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The ν(OH) stretching-mode bands in solution IR spectra of five o-vinylphenol (o-VPh) homologs in the slightly polar solvents CCl4 and n-hexane were studied. Several rotamers with free OH groups were found in solutions of o-VPh and its methyl-substituted derivatives in n-hexane. The proportion of rotamers in o-VPh homologs with intramolecular hydrogen bonds (IHBs) O–H...π varied from 22 to 97% in the gas and cyclohexane according to B3LYP/cc-pVTZ calculations. The theoretically estimated effective enthalpies –ΔH of their IHBs varied in the range 0.20–2.24 kcal/mol.

Absorption bands of OH stretching vibrations in IR spectra of o-vinylphenol (o-VP) in the weakly polar solvents CCl4 and n-hexane were studied. Several rotamers of the free OH group were observed for o-VP in n-hexane. The fraction of o-VP rotamers with an O–H…π intramolecular hydrogen bond (IHB) was less than 20% according to experimental estimates for CCl4 solutions and calculations in the gas phase and cyclohexane. The theoretical effective enthalpy of the o-VP IHB was estimated for rotamer A (–ΔH = 0.20 kcal/mol).

TsOH-Catalyzed reactions of 6,7-disubstituted 2-hydroxynaphthazarins and acyclic or cyclic α,β-enones afforded the corresponding Michael-type adducts, viz., 3-substituted naphthazarins in 17–78% yields. 1H and 13C NMR and IR spectroscopy showed that the adducts with cyclohexenone and methyl vinyl ketone exist in CDCl3 solutions as mixtures of open-chain and cyclic tautomers, whereas the adducts with cyclopentenones exist only as the open-chain forms.

Unusual course of the reaction was revealed on the oxidation of functionally substituted acridine containing the activated methyl groups by well-known oxidants, such as selenous acid and selenium(IV) oxide. Treatment of 2-methoxy-4,9-dimethyl-1-nitroacridine (5) with an excess of H2SeO3 in boiling ethanol gave a mixture of the normal reaction products, 2-methoxy-4-methyl-1-nitro-9-formylacridine (11) (isolated yield 29%) and 2-methoxy-4-methyl-1-nitroacridine-9-carboxylic acid (12) (36%), together with an abnormal product, 3-methoxy-5-methyl-1H-selenopheno[2,3,4-k,l]acridine-1-one (13) (21%), which is the first example of a new seleno-containing ring system. With the use of SeO2 the yield of selenolactone 13 was much lower. J. Heterocyclic Chem., 2011.

3- and 10-Bromofascaplysins was previously found to possess cytotoxic activity. In this study, we investigated their cancer preventive and proapoptotic properties. These effects were tested on mouse skin epidermal JB6 P + Cl41 cell line, its stable transfectants, and human tumor HL-60, THP-1, SNU-C4, SK-MEL-28, DLD-1, MDA-MB-231, and HeLa cells using a variety of assessments, including a cell viability (MTS) assay, flow cytometry, anchorage-independent soft agar assay, luciferase assay, mitochondrial permeability assay, and Western blotting. 3- and 10-Bromofascaplysins were effective at submicromolar concentrations as the anticancer agents, which exerted their action, at least in part, through the induction of caspase-8, -9, -3-dependent apoptosis.

Starting from ethyl 5-hydroxy-2-methyl-1-phenylindole-3-carboxylate, a simple and effective approach to the synthesis of pyrido[4,3,2- mn ]pyrrolo[3,2,1- de ]acridine skeleton of arnoamines A and B, unique pentacyclic alkaloids from the ascidian Cystodytes sp., has been developed. Synthesis of this ring system involves seven steps and produces ethyl 4-methoxy-1-methylpyrido[4,3,2- mn ]pyrrolo[3,2,1- de ]acridine-2-carboxylate in 41.5% overall yield.

The structures of products obtained by reductive debromination and CF3COOH- and KOH-induced transformations of natural chamigrane-type sesquiterpenoid (6S,10R)-10-bromo-3,11,11-trimethyl-7-methylidenespiro[5,5]undec-2-en-4-one (dactylone) isolated from the sea hare Aplysia dactylomela were analyzed. The absolute configurations of the reaction products were established by CD spectra taking into account the configuration of the starting dactylone.

It is shown that the Michael-type adducts with cyclohexanone or methyl vinyl ketone at C-3 exist as a mixture of open-chain and cyclic tautomers in CDCl3 solutions, whereas adducts with cyclopentanones at C-3 exist only in the open-chain form.

Fascaplysin 1, an antimicrobial and cytotoxic red pigment of the marine sponge Fascaplys-inopsis sp., has been synthesized in five steps from tryptamine 2 in 44% overall yield. The key steps in the synthesis are: (a) dehydrogenation of the dihydro-β-carboline intermediate 4 simultaneously with its benzylic oxidation on treatment with MnO2 and (b) the thermal cyclization of the resulting β-carboline 7 into a quaternary salt 8. Similarly, indoloisoquinolines 15 and 16, the tetracyclic analogues of 1, were prepared in six steps from α-amino ketone 9 in 59 and 55% overall yields, respectively.

Polycarpine 1 , a highly cytotoxic marine natural product, has been synthesized in three steps from p-methoxyphenacyl bromide 4 in 57% overall yield. The key reaction for construction of the symmetrically substituted disulfide linkage of polycarpine is the treatment of 2-amino-4-(4-methoxyphenyl)-1-methylimidazole 17 with S2Cl2 in acetic acid. In a similar way ten related compounds, including three thiazole analogues, have been prepared. Most of them exhibit high cytotoxic activities against an array of human cancer cell lines.

Epimeric (20R,23R)- and (20R,23S)-23-hydroxycholestane steroids were synthesized. Their structures were elucidated by extensive 1H and 13C NMR spectroscopy and application of the Mosher's method. All proton and carbon signals of the side chains were assigned. Based on these assignments spectral data allow the determination of the C-23 stereochemistry of (20R)-23-hydroxycholestane side chains of the new natural steroids by comparison with spectra of the obtained model compounds. As a result, the C-23 configuration of two steroid compounds from the starfishes Lethasterias nanimensis chelifera and Lethasterias fusca was established.

Polycarpine 1 , a highly cytotoxic marine natural product, has been synthesized in three steps from p-methoxyphenacyl bromide 4 in 57% overall yield. The key reaction for construction of the symmetrically substituted disulfide linkage of polycarpine is the treatment of 2-amino-4-(4-methoxyphenyl)-1-methylimidazole 17 with S2Cl2 in acetic acid. In a similar way ten related compounds, including three thiazole analogues, have been prepared. Most of them exhibit high cytotoxic activities against an array of human cancer cell lines.

Fascaplysin 1, an antimicrobial and cytotoxic red pigment of the marine sponge Fascaplys-inopsis sp., has been synthesized in five steps from tryptamine 2 in 44% overall yield. The key steps in the synthesis are: (a) dehydrogenation of the dihydro-β-carboline intermediate 4 simultaneously with its benzylic oxidation on treatment with MnO2 and (b) the thermal cyclization of the resulting β-carboline 7 into a quaternary salt 8. Similarly, indoloisoquinolines 15 and 16, the tetracyclic analogues of 1, were prepared in six steps from α-amino ketone 9 in 59 and 55% overall yields, respectively.

A series of aaptamines, including one new alkaloid (1), were isolated from the marine sponge Aaptos sp. collected in Vietnamese waters. The structure of 1 was elucidated using NMR and HRESIMS, as well as by chemical transformation of 1 to the previously known aaptamine and established as 3-N-morpholinyl-9-demethyl(oxy)aaptamine. The isolated compounds showed a potential cancer preventive activity.

3-Demethylubiquinone Q2 (3DMUbQ2), isolated from the ascidian Aplidium glabrum and later synthesized, is known as a natural product inhibiting EGF-induced malignant JB6 P+ Cl 41 cell transformation. However, its in vivo anticancer properties and probable mechanism of this action have not been studied.Preventive and curable effects of3DMUbQ2 on mice with inoculated Ehrlich carcinoma tumors were examined by magnetic resonance tomography. Capability to inhibit human tumor cell colony growth and induce their apoptosis was investigated using the anchorage-independent phenotype expression assay in soft agar and flow cytometry.3DMUbQ2 inhibits the growth of the solid Ehrlich carcinoma in mice, especially using the prophylactic scheme of administration (50% inhibition). It inhibits the phenotype expression of HT-460, HCT-116 and SK-MEL-28 human tumor cells and induces apoptosis of these cell lines, as well as that of HL-60 and THP-1 tumor cells.3DMUbQ2 and other related marine polyprenylquinones have potential for development of a new antitumor agent in cancer prophylactics and treatment and should be further investigated.

A simple and practical approach for the synthesis of the marine sponge pigment fascaplysin was used for the total syntheses of its natural derivatives, the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin. The conditions of each step were revised, and as a result these compounds were produced by identical procedures with total yields of 40–43%.

The anticancer effect of thiacarpine, a synthetic analogue of the known cytotoxic alkaloid polycarpine isolated from the Pacific ascidian Polycarpa aurata, was investigated in vivo in experiments using mouse solid Ehrlich carcinoma tumor as the target. A high-resolution magnetic resonance imaging (MRI) technique using a MR tomograph “PharmaScan” US70/16 (Bruker, Ettlingen, Germany) was used for visualization and quantification of tumor size. Fluorescence microscopy and image analysis were applied to determine Ehrlich carcinoma cell chromatin condensing (apoptosis) and necrosis in Ehrlich carcinoma cells at the action of thiacarpine in in vitro experiments. The scan and size calculations of the tumor and some mouse organs were carried out during the experiments. Thiacarpine in a total dose of 100 mg/kg was found to exhibit the delay in growth of the mouse tumor. The antineoplastic effect of this compound was accompanied by an increase in the lifetime of experimental mice in comparison with the control group of animals. Our data show that the ability of thiacarpine to induce apoptosis in carcinoma cells may contribute to thiacarpine anticancer effects against mice solid Ehrlich carcinoma in vivo detected by MRI.

3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-preventive properties and the structure–activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogs (3–14) are reported. Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer-preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Quinones 1 and 3–14 demonstrated cancer-preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.

Two new diprenylquinones, glabruquinone A (desmethylubiquinone Q 2 ) having cancer preventive properties and its minor isomer Glabruquinone B were isolated from the ascidian Aplidium glabrum . Their structures have been elucidated by NMR and mass spectra and confirmed by synthesis.

Polycarpine from ascidian Polycarpa aurata was previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs.Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker.Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNKI and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs.These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivo and clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.

Epimeric (20 R,23 R)- and (20 R,23 S)-23-hydroxycholestane steroids were synthesized. Their structures were elucidated by extensive 1H and 13C NMR spectroscopy and application of the Mosher's method. All proton and carbon signals of the side chains were assigned. Based on these assignments spectral data allow the determination of the C-23 stereochemistry of (20 R)-23-hydroxycholestane side chains of the new natural steroids by comparison with spectra of the obtained model compounds. As a result, the C-23 configuration of two steroid compounds from the starfishes Lethasterias nanimensis chelifera and Lethasterias fusca was established.

A series of aaptamines, including one new alkaloid (1), were isolated from the marine sponge Aaptos sp. collected in Vietnamese waters. The structure of 1 was elucidated using NMR and HRESIMS, as well as by chemical transformation of 1 to the previously known aaptamine and established as 3-N-morpholinyl-9-demethyl(oxy)aaptamine. The isolated compounds showed a potential cancer preventive activity.