Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid

Autor: Lorenzo Botta, Silvia Cesarini, Raffaele Saladino, Silvia Filippi, Claudio Zippilli, Rebecca Pogni, Bruno Mattia Bizzarri, Maria Camilla Baratto
Rok vydání: 2021
Předmět:
Cell Survival
Dimer
medicine.medical_treatment
Dihydroartemisinin
antimelanoma activity
Antineoplastic Agents
Pharmacology
stereoselectivity
01 natural sciences
Biochemistry
chemistry.chemical_compound
Structure-Activity Relationship
Drug Discovery
medicine
Humans
General Pharmacology
Toxicology and Pharmaceutics
Fibroblast
Melanoma
Cells
Cultured
Cell Proliferation
Dose-Response Relationship
Drug
Molecular Structure
Full Paper
010405 organic chemistry
Chemistry
artemisinin hybrids and dimers
Organic Chemistry
Stereoisomerism
Succinates
Full Papers
medicine.disease
Artemisinins
0104 chemical sciences
010404 medicinal & biomolecular chemistry
medicine.anatomical_structure
Paclitaxel
Cell culture
regioselectivity
Toxicity
Molecular Medicine
Stereoselectivity
Drug Screening Assays
Antitumor
Dimerization
artemisinin hybrids and dimers
stereoselectivity
regioselectivity
EPR spectroscopy
antimelanoma activity
EPR spectroscopy
Zdroj: Chemmedchem
ISSN: 1860-7187
Popis: A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo‐controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4‐hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC50>300 μM) and high antimelanoma activity (IC50=0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer‐type selectivity towards melanoma compared to prostate (PC3) and breast (MDA‐MB‐231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.
Accessing antimelanoma agents: The artesunic acid dimer 22‐α,α, bearing 4‐hydroxybenzyl alcohol as linker, showed higher antimelanoma effect and lower cytotoxicity compared to the parent dimer 8 bearing 4‐hydroxyphenetyl alcohol (tyrosol), highlighting the importance of a methylene group in the final effect. In addition, a melanoma cancer‐type selectivity was registered as well as a correlation between the presence of iron and the biological activity.
Databáze: OpenAIRE
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