Dihydroxyquingdainone Induces Apoptosis in Leukaemia and Lymphoma Cells via the Mitochondrial Pathway in a Bcl-2- and Caspase-3-Dependent Manner and Overcomes Resistance to Cytostatic Drugs In Vitro
Jennifer Baas,
Sebastian Bieringer,
Corazon Frias,
Jerico Frias,
Carolina Soehnchen,
Corinna Urmann,
Steffi Ritter,
Herbert Riepl,
Aram Prokop
Affiliations
Jennifer Baas
Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany
Sebastian Bieringer
Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany
Corazon Frias
Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany
Jerico Frias
Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany
Carolina Soehnchen
Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457 Hamburg, Germany
Corinna Urmann
Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany
Steffi Ritter
Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany
Herbert Riepl
Organic-Analytical Chemistry, Weihenstephan-Triesdorf University of Applied Sciences, 94315 Straubing, Germany
Aram Prokop
Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany
Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression.
