Proanthocyanidin glycosides from the leaves of Quercus ilex L. (Fagaceae)

From the polar extracts of the leaves of Quercus ilex L., two new proanthocyanidin glycosides, namely afzelechin-(4α→8)-catechin-3-O-β-glucopyranoside (1) and afzelechin-(4α→8)-catechin-3-O-α-rhamnopyranoside (2), were isolated in addition to catechin (3), proanthocyanidin B₃ (4), prodelphinidin C (5), dehydrodicatechin A (6), quercetin (7) and six known flavonol glucosides with their acylated derivatives (8-13) and ellagic acid (14). The structures of all isolated compounds were established by spectroscopic means, mainly 1D and 2D NMR, as well as LC/MS and HR-MS spectrometric analyses. The absolute configuration of compound 1 was determined by CD measurements. The proanthocyanidin glycosides are especially interesting, as they possess the sugar in the upper unit of the dimer, which is rare for this type of compounds.     

New resveratrol oligomers in the stem bark of Vatica pauciflora

Five new resveratrol oligomers; pauciflorols A-C (1-3), isovaticanols B (6) and C (8), and three new oligostilbene glucosides; pauciflorosides A (11), B (13), C (14), were isolated from the stem bark of Vatica pauciflora (Dipterocarpaceae) together with known 17 resveratrol oligomers (4, 5, 7, 9, 10, 12 and 15-25) and bergenin (26). The structures of isolates were established on the basis of detailed spectroscopic analysis. The typical and characteristic spectral properties of some resveratrol oligomers were also discussed.     

Autoassembly of cage structures

Thed,l-(1a) andmeso-forms (1b) of α,α'-dihydroxy-α,α'-dimethyladipic acid, dilactone (3), diiminodilactone (4), and lactonolactam (5) were obtained by the reaction of acetonylacetone with KCN and HCl. The transformations of1 to the esters2, dilactone3 to la, and diiminodilactone4 to dilactone3 were studied. It was shown that3 can be readily obtained from la by thermolysis, acid catalysis, and DCC action as well as by acid catalyzed cyclization of2a, while dilactone3 can be obtained from1b and2b in negligible yield only under drastic conditions, obviously, due to the partial epimirization of themeso-forms. The mild thermolysis of1b leads totrans-lactonoacid (6), from which the ester7 has been obtained. The effective acid catalyzed cyclization of amides8 and9 to3, lactamoamide12 to5, and amide14 to model lactone13 was found. The NMR spectra of the products were studied, and a¹H NMR test was suggested for identification ofd,l- andmeso-forms1 and2. The stereochemistry of monolactones6, 7, 9, 10a, 10b, 11, and dilactone3 was established. The differences in the chemical behavior of α,α'-dihydroxyglutaric and adipic acids were explained by the significant reduction of the non-bonded interactions of the substituents in the corresponding monolactones during the transfer from 1,3- to 1,4-substituted systems.     

Biotransformation of two stemodane diterpenes by Mucor plumbeus

The microbiological transformation of 13α,17-dihydroxy-stemodane (2) by the fungus Mucor plumbeus afforded 13α,17,19-trihydroxy-stemodane (3), 3β,13α,17-trihydroxy-stemodane (5), 3-oxo-13α,17-dihydroxy-stemodane (7), 7α,13α,17,19-tetrahydroxy-stemodane (8), 3β,11α,13α,17-tetrahydroxy-stemodane (10), 3β,7α,13α,17-tetrahydroxy-stemodane (12), 3β,8β,13α,17-tetrahydroxy-stemodane (14), 2α,13α,17-trihydroxy-stemodane (16), 2α,13α,17,19-tetrahydroxy-stemodane (17), 2α,3β,13α,17-tetrahydroxy-stemodane (20) and 3β,11β,13α,17-tetrahydroxy-stemodane (22), whilst the incubation of 13α,14-dihydroxy-stemodane (25) gave 3β,13α,14-trihydroxy-stemodane (28), 2α,13α,14-trihydroxy-stemodane (29) and 13α,14,19-trihydroxy-stemodane (30). Preference for hydroxylations of ring A at C-2(α), C-3(β) and C-19 were observed in both incubations. An interesting rearrangement of 13α,14α-dihydroxy-stemodanes to 14-oxo derivatives with an unusual carbon framework has been observed under acetylation conditions. We have named this skeleton prestemodane, which, as a hydrocarbon ion, had been postulated as a biogenetic precursor of stemodane.     

New antitumor sesquiterpenoids from Santalum album of Indian origin

Three new campherenane-type (1, 4, 7) and three new santalane-type (9, 11, 12) sesquiterpenoids, and two aromatic glycosides (21, 22) together with 12 known metabolites including α,β-santalols (14, 18), (E)-α,β-santalals (15, 19), α,β-santaldiols (16, 20), α-santalenoic acid (17), and vanillic acid 4-O-neohesperidoside were isolated from Santalum album chips of Indian origin. The structures of the new compounds, including absolute configurations, were elucidated by 1D- and 2D-NMR spectroscopic and chemical methods. The antitumor promoting activity of these isolates along with several neolignans previously isolated from the same source was evaluated for both in vitro Epstein-Barr virus early antigen (EBV-EA) activation and in vivo two-stage carcinogenesis assays. Among them, compound 1 exhibited a potent inhibitory effect on EBV-EA activation, and also strongly suppressed two-stage carcinogenesis on mouse skin.     

Fluorescent aminoarylcyclotetraphosphazenes

In the present work, octachlorocyclotetraphosphazatetraene (1), N₄P₄Cl₈, is reacted with aniline (2), 1-napthylamine (4) and 2-aminoanthracene (6) to give octakis(arylamino)cyclotetraphosphazenes (3, 5 and 7). These cyclotetraphosphazene compounds (3, 5 and 7) have been fully characterized by elemental analysis, mass (MS), FT-IR, ¹H and ³¹P NMR spectroscopies. The molecular and crystal structures of 5 have been characterized by X-ray crystallography. The structure of 5 is monoclinic with the space group P21/c. The octakis(1-napthylamino)-(5) and octakis(2-aminoanthracene)-(7) cyclotetraphosphazene compounds have been synthesised for the first time in this study. The fluorescence properties of 3, 5 and 7 have been investigated in tetrahydrofuran (THF) and have been shown to have highly fluorescence behavior. This work also presents the quenching of arylamino substituted cyclotetraphosphazene derivatives (3, 5 and 7) by p-benzoquinone (BQ) or hydroquinone (HQ).     

New copper(II) 2-(alkylamino)troponates

The copper aminotropones Cu[ON(R′)C₇H₄R-4]₂ [R = H, R′ = Me (13), Et (14), n-Pr (15), n-Bu (16), Bz (17), MenOCH₂CH₂ (20); R = i-Pr, R′ = Me (18), n-Pr (19), MenOCH₂CH₂ (21)] have been prepared from the corresponding aminotropones HN(R′)OC₇H₄R-4 (1–7) by reacting with copper(II) acetate in aqueous ethanol. 20, 21 contain the flavourant, menthol, as part of the ligand. The structures of 5 (R = H, R′ = Bz), a hydrogen-bonded dimer, 14 and 20, both incorporating square-planar, four-coordinate copper centres, have been determined by X-ray crystallography. The antibacterial activities of complexes 13, 17, 20 and 21 have been assayed against Staphylococcus waneri, an in vitro model of plaque inhibition effects, and found to be more active than a commercial toothpaste formulation, but less active than the O,O-chelated copper(II) complex of ethylmaltol.     

Structural properties of new spiro-1,3-propanediaminocyclotriphosphazene derivatives

New 1,3-propanediaminocyclotriphosphazene derivatives (7-17) were synthesized from the reactions of spiro-1,3-propanediaminocyclotriphosphazene, N₃P₃Cl₄[NH(CH₂)₃NH] (1) with the cyclopropanemethylamine (2), cyclohexylamine (3), pyrrolidine (4) cyclohexanol (5), cyclopropylmethanol (6). The structures of the novel compounds (7-17) were characterized by elemental analysis, mass spectrometry, ¹H and ³¹P NMR spectroscopy. The molecular structures of 8, 12 and 13 were determined by X-ray crystallography. The structures of all these three compounds are in the monoclinic crystal system; compounds 8 and 12 have the P21/c space group while compound 13 has the P21/n space group. The ring conformation of the cyclotriphosphazene and other external rings were investigated based on the X-ray crystal structures.     

Bis-spiro-azaphilones and azaphilones from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05

Four new dimeric spiro-azaplilones, cochliodones A-D (1-4), two new azaphliones, chaetoviridines E and F (5 and 6), a new epi-chaetoviridin A (7), together with five known compounds, chaetoviridin A (8), ergosterol (9), chaetochalasin A (10), 24(R)-5α,8α-epidioxyergosta-6-22-diene-3β-ol (11), and ergosterol-β-d-glucoside (12) were isolated from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05. Structures and stereochemistry of the atropisomers 1-3 were determined by single-crystal X-ray diffraction analysis. Compounds 5, 10, and 11 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, 6, 10, and 11 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, 5 and 6 also showed cytotoxicity against the KB, BC1, and NCI-H187 cell lines.     

New polyesters from Talaromyces flavus

Six new polyesters, talapolyesters A–F (1–4, 14, and 16), together with 11 known ones 15G256ν (5), 15G256ν-me (6), 15G256π (7), 15G256β-2 (8), 15G256α-2 (9), 15G256α-2-me (10), 15G256ι (11), 15G256β (12), 15G256α (13), 15G256α-1 (15), and 15G256ω (17), were isolated from the wetland soil-derived fungus Talaromyces flavus BYD07-13, and their structures were determined by NMR and MS spectroscopic data. Among them, 1–4 and 16 were assembled in a different manner from that of the known 256 polyesters. All the polyesters are composed of (R)-2,4-dihydroxy-6-(2-hydroxypropyl)benzoic acid and (R)-3-hydroxybutyric acid/(S)-3,4-dihydroxybutyric acid residues. The absolute configurations of the residues were determined by alkaline hydrolysis. The cytotoxicity against five tumor cell lines of these compounds was examined, and a tight structure–activity relationship is proposed.     

Triphenyl lead, tin and germanium coordination compounds derived from 9H-3-thia-1,4a,9-triaza-fluorene-2,4-dithione

Reactions of potassium 4-thioxo-3-thia-1,4a,9-triaza-fluorene-2-thiolate with Ph₃PbCl, Ph₃SnCl and Ph₃GeCl provided the corresponding metal pentacoordinated compounds 2-4. Addition of THF afforded their hexacoordinated derivatives (5-7). Adducts of 2 and 3 with DMSO (8, 10), pyridine (9, 11), Ph₃PO (12, 14) CH₃OH (13, 15), respectively were synthesized. Compound 2 afforded the H₂O adduct (16). In all cases the metal atom is chelated by the ligand through a covalent bond with S2 and a coordination bond with N1 forming four membered rings. Compounds were identified by ¹H, ¹³C, ¹⁵N, ¹¹⁹Sn and ²⁰⁷Pb. X-ray diffraction structures of 2, 3, 8, 9, 11, 14 and 16 were obtained.     

Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity

The aim of this work was to synthesize deuterated and tritiated analogues of highly oxidized lupane derivatives known from our group. We selected compounds that previously showed very high cytotoxic activity on multiple cancer cell lines in order to further investigate the mechanism of their action. From starting material (compounds 1–4), we obtained benzyl platanate (5) and its reaction with deuteromethyltriphenylphosphonium iodide gave deuterated compound 6. Following benzyl deprotection gave free acid 7 and oxidation with SeO₂ gave 30-oxo-[29-²H₂]lup-20(29)-en-28-oic acid (8), which is one of the most active compounds synthesized in our group to date (IC₅₀ 6 μmol/L on CEM cell line). The alkylation of benzyl 2-hydroxy-3-oxolupa-1,20(29)-dien-28-oate (9) with methyliodide or deuteromethyliodide followed by a series of deprotection and hydrogenation steps gave compounds 10–14, where 2β-[31-²H₃]methoxy-3-oxolupan-20(29)-en-28-oic acid (13) is especially interesting, it showed lower activity on CEM cell line (IC₅₀ 10 μmol/L) however, it was very active against Ph1—positive human leukemia BV-173 (IC₅₀ 0.91 μmol/L) and against human myelogenous leukemia K562 (IC₅₀ 0.52 μmol/L). Selectively labelled [3α-²H] and [3α-³H] methyl 3β-acetoxy-21,22-dioxolup-18-en-28-oates 24, 25 were prepared in three steps by reduction of corresponding 3-oxo derivatives and they showed moderate activity on CEM cell line (IC₅₀ 10 μmol/L). In total, 11 labelled compounds (6–8, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.     

Sesquiterpenoids from Ligularia virgaurea spp. oligocephala

Four novel eremophilane-type sesquiterpene lactones, 6β,10α-dihydroxy-1-oxoeremophila-7(11),8(9)-dien-12,8-olide (1), 6β-acetyl-2-oxoeremophila-1(10),7(11), 8(9)-trien-12,8-olide (2), 6β,8β-diacetyl-2-oxoeremophila-1(10),7(11)-dien-12,8-olide (3), dimeric eremophilane ligulolide B (5), and known sesquiterpenoid, 6β,8α-diacetyleremophila-1(10),7(11)-dien-12,8-olide (4), were isolated from an extract of the whole plant of Ligularia virgaurea spp. oligocephala. The structure of 1 was confirmed by NMR spectra and single crystal X-ray crystallography investigation, as well as 2, 3, and 5 were elucidated by spectroscopic methods including 1D and 2D NMR spectra. A discussion of biogenesis of 5 was described. Cytotoxicities of compound 1 were measured in vitro against selected cancer cells human promyelocytic leukemia (HL-60), human ovarian (HO-8910) and human lung epithehial (A-549).     

Dimethylthallium(III) complexes with picolinic acid and its hydroxyl derivatives

The reaction of dimethylthallium(III) hydroxide with picolinic acid (Hpic), 3-hydroxypicolinic acid (H₂3hpic) and 6-hydroxypicolinic acid (H₂6hpic) in an aqueous/methanol mixture afforded the complexes [TlMe₂(pic)] (1), [TlMe₂(H3hpic)] (2) and [TlMe₂(H6hpic)] (3), respectively. Complex 3′, [NaTlMe₂(6hpic)₂]_n, was obtained as a minor product from a methanolic solution of 3. Compounds 1–3 were characterized by IR and Raman spectroscopy and, in the cases of 1, 2 and 3′, by single-crystal X-ray diffraction. Complex 3′ is the first example of an H6hpic⁻ heterobimetallic compound to be isolated. The ¹H and ¹³C NMR spectra of 1 and 2 are also discussed.     

Combined biotransformations of 4(20),11-taxadienes

Taxuyunnanine C (1) and its analogs (2 and 3), the C-14 oxygenated 4(20), 11-taxadienes from callus cultures of Taxus sp., were regio- and stereo-selectively hydroxylated at the 7β position by a fungus, Abisidia coerulea IFO 4011, and it was interesting that the longer the alkyl chain of the acyloxyl group at C-14 became, the higher the yield of 7β-hydroxylated product was. Besides the three 7β-hydroxylated products (5, 9, 17), other nine new products (7, 11, 12, 14, 15, 16, 18, 20 and 21) and six known products (4, 6, 8, 10, 13 and 19) were obtained. Subsequently, the acetylated derivatives (24 and 27) of 7β-and 9α-hydroxylated products of 1 were regio- and stereo-specifically hydroxylated at the 9α position by Ginkgo cells and 7β position by A. coerulea, respectively. Thus, the two specific oxidations have been combined. These bioconversions would provide not only valuable intermediates for the semi-synthesis of paclitaxel or other bioactive taxoids from 1 and its analogs, but also some useful hints for the biosynthetic pathway of taxoid in the natural Taxus plant.     

Specific oxidation of C-14 oxygenated 4(20),11-taxadienes by microbial transformation

Three C-14 oxygenated taxanes, 2α,5α,10β,14β-tetraacetoxytaxa-4(20),11-diene (1), 2α,5α,10β-triacetoxy-14β-(2-methylbutyryloxy)taxa-4(20),11-diene (2), and yunanaxane (3), major products of callus cultures of Taxus spp., were regio- and stereoselectively hydroxylated at the 7β position by a fungus, Absidia coerulea IFO 4011. Intriguingly, when 1 was co-administered with β-cyclodextrin and incubated with the fungus cell cultures, three other compounds 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-14β-ol (7), 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-1β-ol (8) and 5α,9α,10β,13α-tetraacetoxy-11(15→1) abeotaxa-4(20),11-dien-15-ol (9) were obtained.     

Polyhydroxy pregnanes from Dregea volubilis

Three new polyhydroxy pregnanes named dregealol (1), volubilogenone (2) and volubilol (3) were isolated from the flowers of Dregea volubilis, and their structures elucidated from extensive 2D NMR analysis. The structure of volubilol (3) was confirmed by X-ray crystallographic studies. The known pregnane derivatives drevogenin D, iso-drevogenin P and 17α-marsdenin were also isolated.     

Further studies on the constituents of the gorgonian octocoral Pseudopterogorgia elisabethae collected in San Andrés and Providencia islands, Colombian Caribbean: isolation of a putative biosynthetic intermediate leading to erogorgiaene

Chemical investigations of the MeOH-CH₂Cl₂ extract of Pseudopterogorgia elisabethae specimens collected in the islands of San Andrés and Providencia, Colombian Caribbean, yielded four new diterpenes (1, 3, 5, 7) along with seco-pseudopterosin J (8), and amphilectosins A (9) and B (10). The structures of the new compounds were established through spectral studies as an elisabethatriene analog named elisabethatrienol (1), 10-acetoxy-9-hydroxy- and 9-acetoxy-10-hydroxy-amphilecta-8,10,12,14-tetraenes (isolated as an interconverting mixture) (3), amphilecta-8(13),11,14-triene-9,10-dione (5), and a seco-pseudopterosin 7-O-α-l-fucopyranoside named seco-pseudopterosin K (7). Elisabethatrienol can be regarded as a biosynthetic intermediate leading to erogorgiaene.     

Synthesis and X-ray diffraction analysis/crystal structure of new germatranes containing methyl substituents in three five-membered chelating rings

Three monomeric germatranes, 1-isopropoxy-3,3,7,7,10,10-hexamethyl-2,8,9-trioxa-5-aza-1-germatricyclo[3.3.3.0^1,5]undecane (1), 1-isopropoxy-3,3,7,7-tetramethyl-2,8,9-trioxa-5-aza-1-germatricyclo[3.3.3.0^1,5]undecane (2), and 1-isopropoxy-3,3-dimethyl-2,8,9-trioxa-5-aza-1-germatricyclo[3.3.3.0^1,5]undecane (3) have been synthesized by the reaction of Ge(O-i-Pr)₄ in refluxing toluene with corresponding triethanolamines, (HOCH₂CH₂)_nN(CH₂CMe₂OH)_3−n (n = 0, L1H₃; n = 1, L2H₃; n = 2, L3H₃), where the number of CMe₂ groups adjacent to a OH functionality varied from 3 (L1H₃) to 2 (L2H₃), and to 1 (L3H₃). These germatranes 1-3 have been characterized by solution ¹H and ¹³C{¹H} NMR and the solid state structure of 2 has been determined by single crystal X-ray diffraction.     

Synthesis and antiproliferative activity in vitro of new 2-aminobenzimidazole derivatives. Reaction of 2-arylideneaminobenzimidazole with selected nitriles containing active methylene group

A series of pyrimido[1,2-a]benzimidazole and α-cyanocinnamic acid derivatives have been synthesized in the reactions of Schiff bases 2–7 with selected nitriles containing an active methylene group: malononitrile 8–12, cyanoacetamide 13–16, benzyl cyanide 17–21, benzoylacetonitrile 22–24, cyanoacetate methyl ester 25–28 and benzylacetamide 29. The structures 8–29 were confirmed by the results of elementary analysis and their IR, ¹H-, ¹³C-NMR and MS spectra. The products 8–29 of various chemical structure pyrimido[1,2-a] benzimidazole 8–12, 14–16, 17–21, 23–24, 26 and α-cyanocinnamic acid derivatives 13, 22, 25, 27, 28 were obtained, which are of interest for biological studies or which can be substrates for further synthesis. The selected compounds 10, 13, 14, 17, 19, 21, 23–25 and 28 were screened for their antiproliferative activity in vitro against neoplastic and normal cell lines. The most active two compounds were: 2-(o-bromophenylene)-3-cyano-4-phenyl-1,2-dihydropyrimido[1,2-a]benzimidazole (24) and 3-cyano-4-phenyl-2-(2,4-dimethoxyphenyl)-1,2-dihydropyrimido[1,2-a]benzimidazole (23). However, similarly like cisplatin used as the control, they showed no selectivity towards cancer cells, by inhibiting proliferation of normal mouse fibroblasts in similar manner.