ABSTRACT
This work describes the study of the mechanism of action and spectrum of activity of MR22388, a novel anti-cancer agent belonging to the tripentone series. MR22388 is highly cytotoxic (within the nanomolar range) against numerous cancer cell lines and studies of its cytotoxicity mechanisms show that it is a weak inhibitor of the polymerization of tubulin and that it induces apoptosis via the MAP kinase pathways. Further MR22388 is a very strong inhibitor of several kinases including the tyrosine kinase FLT3-ITD. FLT3-ITD is a mutated form of the tyrosine kinase receptor (RTK) FLT3, resulting in the constitutive activation of the kinase, occurring in about 25% of normal karyotypes' Acute Myeloid Leukemia (AML) and is linked to a bad prognosis. Consecutively, MR22388 appears as a novel promising anticancer lead agent especially for AML therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Leukemia, Myeloid, Acute/pathology , Protein Kinase Inhibitors/pharmacology , Pyrrolizidine Alkaloids/pharmacology , Tandem Repeat Sequences/drug effects , Tubulin Modulators/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Blotting, Western , Cell Proliferation/drug effects , Humans , Leukemia, Myeloid, Acute/metabolism , Mutation/genetics , Phosphorylation/drug effects , Tubulin/chemistry , Tubulin/metabolism , Tumor Cells, Cultured , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Attempts in view to dearomatize some previously reported tripentones with potent antineoplastic activities led in thiophene series to an unexpected hydrogenative desulphurization reaction. The resulting (Z)-phenethylidenepyrrolizinones were tested in vitro over human epidermoid carcinoma KB cell line. The results of this biological evaluation indicated that the tricyclic core of our model can be cleaved with a partial respect of the activity.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Pyrroles/chemistry , Sulfur/chemistry , Thiopental/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , KB Cells , Molecular Structure , Structure-Activity Relationship , Thiopental/toxicity , Thiophenes/chemistryABSTRACT
We describe herein the synthesis and the biological evaluation of a novel series of a potent anticancer agents: the tripentones. For the first time, a halogen atom was introduced in high yields on the pyrrole ring of the tricycle. This synthesis and the reactivity of the novel halogenated tripentones in metallo-catalysed cross-coupling reactions will be described in that article. Finally their influence on biological activity will be discussed.
