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DOI: 10.1055/a-2360-6586
Development of New N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide Analogues: Exploring Anticancer Potential through MerTK Inhibition
Abstract
Mer proto-oncogene tyrosine-protein kinase (MerTK), a part of the TAM (TYRO3, AXL, and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor is a promising strategy for more-effective chemotherapy. Considering the pharmacophoric features of the active domain of MerTK and the structural characteristics of the investigational drug BMS794833, we designed five new N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide analogues. In cytotoxicity studies, one of the analogues displayed a significantly higher cytotoxicity than cisplatin. It showed IC50 values of 2.09, 1.96, and 3.08 μM against A549, MCF-7, and MDA-MB-231 cancer cell lines, respectively. In drug metabolism and pharmacokinetic studies, it was the most stable analogue and displayed a moderate MerTK inhibitory potential. Molecular-docking studies were performed to corroborate the MerTK inhibition, and the same analogue achieved the most significant docking score (–12.33 kcal/mol). Docking interactions demonstrated that the imine and amine group of the 3-chloropyridine moiety of BMS794833 formed hydrogen bonds with the main chain of the ATP pocket residue Met674, while the oxygen atoms of the 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with the Lys619 and Asp741 amino acid residues of the allosteric pocket of MerTK protein. These promising results provide evidence that the N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide pharmacophore can give potential insights into the development of new MerTK inhibitors.
Key words
cancer chemotherapeutics - pyrrolotriazines - sulfonamides - metabolic studies - kinase inhibitorsSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2360-6586.
- Supporting Information
Publication History
Received: 23 April 2024
Accepted after revision: 04 July 2024
Accepted Manuscript online:
04 July 2024
Article published online:
05 August 2024
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References and Notes
- 1 Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, Mestan J, O’Reilly T, Traxler P, Chaudhuri B, Fretz H, Zimmerman J, Meyer T, Caravatti G, Furet P, Manley PW. Pharmacol. Ther. 2002; 93: 79
- 2 Paul MK, Mukhopadhyay AK. Int. J. Med. Sci. 2004; 1: 101
- 3 Sangwan V, Park M. Curr. Oncol. 2006; 13: 191
- 4 Du Z, Lovly CM. Mol. Cancer 2018; 17: 58
- 5 Kumar B, Singh S, Skvortsova I, Kumar V. Curr. Med. Chem. 2017; 24: 4729
- 6 Safaroghli-Azar A, Emadi F, Lenjisa J, Mekonnen L, Wang S. Drug Discovery Today 2023; 28: 103525
- 7 Zhang J, Yang PL, Gray NS. Nat. Rev. Cancer 2009; 9: 28
- 8 Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. J. Clin. Invest. 2015; 125: 1780
- 9 Dallavalle S, Dobričić V, Lazzarato L, Gazzano E, Machuqueiro M, Pajeva I, Tsakovska I, Zidar N, Fruttero R. Drug Resistance Updates 2020; 50: 100682
- 10 Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB. Nat. Rev. Drug Discovery 2021; 20: 839
- 11 Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. J. Hematol. Oncol. 2019; 12: 27
- 12 Lahey KC, Gadiyar V, Hill A, Desind S, Wang Z, Davra V, Patel R, Zaman A, Calianese D, Birge RB. Int. Rev. Cell Mol. Biol. 2022; 368: 35
- 13 Huelse JM, Fridlyand DM, Earp S, DeRyckere D, Graham DK. Pharmacol. Ther. 2020; 213: 107577
- 14 Chen C.-J, Liu Y.-P. Pharmaceuticals 2021; 14: 130
- 15 Davra V, Kumar S, Geng K, Calianese D, Mehta D, Gadiyar V, Kasikara C, Lahey KC, Chang Y.-J, Wichroski M, Gao C, De Lorenzo MS, Kotenko SV, Bergsbaken T, Mishra PK, Gause WC, Quigley M, Spires TE, Birge RB. Cancer Res. 2021; 81: 698
- 16 Yan D, Earp HS, DeRyckere D, Graham DK. Cancers 2021; 13: 5639
- 17 Caetano MS, Younes AI, Barsoumian HB, Quigley M, Menon H, Gao C, Spires T, Reilly TP, Cadena AP, Cushman TR, Schoenhals JE, Li A, Nguyen QN, Cortez MA, Welsh JW. Clin. Cancer Res. 2019; 25: 7576
- 18 Bae S.-H, Kim J.-H, Park TH, Lee K, Lee BI, Jang H. Exp. Mol. Med. 2022; 54: 1450
- 19 Nissink JW. M, Bazzaz S, Blackett C, Clark MA, Collingwood O, Disch JS, Gikunju D, Goldberg K, Guilinger JP, Hardaker E, Hennessy EJ, Jetson R, Keefe AD, McCoull W, McMurray L, Olszewski A, Overman R, Pflug A, Preston M, Rawlins PB, Rivers E, Schimpl M, Smith P, Truman C, Underwood E, Warwicker J, Winter-Holt J, Woodcock S, Zhang Y. J. Med. Chem. 2021; 64: 3165
- 20 Kaur R, Dwivedi AR, Kumar B, Kumar V. Anti-Cancer Agents Med. Chem. 2016; 16: 465
- 21 Pflug A, Schimpl M, Nissink JW. M, Overman RC, Rawlins PB, Truman C, Underwood E, Warwicker J, Winter-Holt J, McCoull W. Biochem. J. 2020; 477: 4443
- 22 BDS-001 A mixture of intermediate 10 (10 mg, 0.034 mmol, 1.0 equiv) and carboxylic acid 11 (7 mg, 0.034 mmol, 1.0 equiv) in anhyd DMF (1 mL) in a round-bottomed flask was stirred at r.t. After a few minutes, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 25 mg, 0.068 mmol, 2.0 equiv) and DIPEA (8 mg, 0.068 mmol, 2.0 equiv) were added, and the mixture was stirred overnight at r.t. When the reactants were completely consumed (LCMS), H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 50 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in a rotary evaporator then triturated with MeOH to give an off-white solid; yield: 88%. 1H NMR (400 MHz, DMSO-d 6): δ = 12.12 (s, 1 H), 8.59 (d, J = 5.25 Hz, 1 H), 8.14 (d, J = 5.25 Hz, 2 H), 8.00 (d, J = 12.40 Hz, 1 H), 7.63–7.59 (m, 2 H), 7.48–7.40 (m, 4 H), 6.96 (s, 1 H), 6.73 (t, J = 6.91 Hz, 1 H), 2.55 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 164.2, 162.6, 162.1, 161.7, 161.6, 155.4, 152.9, 145.9, 145.4, 141.8, 137.7 (d, J = 20 Hz, 13C–19F), 135.93 (d, J = 20 Hz, 13C–19F), 134.6 (d, J = 13 Hz, 13C–19F), 128.6 (d, J = 20 Hz, 13C–19F), 123.9, 122.2, 117.1, 116.9, 116.5, 115.5, 109.2 (d, J = 20 Hz, 13C–19F), 107.4, 13.0. LCMS: m/z [M + H]+ (C25H17ClF2N5O3): 508.2.
- 23 BDS-002–BDS-005; General Procedure A solution of intermediate 10 (20 mg, 0.068 mmol. 1.0 equiv) in pyridine (1.0 mL) was stirred at r.t. and the appropriate sulfonyl chloride (1.5 equiv) was added (BDS-002: 2,5-dimethoxybenzene-1-sulfonyl chloride; BDS-003: 2,5-dichlorobenzene-1-sulfonyl chloride; BDS-004: 4-methoxybenzene-1-sulfonyl chloride; BDS-005: 4-fluorobenzene-1-sulfonyl chloride). The resulting mixture was stirred overnight at 90 °C until the reaction was complete (TLC and LCMS). The mixture was treated with 1 N aq HCl (25 mL) to remove the pyridine, and then extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure in a rotary evaporator to give a crude product that was purified by flash chromatography (silica gel, 20% EtOAc–hexane). N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}-2,5-dimethoxybenzenesulfonamide (BDS-002) Off-white solid; yield: 68%. 1H NMR (400 MHz, DMSO-d 6): δ = 7.96 (S, 1 H), 7.38 (d, J = 2.38 Hz, 1 H), 7.25 (s, 1 H), 7.18–6.90 (m, 4 H), 6.60 (s, 1 H), 4.01 (s, 3 H), 3.78 (s, 3 H), 2.53 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 161.7, 155.5, 153.5, 152.9, 150.2, 146.4 (d, J = 21 Hz, 13C–19F), 145.1, 136.1 (d, J = 21 Hz, 13C–19F), 126.9, 124.4, 121.3, 117.4 (d, J = 21 Hz, 13C–19F), 116.6, 115.8 (d, J = 21 Hz, 13C–19F), 114.1 (d, J = 21 Hz, 13C–19F), 113.3, 112.2, 110.6, 57.3, 56.2, 12.9. LCMS: m/z [M + H]+ (C21H19ClFN4O5S): 493.07.
- 24 Borzilleri RM, Cai Z.-W. WO 2009094417, 2009
- 25 Meng Q, Han J, Wang P, Jia C, Guan M, Zhang B, Zhao W. J. Bone Oncol. 2024; 1: 100594