Dmitry V. Tsyganov

Polyalkoxybenzenes from Plants. 5. Parsley Seed Extract in Synthesis of Azapodophyllotoxins Featuring Strong Tubulin Destabilizing Activity in the Sea Urchin Embryo and Cell Culture Assays

A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E. These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule as the most active compound. Finally, in Jurkat cells, compound induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway.

cis-Restricted 3-Aminopyrazole Analogues of Combretastatins: Synthesis from Plant Polyalkoxybenzenes and Biological Evaluation in the Cytotoxicity and Phenotypic Sea Urchin Embryo Assays

We have synthesized a series of novel cis-restricted 4,5-polyalkoxydiaryl-3-aminopyrazole analogues of combretastatins via short synthetic sequences using building blocks isolated from dill and parsley seed extracts. The resulting compounds were tested in vivo in the phenotypic sea urchin embryo assay to reveal their antimitotic and antitubulin effects. The most potent aminopyrazole, 14a, altered embryonic cell division at 10 nM concentration, exhibiting microtubule-destabilizing properties. Compounds 12a and 14a displayed pronounced cytotoxicity in the NCI60 anticancer drug screen, with the ability to inhibit growth of multi-drug-resistant cancer cells.

Comparative in vivo evaluation of polyalkoxy substituted 4H-chromenes and oxa-podophyllotoxins as microtubule destabilizing agents in the phenotypic sea urchin embryo assay.

A series of polyalkoxy substituted 7-hydroxy- and 7-methoxy-4-aryl-4H-chromenes were evaluated using the sea urchin embryo model to yield several compounds exhibiting potent antimitotic microtubule destabilizing activity. Data obtained by the assay were further confirmed in the NCI60 human cancer cell screen. The replacement of methylenedioxy ring A and lactone ring D in podophyllotoxin analogues by 7-methoxy, 2-NH2, and 3-CN groups in 4-aryl-4H-chromenes resulted in potent antimitotic microtubule destabilizing agents. Feasible synthesis and high yields render 7-methoxy-4H-chromenes to be a promising series for further anticancer drug development.

A Synthetic Derivative of Plant Allylpolyalkoxybenzenes Induces Selective Loss of Motile Cilia in Sea Urchin Embryos

Polyalkoxybenzenes are plant components displaying a wide range of biological activities. In these studies, we synthesized apiol and dillapiol isoxazoline analogues of combretastatins and evaluated their effect on sea urchin embryos. We have shown that p-methoxyphenyl isoxazoline caused sea urchin embryo immobilization due to the selective excision of motile cilia, whereas long immotile sensory cilia of apical tuft remained intact. This effect was completely reversed by washing the embryos. The compound did not alter cell division, blastulae hatching, and larval morphogenesis. In our hands, the molecule would serve as a convenient tool for in vivo studying morphogenetic processes in the sea urchin embryo. We anticipate that both the assay and the described derivative could be used for studies in ciliary function in embryogenesis.

UNUSUAL EFFECTS OF STERIC HINDRANCES IN NMR SPECTRA OF O,O'-DIALKYLSUBSTITUTED BENZYLIDENE DICHLORIDES

Abstract It has been found that steric hindrances of the CHCl2 group rotation around CAr -CHCl2 bond in o,o′-dialkyl substituted benzylidene dichlorides call forth a non-equivalence of the alkylsin positions 2 and 6. The non-equivalence displays in 1H and 13C NMR spectra at room temperature and at −20 °C. At the latter temperature, the spectra of 2,4,6-trimethyl-3-chloromethylbenzylidene dichloride and bis(dichloromethyl)mesitylene indicate the presence of two conformations, the assignment of signals having been accomplished for each of them.

Synthesis and properties of stable aromatic bis(nitrile oxides)

A number of stable bis(nitrile oxides) based on dimesitylmethane and didurylmethane and their analogs in which two aromatic rings are joined by various bridging groups were synthesized. The thermal isomerization of the bis(nitrile oxides) to diisocyanates and the relative reactivities of the bis(nitrile oxides) in 1,3-dipolar cycloaddition to styrene were studied.

Synthesis of stable functionally substituted nitrile oxides of the aromatic series

Stable functionally substituted mononitrile oxides were obtained from the previously obtained sterically hindered aldehydes of the mesitylene series. The previously unknown bisnitrile oxide was also synthesized from triethyl-benzene; the compound is an effective crosslinking agent. The synthesis was carried out via the stage of oximation and oxidation of the oxime by sodium hypochlorite.

Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes

Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity

A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives 9 starting with readily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides 7 into the respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into the target series 9. The biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and an in vivo sea urchin embryo assay. Both screening platforms confirmed the antimitotic effect of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings, respectively, were less active than the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 μM concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule-destabilizing effect of isoflavones 9cg, 9cd, and 9cf.

Quantum chemical study of the influence of electronic factors on the thermodynamic characteristics of 1,3-dipolar cycloaddition of benzonitrile oxides and benzonitrile sulfides to weakly activated alkenes

The main thermodynamic characteristics of the reactions of para-substituted benzonitrile oxides and benzonitrile sulfides with propylene were calculated by the density functional theory (DFT) method with the B3LYP hybrid functional and 6-31G(d) split-valence basis set using the Gaussian 09 program package. In all cases, introduction of the electron-withdrawing nitro group into the dipole molecule promotes the cycloaddition reaction.