New Method of Synthesis and Biological Evaluation of Some Combretastatin A-4 Analogues

Abstract

A series of novel combretastatin A-4 analogues was synthesized in 36–64% yields by Negishi cross-coupling reaction under mild conditions. The prepared compounds exhibit good cytotoxicity against HBL100 epithelial cell lines (IC₅₀ = 0.022–10.31 µМ).

Key words

antitumor agents - cross-coupling - organometallic reagents - magnesium–zinc exchange - cytotoxicity

• References and Notes

• 1a Pettit GR, Cragg GM, Herald DL, Schmidt JM, Lobavanijaya P. Can. J. Chem. 1982; 60: 1347
• 1b Hamel E, Lin CM. Biochem. Pharmacol. 1983; 32: 3864
• 1c Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, Pettit GR, Hamel E. Mol. Pharmacol. 1988; 34: 200
• 1d Lin CM, Ho HH, Pettit GR. Biochemistry 1989; 28: 6984
• 1e Pettit GR, Singh SB, Niven ML, Hamel E, Schmidt JM. J. Nat. Prod. 1987; 50: 119
• 1f Pettit GR, Singh SB, Boyd MR, Hamel E, Pettit RK, Schmidt JM, Hogan F. J. Med. Chem. 1995; 38: 1666
• 1g Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D. Experientia 1989; 45: 209
• 2a Mooney CJ, Nagaiah G, Fu P, Wasman JK, Cooney MM, Savvides PS, Bokar JA, Dowlati A, Wang D, Agarwala SS, Flick SM, Hartman PH, Ortiz JD, Lavertu PN, Remick SC. Thyroid 2009; 19: 233
• 2b Kingston DG. I. J. Nat. Prod. 2009; 72: 507
• 2c Lippert JW. Bioorg. Med. Chem. 2007; 15: 605
• 2d Dumontet C, Jordan MA. Nat. Rev. 2010; 9: 790
• 3a Pettit GR, Toki B, Herald DL, Verdier-Pinard P, Boyd MR, Hamel E, Pettit RK. J. Med. Chem. 1998; 41: 1688
• 3b Getahun Z, Jurd L, Chu PS, Lin CM, Hamel E. J. Med. Chem. 1992; 35: 1058
• 3c Siles R, Ackley JF, Hadimani MB, Hall JJ, Mugabe BE, Guddneppanavar R, Monk KA, Chapuis J.-C, Pettit GR, Chaplin DJ, Edvardsen K, Trawick ML, Garner CM, Pinney KG. J. Nat. Prod. 2008; 71: 313
• 3d Simoni D, Romagnoli R, Baruchello R, Rondanin R, Rizzi M, Pavani MG, Alloatti D, Giannini G, Marcellini M, Riccioni T, Castorina M, Guglielmi MB, Bucci F, Carminati P, Pisano C. J. Med. Chem. 2006; 49: 3143
• 4a Nam NH. Curr. Med. Chem. 2003; 10: 1697
• 4b Tron GC, Pirali T, Sorba G, Pagliai F, Busacca S, Genazzani AA. J. Med. Chem. 2006; 49: 3033
• 5 Singh R, Kaur H. Synthesis 2009; 2471
• 6a Pettit GR, Singh SB, Boyd MR, Hamel E, Pettit RK, Schmidt JM, Hogan F. J. Med. Chem. 1995; 38: 1666
• 6b Roberti M, Pizzirani D, Simoni D, Rondanin R, Baruchello R, Bonora C, Buscemi F, Grimaudo S, Tolomeo M. J. Med. Chem. 2003; 46: 3546
• 6c Pettit GR, Singh SB. J. Org. Chem. 1989; 54: 4105
• 6d Harrowven DC, Guy IL, Howell M, Packham G. Synlett 2006; 2977
• 7a Lawrence NJ, Ghani FA, Hepworth LA, Hadfield JA, McGown AT, Pritchard RG. Synthesis 1999; 1656
• 7b Brown HC, Zweifel G. J. Am. Chem. Soc. 1961; 83: 3834
• 8 Fürstner A, Nikolakis K. Liebigs Ann. 1996; 2107
• 9a Giraud A, Provot O, Hamze A, Brion J.-D, Alami M. Tetrahedron Lett. 2008; 49: 1107
• 9b Hamze A, Provot O, Brion J.-D, Alami M. Synthesis 2007; 2025
• 10 Lara-Ochoa F, Espinosa-Pérez G. Tetrahedron Lett. 2007; 48: 7007
• 11 Pettit GR, Singh SB, Cragg GM. J. Org. Chem. 1985; 50: 3404
• 12a Gaukroger K, Hadfield JA, Hepworth LA, Lawrence NJ, McGown AT. J. Org. Chem. 2001; 66: 8135
• 12b Zou Y, Xiao C.-F, Zhong R.-Q, Wei W, Huang W.-M, He S.-J. J. Chem. Res. 2008; 354
• 13 Bazin M.-A, Jouanne M, El-Kashef H, Rault S. Synlett 2009; 2789
• 14 Camacho-Davila AA. Synth. Commun. 2008; 38: 3823
• 15a Robinson JE, Taylor RJ. K. Chem. Commun. 2007; 1617
• 15b Chan T.-L, Fong S, Li Y, Man T.-O, Poon C.-D. J. Chem. Soc., Chem. Commun. 1994; 1771
• 15c Yang G, Franck RW, Byun H.-S, Bittman R, Samadder P, Arthur G. Org. Lett. 1999; 1: 2149
• 15d Meyers CY, Malte AM, Matthews WS. J. Am. Chem. Soc. 1969; 91: 7510
• 16a Negishi E. Acc. Chem. Res. 1982; 15: 340
• 16b Klement I, Rottlander M, Tucker CE, Majid TN, Knochel P, Venegas P, Cahiez G. Tetrahedron 1996; 52: 7201
• 17a Cragg GM, Newman DJ. J. Nat. Prod. 2004; 67: 232
• 17b Nicolaou KC, Dai W.-M, Guy RK. Angew. Chem., Int. Ed. Engl. 1994; 33: 15
• 17c Abal M, Andreu JM, Barasoain I. Curr. Cancer Drug Targets 2003; 3: 193
• 18a Bailly C, Bal C, Barbier P, Combes S, Finet J.-P, Hildebrand M.-P, Peyrot V, Wattez N. J. Med. Chem. 2003; 46: 5437
• 18b Rappl C, Barbier P, Bourgarel-Rey V, Gregoire C, Gilli R, Carre M, Combes S, Finet J.-P, Peyrot V. Biochemistry 2006; 45: 9210
• 18c Ganina OG, Daras E, Bourgarel-Rey V, Peyrot V, Andresyuk AN, Finet J.-P, Fedorov AY, Beletskaya IP, Combes S. Bioorg. Med. Chem. 2008; 16: 8806
• 19 Cheung LL. W, Yudin AK. Org. Lett. 2009; 11: 1281
• 20 Knochel P, Normant JF. Tetrahedron Lett. 1986; 27: 4431
• 21 Ren H, Krasovskiy A, Knochel P. Org. Lett. 2004; 6: 4215
• 22 Preparation of (Z)-3,4,5-Trimethoxy-β-Iodostyrene (2)Into a flame-dried 2 L round-bottom flask equipped with a magnetic stirrer and a septum was placed iodomethylene-triphenylphosphonium iodide (62 g, 117 mmol).^19,23 The flask was then put under vacuum for 5 min and purged with nitrogen. Dry THF (350 mL) was added, and the yellow suspension was cooled to –20 °C. Then, NaHMDS in THF (62 mL of 1.9 M solution, 117 mmol) was added dropwise along the flask wall within 30 min. The mixture was stirred at –20 °C for 15 min, then cooled to –78 °C, and 3,4,5-trimethoxybenzaldehyde (17.6 g, 90 mmol) in THF (200 mL) was added at this temperature within 1 h with good stirring. The reaction was stirred in the cooling bath for 2 h more, and quenched while still cold with sat. aq NH₄Cl. Then Et₂O was added to the mixture, the layers were separated, and the aqueous layer was extracted with Et₂O. The combined organic layers were filtered to remove Ph₃PO, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (pentane–EtOAc, 4:1) to give 2 (20.5 g, 64 mmol, 71%, Z/E = 15:1) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.20 (d, J = 8.6 Hz, 1 H), 6.91 (s, 2 H), 6.48 (d, J = 8.6 Hz, 1 H), 3.86 (s, 6 H), 3.85 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.8, 138.2, 138.1, 131.8, 105.8, 78.0, 60.8, 56.2. MS (EI): m/z (%) = 320 (100) [M]⁺, 306 (5), 303 (45), 276 (5), 150 (5). HRMS (EI): m/z calcd for C₁₁H₁₃IO₃: 319.9909; found: 319.9910 [M]⁺
• 23 Conway JC, Quayle P, Regan AC, Urch CJ. Tetrahedron 2005; 61: 11910
• 24 Typical Procedure for the Preparation of 4a-OTBSA dry nitrogen-flushed Schlenk flask, equipped with a magnetic stirrer and a septum, was charged with a solution of alkenyl iodide (320 mg, 1 mmol) in dry THF (3 mL). The solution of i-PrMgCl·LiCl (0.92 mL of 1.19 M in THF, 1.1 mmol) was added slowly at –40 °C, and the reaction mixture was stirred at this temperature for 15 min to complete the I–Mg exchange. A solution of ZnCl₂ (0.5 mL of 1 M in THF, 0.5 mmol) and NMP (0.1 mL) was added dropwise within 1 min, and the reaction was warmed to r.t. 4-Methoxy-3-(tert-butyldimethylsilyloxy)iodobenzene (400 mg, 1.1 mmol) and (A-^taPhos)₂PdCl₂ (14 mg, 0.02 mmol) were added. The reaction mixture was stirred at r.t. for 30 min, poured into sat. aq NH₄Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to get brown oil. It was purified by flash chromatography on silica gel (pentane–EtOAc, 5:1) to give 4a-OTBS (267 mg, 0.62 mmol, 62%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 6.85 (dd, J = 8.3, 2.1 Hz, 1 H), 6.79 (d, J = 2.1 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 1 H), 6.50 (s, 2 H), 6.47 (d, J = 12.1 Hz, 1 H), 6.41 (d, J = 12.1 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.70 (s, 6 H), 0.93 (s, 9 H), 0.06 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 153.1, 150.4, 144.7, 137.2, 133.2, 130.2, 129.8, 128.9, 123.0, 121.4, 111.8, 106.0, 61., 56.0, 55.6, 25.8, 18.5, –4.7. MS (EI): m/z (%) = 430 (40) [M]⁺, 373 (22), 359 (23), 358 (100), 343 (25). HRMS (EI): m/z calcd for C₂₄H₃₄O₅Si: 430.2176; found: 430.2180 [M]⁺