Irina Yu. Strobykina

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

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.

Synthesis and antituberculosis activity of novel unfolded and macrocyclic derivatives of ent-kaurane steviol.

New derivatives of steviol 1, the aglycone of the glycosides of Stevia rebaudiana, including a novel class of semisynthetic diterpenoids, namely macrocyclic ent-kauranes were synthesized. These compounds possess antituberculosis activity inhibiting the in vitro growth of Mycobacterium Tuberculosis (H37R(V) strain) with MIC 5-20 μg/ml that is close to MIC 1 μg/ml demonstrated by antituberculosis drug isoniazid in control experiment. For the first time it was found that the change of ent-kaurane geometry (as in steviol 1) of tetracyclic diterpenoid skeleton to ent-beyerane one (as in isosteviol 2) influences on antituberculosis activity.

Novel biomimetic systems based on amphiphilic compounds with a diterpenoid fragment: Role of counterions in self-assembly

Novel biomimetic systems are designed based on cationic surfactants composed of an isosteviol moiety and different counterions, namely bromide (S1) and tosylate (S2). The counterion structure is shown to play a crucial role in the surfactant association. A number of methods used provide evidence that only one type of aggregate, i.e., micelles are observed in the S2 systems, while a concentration-dependent association occurs in the case of S1. The DLS and fluorescence anisotropy measurements reveal that the micelle-vesicle-micelle transitions probably occur with the S1 system. The occurrence of small aggregates near the critical micelle concentration with radii of 2.5 nm is supported by NMR self-diffusion data. The Orange OT solubilization results strongly support the idea of a second threshold in the S1 system around 0.025 mM and provide evidence that hydrophobic domains occur in the aggregates. The latter property and the capacity to integrate with the lipid bilayer make it possible to suggest the newly synthesized surfactants as effective nanocontainers for hydrophobic guests.

Synthesis and antituberculosis activity of the first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol

The first macrocyclic glycoterpenoids comprising glucosamine and diterpenoid isosteviol moieties were synthesized and evaluated for inhibition activity against Mycobacterium tuberculosis H37Rv.

Unfolded and macrocyclic ammonium derivatives of diterpenoids steviol and isosteviol having choline moieties. Synthesis and inhibitory activities toward acetylcholine- and butyrylcholinesterases

A series of unfolded and macrocyclic ammonium derivatives of diterpenoids isosteviol 2 and steviol 17 possessing choline moieties have been synthesized and assayed for inhibitory activities toward AchE and BchE. Compounds 5–8, 13, 16, 20, and 21 showed moderate activity within the range of IC50 values 8.0 × 10−4 to 2.2 × 10−6 mol L−1. Isosteviol derivative 16 exhibited the best inhibition selectivity against acetylcholinesterase among the compounds tested. It inhibited AchE of human erythrocytes at IC50 = 80 μM, whereas inhibition of BchE occurred at IC50 > 1000 μM.

Z′ = 2 crystallization of the three isomeric piridinoylhydrazone derivatives of isosteviol

Crystallization of three diterpenoid isosteviol derivatives with a structural fragment of isoniazid (isonicotinic acid hydrazide) and its isomers – hydrazides of nicotinic and picolinic acids (structures 5, 6 and 7 respectively) was studied by single-crystal and powder XRD. These homochiral compounds crystallize in “Sohnke” space group P21 with two independent molecules. In crystals 5 and 6, an infinite H-bonded chain of alternating molecules A and B formed by N–H⋯OC interaction is observed, while only pairwise the same interactions between molecules A and B are realized in crystal 7. In the H-bonded associates of both types, the local (non-crystallographic) mirror-symmetry of nitrogen containing substituents in molecules A and B is observed. Such type of crystal packing – H-bonded chains or dimers formed by the N–H⋯OC interaction through the glide plane – is the most typical packing in achiral compounds with a structural fragment of isoniazid and its isomers, as the CCDC analysis showed. Thus, structures 5–7 represent an interesting example of transferring a robust supramolecular mirror-symmetry motive from a racemic environment into a homochiral one, but inclusion of an “extra” molecule in a unit cell is the crystallographic “cost” of such transfer.