concentrations of 1 pM and 100 pM. Furthermore, it decreased osteoblast cell apoptosis at 1 pM and 100 pM, while increasing cell survival in serum-deprived conditions. All these results suggested that the compound has great potential as a bone anabolic agent to improve bone health.

Key words

chromenes - bone anabolic agents - medicinal chemistry - osteoblast differentiation - ring transformation reaction - pyranones

Publication History

Received: 09 November 2024

Accepted: 30 December 2024

Accepted Manuscript online:
30 December 2024

Article published online:
10 February 2025

• References and Notes

• 1 Hu C, Ashok D, Nisbet DR, Gautam V. Biomaterials 2019; 219: 119366
• 2 Rossi M, Battafarano G, Pepe J, Minisola S, Del Fattore A. Int. J. Mol. Sci. 2019; 20: 4502
• 3 Loebel C, Burdick JA. Cell Stem Cell 2018; 22: 325
• 4 Maurya R, Singh G, Yadav PP. Stud. Nat. Prod. Chem. 2008; 35: 517
• 5 Kanis JA, Johnell O, Oden A, Sernbo I, Redlund-Johnell I, Dawson A, De Laet CE, Jonsson B. Osteoporosis Int. 2000; 11: 669
• 6 Melton LJ. III, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL. J. Bone Miner. Res. 1998; 13: 1915
• 7 Curtis EM, van der Velde R, Moon RJ, van den Bergh JP, Geusens P, de Vries F, van Staa TP, Cooper C, Harvey NC. Bone (New York, NY, United States) 2016; 87: 19
• 8 Kobayashi S, Takahashi HE, Ito A, Saito N, Nawata M, Horiuchi H, Ohta H, Iorio R, Yamamoto N, Takaoka K. Bone 2003; 32: 163
• 9 Bartl R, Bartl C. Bone Disorders: Biology, Diagnosis, Prevention, Therapy. Springer; Cham: 2017: 31
• 10 David R. Nat. Rev. Mol. Cell Biol. 2011; 12: 767
• 11 Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM. N. Engl. J. Med. 1995; 332: 767
• 12 Reagan MR, Rosen CJ. Nat. Rev. Rheumatol. 2016; 12: 154
• 13 Sheu Y, Amati F, Schwartz AV, Danielson ME, Li X, Boudreau R, Cauley JA. Bone 2017; 97: 299
• 14 Greco EA, Lenzi A, Migliaccio S. Ther. Adv. Endocrinol. Metab. 2015; 6: 273
• 15 Drake MT, Clarke BL, Khosla S. Mayo Clin. Proc. 2008; 83: 1032
• 16 Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Endocr. Rev. 1993; 14: 690
• 17 Miller PD, Hattersley G, Riis BJ, Williams GC, Lau E, Russo LA, Alexandersen P, Zerbini CA, Hu M.-y, Harris AG, Fitzpatrick LA, Cosman F, Christiansen C. JAMA J. Am. Med. Assoc. 2016; 316: 722
• 18 Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. JAMA J. Am. Med. Assoc. 2010; 304: 657
• 19 Bhargavan B, Gautam AK, Singh D, Kumar A, Chaurasia S, Tyagi AM, Yadav DK, Mishra JS, Singh AB, Sanyal S, Goel A, Maurya R, Chattopadhyay N. J. Cell. Biochem. 2009; 108: 388
• 20 Singh KB, Dixit M, Dev K, Maurya R, Singh D. Br. J. Nutr. 2017; 117: 1511
• 21 Khan K, Pal S, Yadav M, Maurya R, Trivedi AK, Sanyal S, Chattopadhyay N. J. Nutr. Biochem. 2015; 26: 1491
• 22 Singh KB, Awasthi P, Srivastava K, Rawat KS, Rai R, Parveen S, Gautam AK, Vats RP, Goel A, Singh D. Bioorg. Med. Chem. Lett. 2023; 80: 129118
• 23 Sharma K, Awasthi P, Prakash R, Khanka S, Bajpai R, Sahasrabuddhe AA, Goel A, Singh D. J. Cell. Biochem. 2022; 123: 1762
• 24 Tyagi AM, Srivastava K, Kureel J, Kumar A, Raghuvanshi A, Yadav D, Maurya R, Goel A, Singh D. Osteoporosis Int. 2012; 23: 1151
• 25 Tominaga Y. Trends Heterocycl. Chem. 1991; 28: 43
• 26 Junjappa H, Ila H, Asokan CV. Tetrahedron 1990; 46: 5423
• 27 Purohit D, Sharma CP, Raghuvanshi A, Jain A, Rawat KS, Gupta NM, Singh J, Sachdev M, Goel A. Chem. Eur. J. 2019; 25: 4660
• 28 Sharma CP, Gupta NM, Singh J, Yadav RA, Dubey DK, Rawat KS, Jha AK, Jou JH, Goel A. J. Org. Chem. 2019; 84: 7674
• 29 Brenna E, Gatti FG, Malpezzi L, Monti D, Parmeggiani F, Sacchetti A. J. Org. Chem. 2013; 78: 4811
• 30 Kaoukabi A, Belachemi L, Lahcini M, Massuard MC, Croix C. J. Heterocycl. Chem. 2019; 56: 1260
• 31 Shin SY, Jung H, Ahn S, Hwang D, Yoon H, Hyun J, Yong Y, Cho HJ, Koh D, Lee YH, Lim Y. Bioorg. Med. Chem. 2014; 22: 1809
• 32 Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. J. Clin. Invest. 1999; 104: 439
• 33 6-Aryl-4-(methylsulfanyl)-2-oxo-2H-pyran-3-carbonitriles 3a–h; General Procedure A mixture of methyl 2-cyano-3,3-bis(methylsulfanyl)acrylate (1; 10 mmol), the appropriate acetophenone 2a–h (11 mmol), and KOH (12 mmol) in DMSO (50 mL) was stirred at r.t. for 14–16 h. When the reaction was complete, the mixture was poured into ice-cold H₂O, and the resulting precipitate was collected by filtration, washed with cold H₂O, and purified by column chromatography (silica gel, CHCl₃). 6-aryl-2-oxo-4-piperidin-1-yl-2H-pyran-3-carbonitriles 4a–h; General Procedure The appropriate nitrile 3a–h (1 mmol) and piperidine (1.2 mmol) were refluxed in MeOH for 5–6 h. The mixture was then cooled to r.t. and the solid that formed was collected by filtration. 2-Oxo-6-phenyl-4-piperidin-1-yl-2H-pyran-3-carbonitrile (4a) White solid; yield: 86%; mp 220–222 °C (CHCl₃–MeOH). IR (KBr): 2212 cm^–1 (CN). ¹H NMR (400 MHz, DMSO-d₆ ): δ = 7.96–7.92 (m, 2 H), 7.55–7.48 (m, 3 H), 7.02 (s, 1 H), 3.84–3.86 (m, 4 H), 1.66–1.68 (m, 6 H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆ ): δ = 162.42, 160.34, 159.57, 132.13, 131.08, 129.44, 126.75, 118.20, 96.05, 70.47, 50.86, 26.62, 23.79. HRMS (ESI); m/z [M + H]⁺ calcd for C₁₇H₁₇N₂O₂: 281.3350; found: 281.3348. 3-(7-Methoxy-2H-chromen-3-yl)-5-piperidin-1-ylbiphenyl-4-carbonitrile (8i) A mixture of 4a (560 mg, 2 mmol, 2 equiv), 1-(7-methoxy-2H-chromen-3-yl)ethanone (204 mg, 1 mmol, 1 equiv), and a 60% oil dispersion of NaH (4 mmol, 4 equiv) in anhyd DMF (8 mL) was stirred at r.t. for 2 h. When the reaction was complete (TLC), the mixture was poured onto crushed ice with vigorous stirring, and the resulting mixture was then neutralized with 10% aq HCl. The precipitate that formed was collected by filtration and purified by column chromatography (silica gel, 5% EtOAc–hexane) to give a light-yellow solid; yield: 84%; mp 130–132 °C. IR (KBr): 2212 (CN) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.61–7.54 (m, 2 H), 7.51–7.39 (m, 3 H), 7.16–7.09 (m, 2 H), 7.05 (d, J = 8.3 Hz, 1 H), 6.81 (s, 1 H), 6.54–6.44 (m, 2 H), 5.12 (s, 2 H), 3.81 (s, 3 H), 3.30–3.16 (m, 4 H), 1.88–1.77 (m, 4 H), 1.68–1.58 (m, 2 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 161.36, 158.89, 155.11, 146.37, 144.81, 139.88, 129.00, 128.58, 128.36, 127.36, 127.27, 125.77, 119.51, 118.05, 116.56, 116.01, 107.83, 103.01, 101.58, 67.89, 55.44, 53.63, 26.18, 24.09. MS (ESI): m/z = 423.4 [M + H]⁺. HRMS (ESI); m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O₂: 423.2073; found: 423.2067.