title: Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model.
abstract: 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.
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Irina Yu
authors.initials: IY
authors.lastname: Strobykina
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Mayya G
authors.initials: MG
authors.lastname: Belenok
authors.affiliation: ‡N. K. Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Street, 26, 119334, Moscow, Russian Federation.|§Chemical Block Ltd., 3 Kyriacou Matsi, 3723 Limassol, Cyprus.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Semenova
authors.affiliation: ⊥N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, 119991, Moscow, Russian Federation.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Vasiliy M
authors.initials: VM
authors.lastname: Babaev
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Ildar Kh
authors.initials: IKh
authors.lastname: Rizvanov
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Vladimir F
authors.initials: VF
authors.lastname: Mironov
authors.affiliation: †A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088, Kazan, Russian Federation.
authors.forename: Vladimir E
authors.initials: VE
authors.lastname: Kataev
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations / Q000737:chemistry; D004195:Disease Models, Animal; D004224:Diterpenes / Q000737:chemistry; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008522:Mediterranean Sea; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012617:Sea Urchins / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D002412:Cations; D004224:Diterpenes; D045786:Diterpenes, Kaurane; D009943:Organophosphorus Compounds; C572286:isostevic acid; C515747:isosteviol