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Ouellette, Vincent ; Bouzriba, Chahrazed ; Alvarez, Atziri Corin Chavez , et al. RSC Med. Chem.,2024,15,3728-3745. DOI: 10.1039/D4MD00476K
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Abstract: We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC50: 0.03-3.3 μM) and high selectivity (8-> 1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55-120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.
Keywords: Anticancer agents ; Antimitotics ; Antimicrotubule agents ; CYP1A1-activated prodrugs ; Pyridinyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates ; PYRAIB-SOs ; Pyridinyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates ; PYRIB-SOs ; Phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates ; PAIB-SOs ...More
Purchased from AmBeed: 328087-38-3 ; 109345-94-0 ; 74115-12-1 ; 36953-40-9 ; 74115-13-2
CAS No. : | 36953-40-9 | MDL No. : | MFCD00234040 |
Formula : | C5H4BrNO | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | GGXSDQDNOMWAFV-UHFFFAOYSA-N |
M.W : | 174.00 | Pubchem ID : | 2762840 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | |
GHS Pictogram: |
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* 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 |
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91.1% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 0.5h; | Step 1: To solution of 2-bromopyridin-4-ol (0.4 g, 2 mmol) and <strong>[894807-98-8]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole</strong> (0.99 g, 3 mmol) in Dioxane/H2O (3 ml/1.5 ml) was added PEPSI-IPr catalyst (0.078 g, 0.115 mmol) and followed by the addition of Cs2CO3 (1.65 g, 5 mmol). The reaction mixture was stirred at 90° C. for 30 minutes. The reaction mixture was diluted with EtOAc and washed with HCl (1N). Two phases were separated and the aqueous phase was extracted with EtOAc (3×). Organic phase were combined and concentrated down under vacuo. The residue was purified by silicone gel column. And 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-ol was obtained (0.61 g, 91.1percent). |