Experiments Directed toward the Total Syntheses of Polycyclic Terpenes

A synthetic sequence for the conversion of 2-methoxycarbonyl-methyl-3-methoxy-carbonyl-4-methylindanone to (±)-7-deoxyepiallo-gibberic acid methyl ester norketone is described.

A synthetic sequence for conversion of m-methoxy benzaldehyde to 2-methoxycarbonyl-methyl-3-methoxycarbonyl-5-methoxy indanone and its reaction with methyl vinyl ketone are described.     

Dimeric hydroanthracenes from the unripe seeds of Cassia torosa

From the unripe seeds of Cassia torosa three new dimeric hydroanthracene derivatives were isolated along with stigmasterol, sitosterol, campesterol, physcion-9-anthrone, torosachyrsone and the phlegmacins A₂ and B₂. The structures of the new derivatives were established as physcion-10, 10′-bianthrone, anhydrophlegmacin B₂ [2-(6′-methoxy-3′-methyl-3′, 8′, 9′-trihydroxy-1′-oxo-1′, 2′, 3′, 4′-tetrahydroanthracene-10′-yl)-1, 8-dihydroxy-3-methoxy-6-methyl-9-oxo-9, 10-dihydroanthracene] and torosanin [2-(6′-methoxy-3′-methyl-3′, 8′,9′-trihydroxy-1′-oxo-1′, 2′, 3′,4′-tetrahydroanthracene-5′-yl)-1, 8-dihydroxy-3-methoxy-6-methyl-9-oxo-9, 10-dihydroanthracene], respectively.     

N/C-4 substituted azetidin-2-ones: synthesis and preliminary evaluation as new class of antimicrobial agents

A series of 3-chloro-4-(3-methoxy-4-acetyloxyphenyl)-1-[3-oxo-3-(phenylamino)propanamido] azetidin-2-ones 3a-g and 3-chloro-4-[2-hydroxy-5-(nitro substituted phenylazo)phenyl]-1-phenylazetidin-2-ones 6a-h were synthesized using appropriate synthetic route. Structures of all the synthesized compounds were established on the basis of elemental analysis and spectroscopic data. The antimicrobial activity of the synthesized compounds was screened against several microbes. Several of these molecules showed potent antimicrobial activity against Bacillus anthracis, Staphylococcus aureus and Candida albicans and significant structure-activity relationship (SAR) trends.     

Neolignans from an Aniba species

A benzene extract of the trunk of an Aniba species (Lauraceae) contained benzyl benzoate, benzyl salicylate, sitosterol and the neolignans (2S,3S,3aR)-3a-allyl-5-methoxy-3-methyl-2-piperonyl-2,3,3a,6-tetrahydro-6-oxobenzofuran (burchellin); (2S,3S,3aR)-3a-allyl-5-methoxy-3-methyl-2-veratryl-2,3,3a,6-tetrahydro-6-oxobenzofuran; (2S,3S,3aR)-3a-allyl-5,7-dimethoxy-3-methyl-2-veratryl-2,3,3a,6-tetrahydro-6-oxobenzofuran; (2S,3S,5S)-5-allyl-5-methoxy-3-methyl-2-veratryl-2,3,5,6-tetrahydro-6-oxo-benzofuran; (2R,3R)-7-methoxy-3-methyl-5-propenyl-2-veratryl-2,3-dihydrobenzofuran; rel-(1R,5R,6R,7R,8S)-1-allyl-8-hydroxy-3-methoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene (guianin); rel-(1S,5S,6S,7R,8R)-1-allyl-8-hydroxy-3,5-dimethoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene; rel-(1S,5S,6S,7R,8R)-8-acetoxy-1-allyl-3-hydroxy-5-methoxy-7-methyl-4-oxo-6-piperonyl-bicyclo[3,2,1]oct-2-ene; rel-1S,5S,6S,7R,8R)-8-acetoxy-3,5-dimethoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene; rel-(1R,5S,6R,7R)-1-allyl-3-methoxy-7-methyl-4,8-dioxo-6-piperonylbicyclo[3,2,1]oct-2-ene.     

Design and synthesis of chromone-nitrogen mustard derivatives and evaluation of anti-breast cancer activity

Chromone has emerged as one of the most important synthetic scaffolds for antitumor activity, which promotes the development of candidate drugs with better activity. In this study, a series of nitrogen mustard derivatives of chromone were designed and synthesised, in order to discover promising anti-breast tumour candidates. Almost all target derivatives showed antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. In particular, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed the most potent antiproliferative activity with IC₅₀ values of 1.83 and 1.90 μM, respectively, and it also exhibited certain selectivity between tumour cells and normal cells. Further mechanism exploration against MDA-MB-231 cells showed that it possibly induced G2/M phase arrest and apoptosis by generating intracellular ROS and activating DNA damage. In addition, it also inhibited MDA-MB-231 cells metastasis, invasion and adhesion. Overall, methyl (S)-3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(5-(((6-methoxy-4-oxo-4H-chromen-3-yl)methyl)amino)-5-oxopentanamido)propanoate showed potent antitumor activities and relatively low side effects, and deserved further investigation.     

Cytotoxic tirucallane C26 triterpenoids from the stem barks of Aphanamixis grandifolia

Five tirucallane type C₂₆ triterpenoids, accompanied by two known compounds, 3α-hydroxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone and 3-oxo-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, were isolated from the stem barks of Aphanamixis grandifolia. Their structures were established mainly by means of a combination of 1D and 2D NMR spectroscopic and mass spectrometry techniques as 3α-hydroxyl-21α-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3α-hydroxy-21β-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3-oxo-21α-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, 3-oxo-21β-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, and 3-oxo-21α-ethoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone. All isolates were in vitro evaluated for their cytotoxic activities against five tumor cell lines (MCF-7, HeLa, HepG2, SGC-7901 and BGC-823).     

Xanthones from a microfungus of the genus Xylaria

Chemical investigations of a microfungus Xylaria sp. isolated from the Australian rainforest tree Glochidion ferdinandi have afforded two new natural products, 2-hydroxy-6-methyl-8-methoxy-9-oxo-9H-xanthene-1-carboxylic acid (1) and 2-hydroxy-6-hydroxymethyl-8-methoxy-9-oxo-9H-xanthene-1-carboxylic acid (2). Compound 1 has previously been synthesised but only partially characterised. Methylation of 1 using diazomethane afforded the crystalline compound 2,8-dimethoxy-6-methyl-9-oxo-9H-xanthene-1-carboxylic acid methyl ester (3), whose structure was determined by single crystal X-ray analysis. This paper reports the full spectroscopic characterisation of compounds 1-3 by NMR, UV, IR and MS data. All compounds were inactive in a brine shrimp lethality assay and several antimicrobial screens.     

Synthesis of novel quinolone and quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides: a late-stage diversification approach to potent 5HT1B antagonists

Multiparallel amenable syntheses of 6-methoxy-8-amino-4-oxo-1,4-dihydroquinoline-2-carboxylic acid-(4-morpholin-4-yl-phenyl)amides (I) and 4-amino-6-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides (II) which facilitate late-stage diversification at the 8-position of (I) and at the 4- and 8-positions of (II) are described. The resulting novel series were determined to contain potent 5HT(1B) antagonists. Preliminary SAR data are presented.     

A New Metabolic Pathway for meta Ring-fission Compounds of Biphenyl

The double bonds of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) were stabilized by methylation to establish which of the double bonds of the meta ring-fission compound of biphenyl was reduced by the HOPDA reducing enzyme. HOPDA reducing enzyme III converted 2-methoxy-6-oxo-6-phenylhexa-2,4-dienoic acid methyl ester into 2-methoxy-6-oxo-6-phenylhexa-2-enoic acid methyl ester. To discover the metabolic pathway of HOPDA, partially purified enzyme fractions were used. The eluate from a 2nd column of DEAE-cellulose transformed HOPDA to γ-benzoylbutyric acid, 2,6-dioxo-6-phenylhexanoic acid, and γ-benzoylbutyraldehyde. Fractions passed through the 1st column of DEAE-cellulose formed γ-benzoylbutyric acid and 2-hydroxy-6-oxo-6-phenylhexanoic acid from HOPDA. Based on these data and previous reports, a new metabolic divergence of biphenyl and related compounds was proposed.     

Determination of photostability and photodegradation products of moxifloxacin in the presence of metal ions in solutions and solid phase. Kinetics and identification of photoproducts

Photostability of moxifloxacin (MOXI) after UVA irradiation in solutions and solid phase, with and without participation of Cu(II), Zn(II), Al(III), and Fe(III) was tested. The studies were carried out by the TLC-densitometric method and LC-MS/MS method. Elaborated and validated chromatography-densitometric method was used for assaying. It was shown that the number and type of photoproducts depend on the environment and type of the metal ion. The studied ions enhanced the degradation of MOXI in solutions, and the influence of Cu(II) and Fe(III) ions was higher than that of Zn(II) and Al(III) ions. In solid phase, in contrast to solutions, all metal ions decreased the photodegradation, however the influence of ions, Al(III) and Zn(II), was weaker than that of Cu(II) and Fe(III) ions. Identification of the degradation products performed with LC-MS/MS and (1)H NMR identified them as: 1-cyclopropyl-6-fluoro-7-amino-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(2-oxo-octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1,4-dihydroquinoline-3-carboxylic acid, 7-[3-hydroxyamino-4-(2-carboxyethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.     

Transformation of 25-Hydroxycholesterol by Rhizoctonia muneratii

Rhizoctonia muneratii ATCC 13247 was capable of catalyzing the conversion of 25-hydroxycholesterol to the 3-oxo-4-ene. Hydroxylation at the 6α and 6β positions with the concomitant 3-oxo-4-ene transformation was also observed. The addition of Triton X-100 to the growth medium immediately before steroid addition selectively prevented the appearance of the respective 6α-hydroxylated products. The observed conversions were indicative of the utility of microbial transformations in preparing hydroxylated steroids which can be useful for further synthetic modification or for study as pharmacological agents.     

A cinnamoyl pyrrolidine amide from Piper peepuloides

Analysis of a petrol extract of the leaves of Piper peepuloides resulted in the isolation of a new cinnamoyl pyrrolidine amide characterized as Z-pyrrolidine-1-3-(6-methoxy-1,3-benzodioxol-5-yl)-1-oxo-2-propenyl along with peepuloidin, 2-methoxy-4,5-methylenedioxy-Z-cinnamoyl piperidide, β-sitosterol and β-sitosterol glucoside.     

Synthesis of compounds of potential value in the radioimmunoassay of 17 alpha-ethynylestradiol and mestranol

The 6-(0-carboxymethyl)oxime derivatives of 6-oxomestranol and 6-oxo-17α-ethynylestradiol were prepared from 3-methoxy-6-oxoestrone. These haptens were then coupled to bovine serum albumin by the mixed anhydride technique to yield the steroid-protein conjugates required for the production of specific antisera for the radioimmunoassay of mestranol and 17a-ethynylestradiol. In addition we have described the preparation of certain expected metabolites of mestranol and 17α-ethynylestradiol which are also required for studying cross-reactivity in the radioimmunoassay.     

Benzofuranoid Neolignans from Piper kadsura

In a continuing research for neolignans from Piper kadsura (Choisy) Ohwi, six benzofuranoid neolignans were isolated from the aerial part of the plant. Their structure determination were based on the spectroscopic analysis (UV, IR, MS, NMR and CD) and derivative synthesis. Three of the isolated compounds were identified as new structures: 7R, 8R, 1′S-△8′-3, 4-methylenedioxy-5′-methoxy-l′, 4′-dihydro-4′-oxo-7, 0, 2′, 8. l′-neolignan ( Ⅰ ), 7 R, 8 R, 1 ′ R- △8′ - 3,4- methylenedioxy- 1 ′- methoxy - 1′,6′- dihydro- 6′- oxo- 7.0.4′,8. 3′-neolignan (Ⅳ) and 7R, 8R, 1′S-△8′-3, 4-methylenedioxy-l′-methoxy-1′,6′-dihydro-6′-oxo-7.0.4′,8.3′-neolignan (Ⅴ). Known compounds among them are 7R, 8S,1′S-△8′-3, 4-methylenedioxy-5′-methoxy-1′, 4′-dihydro-4′-oxo-7. 0. 2′, 8. 1′-neolignan(Ⅱ), 7S, 8S, 1′R-△8′-3, 4, 5′-trimethoxy-1′, 4′-dihydro-4′-oxo-7.0. 2′, 8. 1′-neolignan (Ⅲ) and 75, 85, 1′S-△8′-3, 4, l′-trimethoxy-l′, 6′-dihydro-6′-oxo-7. 0. 4′, 8. 3′-neolignans (Ⅵ). All of them were isolated from the plant for the first time.     

Guianin: A neolignan from Aniba guianensis

The wood of Aniba guianensis Aubl. (Lauraceae) contains benzyl benzoate, benzyl salicylate, sitosterol, O-methyleugenol, O-methylisoeugenol and the neolignan guianin for which the structure of 1-allyl-8-hydroxy-3-methoxy-7-methyl-4-oxo-6-piperonylbicyclo[3,2,1]oct-2-ene (VI) is proposed.     

In vitro cytotoxic potential of newly synthesized furo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyran-4-one derivatives in cultured human lymphocytes

The in vitro cytotoxic potentials of Furo[3,2-c]pyran-4-one derivatives in human lymphocytes were investigated. Blood samples were obtained from six healthy donors, non-smoking volunteers, which were incubated and exposed to increasing concentrations (0.05, 0.1, 0.5, 1 and 2 mg/mL) of Furo[3,2-c]pyran-4-one derivatives which are methyl 2-methoxy-7-(4-methylbenzoyl)-6-(4-methylphenyl)-4-oxo-4H-furo[3,2-c]pyran-3-carboxylate (1a) and methyl 2-methoxy-7-(4-methoxybenzoyl)-6-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]pyran-3-carboxylate (1b). Compounds 1a and 1b induced micronucleus, mitotic and replication indexes in human lymphocytes (1 and 2 mg/mL). The increases of micronucleus, mitotic and replication indexes show that compounds at high concentrations may become cytotoxic, genotoxic and carcinogenic.     

Rapid synthesis of 2-desoxy-2-amino-3-phosphocholine-glycerinic-acid- alkylester, 1-alkyl-1-desoxy- and 1-O-alkyl-2-desoxy-2-amino-sn-glycero-3- phosphocholines, -3-phospho-N,N'-dimethylethanolamine and -3-phospho-Fmoc- serine-methylester.

A convenient sequence for the rapid synthesis of 2-desoxy-2-amino-3-phosphocholine-glycerinic-acid-alkylester , 1-alkyl-1-desoxy- and 1-O-alkyl-2-amino-2-desoxy-3-phospho-derivatives is described. Key steps are the reaction of 1-carbonyloxyalkyl-, 1-alkyl- or 1-O-alkyl-amino-alcohols with phosphorus oxychloride to 1-carbonyloxyalkyl-, 1-alkyl- or 4-substituted 2-chloro-2-oxo-1,3,2-oxazaphospholane followed by nucleophilic displacement with choline tosylate, 1-bromoethane-2-ol or Fmoc-L-serine-methylester and subsequent hydrolysis to 2-amino-lysophospholipids giving the desired compounds in yields ranging between 68% and 81%. Several 2-amino-lysophospholipid analogs can then be prepared by this synthetic scheme utilizing the same oxazaphospholane intermediate. A brief method for the preparation of 2-amino-3-hydroxy-propionic-acid-pentyl- and -octylester from L-serine is described, opening a facile access to chiral precursors of phospholipid analogs.     

Short-chain 3-ketoceramides, strong apoptosis inducers against human leukemia HL-60 cells

Ceramides act as a second messenger of the apoptotic signaling process. The allylic alcohol portion comprising the C-3, C-4, and C-5 carbons is essential for this function. The suggestion has been made that this alcohol moiety is oxidized in mitochondria to a carbonyl moiety, with the generation of reactive oxygen species. However, there is no established precedent for the apoptotic performance of 3-ketoceramides thus presumed. In this work, we have synthesized three different types of short-chain 3-ketoceramides, that is, (2S,4E)-2-acetylamino-3-oxo-4-octadecen-1-ol (A), (2S,4E,6E)-2-acetylamino-3-oxo-4,6-octadecadien-1-ol (B), and (2S,4E)-2-acetylamino-1-methoxy-3-oxo-4-octadecene (C), and demonstrated that these 3-ketoceramides are capable of inducing effective apoptosis in human leukemia HL-60 cells. In particular, the two monoenoic compounds, A and C, are far more powerful than the corresponding alcoholic analogue, N-acetyl-D-erythro-sphingosine. Observations of DNA fragmentation, caspase-3 activation, and cytochrome c release from mitochondria provide substantiated evidence for mitochondrial apoptosis and the effects of exogenous glutathione on these phenomena are also discussed.     

2,3-dihydrojaborosalactone A,a withanolide from Acnistus breviflorus

From Acnistus breviflorus the new 27-hydroxy-5β,6β-epoxy-1-oxo-(22R)-witha-24-enolide (2,3-dihydrojaborosalactone A) as well as seven known withanolides, withaferin A, 2,3-dihydrowithaferin A, 6α-chloro-5β-hydroxywithaferin A, 5,6-deoxywithaferin A, jaborosalactone A, jaborosalactone D and jaborosalactone E were isolated and characterized by means of spectroscopic (¹H NMR, ¹³ C NMR and mass spectral) methods. Depending on the extraction solvent (methanol or ethanol), a known artifact (3β-methoxy-2,3-dihydrowithaferin A) and the new 5α-methoxy-4,5-dihydrojaborosalactone B and 5α-ethoxy-4,5-dihydrojaborosalactone B were also isolated and characterized.     

Mycochromone and mycoxanthone: Two new metabolites from Mycosphaerella rosigena

Two new metabolites, dimethyl 2-(2-ethenyl-5-hydroxy-4H-1-benzopyran-4-onyl-3)-malonate (mycochromone 1a) and methyl 2-methoxy-8-hydroxy-9-oxo-9H-xanthene-1-carboxylate (mycoxanthone 6a), have been isolated and identified from the mycelium of Mycosphaerella rosigena grown on potato-agar.