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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Wen Ren ; Yuling Deng ; Jacob D. Ward ; Rebecca Vairin ; Ruoli Bai b ; Hashini I. Wanniarachchi , et al.
Abstract: The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.
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Keywords: Inhibitors of tubulin polymerization ; Vascular disrupting agents ; Indole synthesis ; Molecular docking ; Antiproliferative agents ; Inhibitors of cell migration
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Purchased from AmBeed: 128796-39-4 ; 10365-98-7 ; 98-80-6 ; 98437-24-2 ; 5720-05-8 ; 64-86-8 ; 13331-27-6 ; 206551-43-1 ; 63139-21-9 ; 622864-48-6 ; 5720-07-0 ; 87199-18-6 ; 30418-59-8 ; 4521-61-3 ; 4521-61-3 ; 87199-18-6 ; 64-86-8 ; 64-86-8 ; 128796-39-4 ; 5720-05-8 ; 64-86-8
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Pieterse, Lianie ; Beteck, Richard M. ; Baratte, Blandine ; Jesumoroti, Omobolanle J. ; Robert, Thomas ; Ruchaud, Sandrine , et al.
Abstract: Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesized and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, resp. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.
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Keywords: 7-Deazapurine ; Anticancer ; CDK9/CylinT ; Haspin ; Protein kinase
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Purchased from AmBeed: 98437-24-2 ; 71597-85-8 ; 3680-69-1 ; 6165-68-0 ; 51067-38-0 ; 87199-18-6
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CAS No. : | 98437-24-2 |
Formula : | C8H7BO3 |
M.W : | 161.95 |
SMILES Code : | OB(C1=CC2=CC=CC=C2O1)O |
MDL No. : | MFCD00236019 |
InChI Key : | PKRRNTJIHGOMRC-UHFFFAOYSA-N |
Pubchem ID : | 2776266 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In dimethylethylene glycol ether; dichloromethane; | A. 3-benzo[b]Furan-2-yl-1-Perhydro-2H-Pyran-2-Yl-1H-Indazole-5-Carbonitrile To a flask containing 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.30 mmol) in dimethyl glycol ether (15 mL) was added potassium phosphate (2.75 g), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (106 mg, 0.130 mmol), and benzo[b]furan-2-boronic acid (315 mg, 1.95 mmol). The reaction mixture was brought to 90° C. under nitrogen conditions for 18 hours. The mixture was condensed and extracted with water (25 mL) and ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by chromatography (SiO2, 20percent ethyl acetate/hexanes) to afford the title compound (278 mg, 62percent). ES-MS (m/z) 344[M+1]+. |
62% | In dimethylethylene glycol ether; dichloromethane; | A. 3-benzo[b]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile To a flask containing 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.30 mmol) in dimethyl glycol ether (15 mL) was added potassium phosphate (2.75 g), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (106 mg, 0.130 mmol), and benzo[b]furan-2-boronic acid (315 mg, 1.95 mmol). The reaction mixture was brought to 90° C. under nitrogen conditions for 18 hours. The mixture was condensed and extracted with water (25 mL) and ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by chromatography (SiO2, 20percent ethyl acetate/hexanes) to afford the title compound (278 mg, 62percent). ES-MS (m/z) 344[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; for 90.0h;Heating / reflux; | A mixture of Intermediate 5 (0.5 g, 1.73 mmol), benzo[b]furan-2-boronic acid (0.293 g, 1.92 mmol), tetrakistriphenylphosphine palladium catalyst (50 mg) and 2N sodium carbonate (7.78 ml) were heated under reflux in dimethoxyethane (15 ml) for approximately 18 hours. Fresh catalyst (50 mg) was added and heating continued for approximately an addition 72 hours. The solids from the reaction mixture were removed by filtration. The aqueous and organic layers were separated. The organic layer was washed with water and the aqueous washings were back extracted with EtOAc and combined with the organic phases. and al of the organic layers were combined. The combined organic layers were dried using a drying agent such as molecular sieves, filtered, and volatiles removed in vacuo. The resulting residue was chromatographed on silica gel using a gradient eluent of 2-6percent EtOAc/iHexane and the desired product was isolated after combining the appropriate fractions and removing solvent in vauo (18.6 mg, 38percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.67 g | With palladium diacetate; cesium fluoride; XPhos; In 1,4-dioxane; at 100℃; for 2h; | A mixture of benzofuran-2-boronic acid (2.19 g, 13.51 mmole), 6- bromo-2-naphthaleneamine (3 g, 13.51 mmole), cesium fluoride (6.45 g, 42.46 mmole), Pd(OAc)2 (0.1517 g, 0.678 mmole), XPhos (0.676 g, 1.42 mmole) in 1,4-dioxane (60 ml) was stirred at 100°C for 2 hours totally. After that the mixture was cooled down, passed thorugh a filter filled with silica gel and Celite® eluting with dichloromethane. The residue after evaporation of solvent was absorbed on Celite® and subjected to chromatography purification on silica gel using gradient elution with mixtures of hexanes and dichloromethane to dichloromethane. Fractions containing product collected, eluent evaporated using rotary evaporator to minimal volume, diluted with hexanes. Precipitates formed upon dilution with hexanes and by partial evaporation of filtrates were collected, dried in vacuum to give 1.67 g of the product.1H-NMR (toluene-d8, 500 MHz): 3.01 (s, 2H), 6.47-76.50 (m, 2H), 6.71 (s, 1H), 7.09-7.15 (m, 3H), 7.44-7.46 (d, 2H, J = 9 Hz), 7.48 (d, 1H, J = 9 Hz), 7.76 (dd, 1H, J1 = 2 Hz, J2 = 9 Hz), 8.24 (s, 1H). MS: MH+ = 260. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; toluene;Inert atmosphere; Reflux; | General procedure: <strong>[1458-01-1]Methyl 3,5-diamino-6-chloropyrazine-2-carboxylate</strong> 2 (1 eq.) was combined with K2CO3 (10 eq.), the appropriate (het)aryl boronic acid (1.5 eq.) and Pd(PPh3)4 (5 mol%) in a two-neck round bottom flask. The flask was connected to a condenser and purged with nitrogen. A 4:1 mixture of anhydrous toluene: MeOH (60 mL) was added via syringe and the reaction mixture was heated at reflux for 0.5-18 h. The mixture was allowed to cool to room temperature and filtered through Celite (10 x 3 cm, eluting with 3 x 20 mL EtOAc). The filtrate was evaporated to dryness and the residue purified by silica gel flash column chromatography using EtOAc/pet spirit. |