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N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia
- Source :
- European journal of medicinal chemistry. 96
- Publication Year :
- 2014
-
Abstract
- Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.
- Subjects :
- Models, Molecular
Vincristine
medicine.drug_class
HL60
Antineoplastic Agents
Apoptosis
Mice, SCID
Pharmacology
Anisoles
Microtubules
Vinca alkaloid
chemistry.chemical_compound
Mice
Structure-Activity Relationship
In vivo
Cell Movement
Mice, Inbred NOD
Tubulin
Drug Discovery
medicine
Tumor Cells, Cultured
Animals
Humans
Cytotoxicity
Cell Proliferation
biology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Organic Chemistry
Cell Cycle
Hydrazones
General Medicine
Neoplasms, Experimental
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
Acute toxicity
Leukemia
Biochemistry
biology.protein
Drug Screening Assays, Antitumor
medicine.drug
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 96
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....65570ed8efb502411bb0861cb21c04b4