Potent antiproliferative activity of bradykinin B2 receptor selective agonist FR-190997 and analogue structures thereof: A paradox resolved?

Studies towards the Synthesis of Novel 3-Aminopropoxy-Substituted Dioxins Suitable for the Development of Aptamers for Photonic Biosensor Applications

“…Taking into consideration that (a) the methoxy group is, in fact, a protected form of aromatic hydroxyl functions [ 20 ], (b) nitro groups in the polychlorinated aromatics facilitate the afore mentioned reaction, and (c) a nitro group can be readily replaced at a later stage by a chlorine atom through reduction and Sandmeyer reaction [ 21 ], we examined the condensation of 3,4-dichloro-2,6-dinitroanisole ( 10 ) with 4,5-dichlorocatechol ( 11 ) ( Scheme 1 ). The former was readily obtained in 92% yield from 3,4-dichloanisole ( 9 ) upon nitration with the use of KNO 3 /96% H 2 SO 4 system for 12 h at ambient temperature [ 22 ].…”

“…Next, anisole 10 and catechol 11 were condensed under mild conditions, that is using potassium carbonate as base in refluxing acetone for 2 h, yielding the anticipated substituted PCDD 12 in 70% yield. The reduction of nitro group of compound 12 was effected with hydrazine hydrate in the presence of ferric chloride trihydrate and activated C [ 22 ] to give the corresponding amino-substituted PCDD 13 in 70% yield. Compound 13 , was then subjected to a Sandmeyer chlorination reaction, using initially sodium nitrite and 37% aqueous HCl at 0 °C for 30 min and then Cu 2 Cl 2 at 100 °C for 40 min, to give the methoxy-substituted tetrachlorodibenzo[ b,e ][1,4]dioxin (TCDD) 14 in 63% yield.…”

“…Compound 13 , was then subjected to a Sandmeyer chlorination reaction, using initially sodium nitrite and 37% aqueous HCl at 0 °C for 30 min and then Cu 2 Cl 2 at 100 °C for 40 min, to give the methoxy-substituted tetrachlorodibenzo[ b,e ][1,4]dioxin (TCDD) 14 in 63% yield. From the latter compound, the methyl protecting group was removed using 1 M BBr 3 in DCM at 0 °C for 30 min and then at ambient temperature for 4 h [ 22 ] to yield the hydroxyl-substituted TCDD 15 in 87% yield. The free phenolic hydroxyl was then subjected to Williamson etherification using the Dde-protected 3-bromopropan-1-amine [ 22 ] in DMF in the presence of potassium carbonate at ambient temperature for 2 h, affording the ether 16 in 86% yield.…”

“…From the latter compound, the methyl protecting group was removed using 1 M BBr 3 in DCM at 0 °C for 30 min and then at ambient temperature for 4 h [ 22 ] to yield the hydroxyl-substituted TCDD 15 in 87% yield. The free phenolic hydroxyl was then subjected to Williamson etherification using the Dde-protected 3-bromopropan-1-amine [ 22 ] in DMF in the presence of potassium carbonate at ambient temperature for 2 h, affording the ether 16 in 86% yield. The resulting alkoxy-substituted TCDD 16 was then Dde-deprotected upon treatment with 2% hydrazine hydrate in DMF at ambient temperature for 30 min to provide, after purification with FCC, the targeted 3-(2,4,7,8-tetrachlorodibenzo[ b,e ][1,4]dioxin-1-yloxy)propan-1-amine ( 17 ) in 80% yield.…”

A Robust Bioassay of the Human Bradykinin B2 Receptor That Extends Molecular and Cellular Studies: The Isolated Umbilical Vein

“…This may be related to the persistent endocytosis of the ligand-B2R complexes followed by receptor destruction induced by metabolically resistant agonists such as Compound 47a and B-9972 in cellular systems, whereas BK has a reversible effect with complete recycling of the B2R population at the cell surface [42,49]. Therapeutic applications of the nonpeptide partial agonists such as FR190997: have been proposed: topically, as agents that decrease excessive intraocular pressure via B2R stimulation in intraoccular structures following efficient tissue penetration [77] and in oncology, where B2R downregulation following persistent endocytosis may be salutary in tumor cells where overexpressed kinin receptors fuel proliferation [78].…”