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Wen Ren ; Yuling Deng ; Jacob D. Ward , et al. Eur. J. Med. Chem.,2024,263,115794. DOI: 10.1016/j.ejmech.2023.115794
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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.
Keywords: Inhibitors of tubulin polymerization ; Vascular disrupting agents ; Indole synthesis ; Molecular docking ; Antiproliferative agents ; Inhibitors of cell migration
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 ...More
CAS No. : | 30418-59-8 | MDL No. : | MFCD00007755 |
Formula : | C6H8BNO2 | Boiling Point : | No data available |
Linear Structure Formula : | C6H4(B(OH)2)NH2 | InChI Key : | JMZFEHDNIAQMNB-UHFFFAOYSA-N |
M.W : | 136.94 | Pubchem ID : | 92269 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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 |
---|---|---|
78% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90 - 99℃; for 4h; | Step 2. N-(5-(3-aminophenyl)thiazolo[5.4-b1pyridin-2-yl)acetamide (Example 156); <strong>[1112982-76-9]N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide</strong> (1.504 g, 5.527 mmol), 3-aminophenylboronic acid monohydrate (1.316 g, 8.493 mmol), Pd(dppf)Cl2-DCM complex (604.4 mg, 0.7401 mmol), and potassium carbonate (2.292 g, 16.58 mmol) were suspended in 1,4-dioxane (45 ml) and water (15 ml) was added. Argon was bubbled through the solution for about 30 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (90 - 99 C) and stirred under argon for 4 hours. The reaction was cooled to room temperature, filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM and MeOH, and filtered. The solid was collected and set aside, and the filtrate was concentrated, treated with Et2O, and filtered. Solid washed with Et2O. This solid was combined with the first batch and dried under high vacuum first at room temperature, anphithen at ~ 50 C. This solid was treated with deionized water and filtered, and the solid was washed with water, collected, and dried under high vacuum in water bath (~ 50 C) to afford N-(5-(3- aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (1.22 g, 78% yield). MS (ESI pos. ion) m/z: 285. Calculated exact mass for C14H]2N4OS 284. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In acetonitrile; at 85℃;Inert atmosphere; Sealed tube; | A solution of 19 (100 mg, 0.473 mmol) and 23 (62 mg, 0.4739 mmol) in acetonitrile (5 mL) was added cesium carbonate (310 mg, 0.946 mmol). The reaction was degassed and purged with nitrogen for 15 min. Pd(dppf)Cl2 (25.4 mg, 0.0218 mmol) was added and again degassed and purged with nitrogen for 15 min. The reaction was stirred overnight at 85 C., allowed to cool to rt, then diluted with DCM (25 mL) and filtered through Celite plug and concentrated to get the crude compound. The resulting oil was purified via silica gel chromatography using a gradient of 40% ethyl acetate:hexane to afford compound 24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.4% | Inert atmosphere; | A PT-TFP ligand was obtainedfrom the reaction of <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (1.82 g, 8.03 mmol) and(3-aminophenyl)boronic acid (1.00 g, 7.30 mmol) by Suzuki coupling. The abstraction and purification processes are the same as described above. Yield: 87.4percent (1.52 g); 1H NMR(CDCl3, 500 MHz): deltaH(ppm) 8.38(s, 1H), 8.06(s, 1H), 7.66(s, 1H), 7.47(s, 1H), 7.15(s,1H), 6.65(s, 1H), 6.27(d, 2H) |
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