Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA)

Journal Article · Sun Dec 15 04:00:00 EST 2019 · Medicinal Chemistry Research (Print)

DOI:https://doi.org/10.1007/S00044-019-02443-0· OSTI ID:22936154

Mielczarek-Puta, Magdalena; Struga, Marta ^[1]; Roszkowski, Piotr ^[2]

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1. Medical University of Warsaw, Chair and Department of Biochemistry (Poland)
2. University of Warsaw, Faculty of Chemistry (Poland)

Doxorubicin (DOX) is a leading cytostatic drug with many adverse effects in use. We are still looking for methods that will allow us to preserve the therapeutic effect against the tumor cells and reduce the toxicity to the normal cells. In our work, we obtained amide derivatives of DOX by reaction of the amino group with α-linolenic (LNA) and docosahexaenoic (DHA) acids (2, 3), as well as double-substituted derivatives via amide and ester linkages (4, 5). The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and High Resolution Mass Spectrometry (HRMS) analyses. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human cancer cell lines (SW480, SW620, and PC3) and Chinese hamster lung fibroblasts (V79) that were used as a control. The cytotoxic activity was established by calculation of the inhibitory concentration IC{sub 50}. In addition, a cytotoxic capacity against tumor cells for tested compounds was expressed as a selectivity factor (selectivity index, SI). Lactate dehydrogenase (LDH) assay was performed for all compounds to assess the level of cell damage. To explain the basic mechanism of cell death induction the Annexin V-FITC/IP flow cytometry analysis was investigated. We found that all studied conjugates exhibit lower cytotoxicity but higher selectivity than DOX. Among the all derivatives, the conjugates formed by the amide and ester linkages (4, 5) were found to be more promising compared with conjugates (2, 3) formed only by the amide linkage. They show high cytotoxicity toward the tumor cell lines and moderate cytotoxicity towards the normal cell line.

• OSTI ID: 22936154
• Journal Information: Medicinal Chemistry Research (Print), Journal Name: Medicinal Chemistry Research (Print) Journal Issue: 12 Vol. 28; ISSN 1054-2523
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMIDES
ANTIMITOTIC DRUGS
APOPTOSIS
BROMIDES
CARBON 13
CARBOXYLIC ACIDS
DOXORUBICIN
ESTERS
FIBROBLASTS
HAMSTERS
HYDROGEN 1
LACTATE DEHYDROGENASE
NUCLEAR MAGNETIC RESONANCE
TOXICITY
TUMOR CELLS