Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model

• Published in: Journal of natural products (Washington, D.C.) Vol. 78; no. 6; pp. 1300 - 1308
• Main Authors: Strobykina, Irina Yu, Belenok, Mayya G, Semenova, Marina N, Semenov, Victor V, Babaev, Vasiliy M, Rizvanov, Ildar Kh, Mironov, Vladimir F, Kataev, Vladimir E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 26.06.2015; Amer Chemical Soc
• Subjects: Animals; Antimitotic Agents - chemical synthesis; Antimitotic Agents - chemistry; Antimitotic Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cations - chemistry; Chemistry, Medicinal; Disease Models, Animal; Diterpenes - chemistry; Diterpenes, Kaurane - chemical synthesis; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; Humans; Life Sciences & Biomedicine; Mediterranean Sea; Mitochondria - drug effects; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology & Pharmacy; Plant Sciences; Science & Technology; Sea Urchins - drug effects; Structure-Activity Relationship; Mediterranean Sea; BETULINIC ACID; BIOLOGICAL EVALUATION; DNA-POLYMERASE; STEREOSELECTIVE-SYNTHESIS; IN-VIVO EVALUATION; NATURAL COMPOUND; DERIVATIVES; CU-64-LABELED TRIPHENYLPHOSPHONIUM; POLYALKOXY SUBSTITUTED 4H-CHROMENES; CELL-DEATH
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.5b00124

A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (1, 16-oxo-ent-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure–activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents.