Withaphysanolide A, a novel C-27 norwithanolide skeleton, and other cytotoxic compounds from Physalis divericata

A novel C-27 norwithasteroid, withaphysanolide A (1) containing a pyran ring was isolated from the aerial parts of Physalis divericata. Four known withaphysalins (2-5) and five physalins (6-10) were also isolated. The structural assignment for 1 was done based on spectroscopic and single-crystal X-ray diffraction data. Logical biosynthetic pathways were postulated. Compounds 6, 7, and 10 displayed potent cytotoxic activity against HCT-116 and H460 human cancer cell lines, with IC₅₀ values less than 2.0 μM.     

Two novel diterpenoids from Isodon rubescens var. lushanensis

Two novel diterpenoids, luanchunins A (1) and B (2), along with their precursor, kamebakaurin (3), had been isolated from the stems and leaves of Isodon rubescens var. lushanensis. Their structures were elucidated on the basis of extensive spectroscopic analyses. Compounds 1 and 2 showed potent cytotoxic activity against HL-60 with IC₅₀ values of 4.81 μM and 3.52 μM, respectively. Plausible pathways for the biosynthesis of 1 and 2 were also postulated.     

Ferrocene-indole hybrids for cancer and malaria therapy

We report the synthesis, characterization, and cytotoxic and antimalarial activity of ferrocene-indole hybrids 8-14. The 2-phenylindole scaffold was chosen because of its potent antimitotic activity and ferrocene was chosen following the development of ferrocifens, ferrocene derivatives of tamoxifen, which are prototypes of a new family of organometallic anti-estrogens. Ferrocene-indole hybrids 8-14 and their corresponding organic analogues 1-7 showed only moderate antimalarial activities, while ferrocene-indole hybrids 11 and 12 showed excellent in vitro activities against the A549 human carcinoma cell line, with IC₅₀ values of 5 and 7 μM respectively. These ferrocene-indole hybrids were up to 25-fold more potent as cytotoxic agents than their purely organic analogues.     

Axiplyns A-E, new sesquiterpene isothiocyanates from the marine sponge Axinyssa aplysinoides

Five new isothiocyanate sesquiterpenes, designated axiplyns A-E (1-5) have been isolated, together with two known isothiocyanate sesquiterpenes (6, 7), from the sponge Axinyssa aplysinoides collected at Misali Island, Tanzania. Axiplyns 4 and 5 embody a new indane sesquiterpene skeleton, and compounds 1, 2, and 5 contain unprecedented ring systems, namely a 6,8-dioxabicyclo[3.2.1]octane and a 2-oxabicyclo[2.2.1]heptane. Axiplyns A, B, and C are potent brine shrimp toxins with LD₅₀ values between 1.5 and 1.8 μg/mL.     

Concise synthesis of di- and trisaccharides related to the O-antigens from Shigella flexneri serotypes 6 and 6a,based on late stage mono-O-acetylation and/or site-selective oxidation

Shigella flexneri serotypes 6 and 6a are closely related bacteria causing shigellosis in humans. Their O-antigens are {→4)-β-d-GalpA-(1→3)-β-d-GalpNAc-(1→2)-[3Ac/4Ac]-α-l-Rhap-(1→2)-α-l-Rhap-(1→}_n acidic polysaccharides ({AB_AcCD}_n), which only differ in the degree of O-acetylation. A concise synthesis of two disaccharides (BC, B_AcC) and four trisaccharides, representing portions and/or analogs of the O-antigens, is described. A protected intermediate compatible with late stage 3_C-O-acetylation, and/or galactosyl (A°) to galacturonic acid (A) conversion, was designed and assembled from trichloroacetimidate and thioglycoside donors tuned for high yielding glycosylation and excellent stereocontrol. The galacturonic moiety was efficiently introduced from galactose using a TEMPO/NaOCl/NaClO₂-based oxidation protocol optimized for full compatibility with sensitive moieties, such as allyl ethers and acetates. Final Pd/C-mediated deprotection provided the targets, including the propyl glycoside AB_AcC, its non O-acetylated counterpart ABC, and the non acidic analogs A°B_AcC and A°BC. The BC and ABC oligosaccharides are also portions of the O-antigen from Escherichia coli O147, which causes diarrhea in pigs.     

Antitrypanosomal pyridoacridine alkaloids from the Australian ascidian Polysyncraton echinatum

Bioassay-guided fractionation of the crude CH₂Cl₂/MeOH extract from the Australian ascidian Polysyncraton echinatum led to the isolation of a new pyridoacridine alkaloid, 12-deoxyascididemin (1), along with two known analogues, ascididemin (2) and eilatin (3). The structure of 1 was determined following extensive analysis of 1D/2D NMR and MS data. Biological evaluation showed that compounds 1-3 are potent antitrypanosomal agents with IC₅₀ values of 0.077, 0.032, and 1.33 μM against Trypanosoma brucei brucei, respectively.     

Lyconadins C and F, new Lycopodium alkaloids from Lycopodium complanatum

New Lycopodium alkaloids, lyconadins C (1) and F (2), were isolated from the club moss Lycopodium complanatum. Lyconadin C (1) is a new C₁₆N₂-type Lycopodium alkaloid possessing unique fused-tetracyclic ring system consisting of a cycloheptene ring fused to a decahydroquinoline and pyridone rings. Lyconadin F (2) possesses a primary amide moiety in its molecular, which is the first example of Lycopodium alkaloids. Biogenetically, lyconadins C (1) and F (2) might be related to lyconadins A (4) and B (5). The structures and relative stereochemistry of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute stereochemistry of 2 was elucidated by chemical correlations with lyconadin B (5) through hemiaminal form of lyconadin F (3).     

Novel cytotoxic nine-membered macrocyclic polysulfur cembranoid lactones from the soft coral Sinularia sp.

One novel nine-membered macrocyclic polysulfur cembranoid lactone, sinulariaoid A (1); three new multioxygenated cembranoids, sinulariaoid B (2), sinulariaoid C (3), sinulariaoid D (4); and four known cembranoids, capilloloid (5), dihydrosinularin (6), sinularin (7), and dihydrosinuflexolide (8) were isolated from the soft coral Sinularia sp. collected off of Sanya Bay in the South China Sea. Their stereochemical structures were determined on the basis of extensive spectroscopic methods, including single crystal X-ray diffraction analysis. Sinulariaoid A (1) is the first reported nine-membered macrocyclic polysulfur cembranoid from soft coral. The cytotoxic activities of compounds 1–8 were determined in four human cancer cell lines (HepG2, HepG2/ADM, MCF-7, and MCF-7/ADM). Of these, sinulariaoid A (1) exhibited the most potent anticancer activity in vitro, and its cytotoxicity in HepG2/ADM was more potent than in the other three cell lines. Furthermore, it was found that sinulariaoid A (1) induced apoptosis, and its selective toxicity toward HepG2/ADM cells was not related to P-glycoproteins.     

Vernodalidimers A and B, novel orthoester elemanolide dimers from seeds of Vernonia anthelmintica

Two novel elemanolide dimers, vernodalidimers A (1) and B (2), possessing a rare tricyclic ortho ester moiety, were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by 1D and 2D NMR data and CD spectra. Vernodalidimers A (1) and B (2) exhibited potent cell growth inhibitory activity against HL-60 cells (IC₅₀ 0.72 and 0.47 μM, respectively).     

Constituents of the Leaves and Stem Bark of Aglaia foveolata

The previously known potent cytotoxic agent silvestrol (1) (0.002% w/w yield) and five new flavagline derivatives (2-6) were isolated from the leaves of Aglaia foveolata collected in Indonesia. The new compound 5 has an unprecedented cyclic amide moiety in its cyclopenta[b]benzopyran skeleton, while compound 6 is a novel benzo[b]oxepine derivative in which the oxepine ring is cleaved. Pyramidatine (7), a biogenetic precursor of the new flavaglines 2-6, was isolated from the leaf extract investigated. Silvestrol was also isolated from the stem bark of A. foveolata (yield of 0.02% w/w) along with a new baccharane-type triterpenoid (8). The structures of the new compounds were elucidated on the basis of their NMR and mass spectrometric data. All new compounds isolated were tested against a panel of cancer cell lines, but only compound 2 was cytotoxic (IC₅₀ range=1.4-1.8 μM), and is the first member of the cyclopenta[b]benzopyran class found to exhibit this type of activity. Compound 2 also showed significant NF-κB inhibitory activity in an Elisa assay (IC₅₀=0.37 μM).     

N-Hydroxypyridone alkaloids,chromone derivatives,and tetrahydroxanthones from the scale-insect pathogenic fungus Orbiocrella sp. BCC 33248

Six new compounds, an N-hydroxypyridone glucoside, orbiocrellin A (1), its aglycone orbiocrellin B (2), chromone glucosides 3 and 4, a dihydrochromone 5a/5b, and a chromone 6, were isolated from the scale-insect pathogenic fungus Orbiocrella sp. BCC 33248. Orbiocrellin A (1) exhibited antimalarial activity against Plasmodium falciparum K1 (IC₅₀ 3.1 μg/mL) while it was non-cytotoxic. In contrast, orbiocrellin B (2) showed both antimalarial (IC₅₀ 2.1 μg/mL) and cytotoxic (NCI-H187 cells, IC₅₀ 0.70 μg/mL) activities.     

Monanchomycalins A and B, unusual guanidine alkaloids from the sponge Monanchora pulchra

New pentacyclic guanidine alkaloids, monanchomycalins A (1) and B (2) were isolated from the marine sponge, Monanchora pulchra and their structures elucidated using NMR, HRMALDI-TOF-MS, and HRESI MS, as well as by chemical transformations of 1. Compounds 1 and 2 exhibited potent cytotoxic activities against HL-60 human leukemia cells with IC₅₀ values of 120 and 140 nM, respectively.     

A novel and easy two-step,microwave-assisted method for the synthesis of halophenyl pyrrolo[2,3-b]quinoxalines via their pyrrolo precursors. Evaluation of their bioactivity

A novel, two-step, facile route for the synthesis of pyrrolo[2,3-b]quinoxalines via 2,3-dioxopyrroles, enhanced by microwave irradiation, is presented. The newly synthesized 2,3-dioxo-5-halophenyl pyrrolo precursors 4a–c as well as the non-aromatized ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 6a–c and the aromatized ethyl 2-(4-halophenyl)-1-methyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 7a–c were evaluated for their antioxidant, cytostatic, and antiviral properties. Most of them proved to be potent hydroxyl radical scavengers and inhibited in vitro lipid peroxidation. The compounds showed moderate antiproliferative activity, while 6a inhibited vaccinia virus at an EC₅₀ value of 2 μM, and 4c and 6c inhibited Sindbis virus at EC₅₀ values of 4 μM.     

Design and synthesis of a potent biotinylated Smac mimetic

A biotinylated Smac mimetic (2) was designed based upon our previously reported potent, conformationally constrained Smac mimetic (1). Smac mimetic (2) was synthesized and determined to bind to XIAP protein with a high-affinity (K_i value of 13 nM) and is therefore a useful pharmacological tool for probing the intracellular targets of this class of potent Smac mimetics.     

Synthesis and molecular structures of dinuclear complexes with 1,2-dihydro-1,2-diphenyl-naphtho[1,8-c,d]1,2-diphosphole as a bridging ligand

A bisphosphine in which a PhP-PPh bond bridges 1,8-positions of naphthalene, 1,2-dihydro-1,2-diphenyl-naphtho[1,8-cd]-1,2-diphosphole (1), was used as a bridging ligand for the preparation of dinuclear group 6 metal complexes. Free trans-1, a more stable isomer having two phenyl groups on phosphorus centers mutually trans with respect to a naphthalene plane, was allowed to react with two equivalents of M(CO)₅(thf) (M = W, Mo, Cr) at room temperature to give dinuclear complexes (OC)₅M(μ-trans-1)M(CO)₅ (M = W (2a), Mo (2b), Cr (2c)). The preparation of the corresponding dinuclear complexes bridged by the cis isomer of 1 was also carried out starting from the free trans-1 in the following way. Mono-nuclear complexes M(trans-1)(CO)₅ (M = W (3a), Mo (3b), Cr (3c)) which had been prepared by a reaction of trans-1 with one equivalent of the corresponding M(CO)₅(thf) (M = W, Mo, Cr) complex, were heated in toluene, wherein a part of the trans-3a-c was converted to their respective cis isomer M(cis-1)(CO)₅. Each cis trans mixture of the mono-nuclear complexes 3a-c was treated with the corresponding M(CO)₅(thf) to give a cis trans mixture of the respective dinuclear complexes 2a-c. The cis isomer of the ditungsten complex 2a was isolated, and its molecular structure was confirmed by X-ray analysis, showing a shorter W?W distance of 5.1661(3) Å than that of 5.8317(2) Å in trans-2a.     

Complanadine B, obscurumines A and B, new alkaloids from two species of Lycopodium

A new dimer of C₁₆N₂ type alkaloid, complanadine B (1), and two new C₁₆N type alkaloids, obscurumines A (2) and B (3), have been isolated from the club moss Lycopodium complanatum and L. obscurum, respectively. The structures and stereochemistry of 1-3 were elucidated by combination of 2D NMR spectra and chemical transformation. Complanadine A (4) isolated together with 1 induced secretion of neurotrophic factors from human astrocytoma cells.     

Antioxidative acylphloroglucinols from the roots of Lysidice rhodostegia

Four new acylphloroglucinols, lysidicins I and J (1 and 2), and lysidisides V and W (3 and 4), were isolated from the roots of Lysidice rhodostegia. Among them, compound 1 is a novel acylphloroglucinol, and compound 2 is the first naturally occurring acylphloroglucinol derivative with an uncommon spiro(benzofuran-[2H]pyran) skeleton. Their structures were elucidated by spectroscopic and chemical methods. The absolute configuration of 1 was assigned by employing dimolybdenum tetraacetate-induced CD spectrum method, and that of 2 was determined by analysis of their experimental and theoretically calculated CD spectra. Compounds 3 and 4 exhibited potent antioxidative activity with IC₅₀ values of 3.29 and 3.39 μM, respectively.     

From lithium ketazides to isomeric silylketazine-rings - imine-enamine tautomerism

Di(tert-butylmethyl)ketazine (I) reacts with n-BuLi in a 1:1 molar ratio to give a monolithium salt (II). The reaction of II with ^tBu₂SiF₂ in n-hexane leads, even in a 1:1 molar ratio, to the formation of the isomeric five- and four-membered ring compounds 1 and 2. Compound 1 has an endocyclic imine and an exocyclic enamine unit. The opposite is found for 2. The acyclic monosubstitution product, ^tBu₂SiFCH₂-C^tBuN-NC^tBuCH₃ (III) could not be isolated. It reacts with the lithium ketazide to give 1 or 2. I is reformed. The reaction in THF yields only the four-membered ring 2. In a comparable reaction of the lithium ketazide and (H₃C)₂SiF₂, the substitution product 3 could be isolated. A possible formation mechanism for 2 includes an intermediate silene IV. Both compounds 1 and 2 react with H₃C-OH under cleavage of the endocyclic Si-N-bond to give the addition product 5. The reaction mechanism includes a hydrogen shift from a nitrogen atom to a carbon atom via an imine-enamine tautomerism. In a 2:1 molar ratio, n-BuLi and the di(tert-butylmethyl)-ketazine (I) form the dilithium salt, 6. Compound 6 crystallizes from THF as trimer with four imine and two enamine units. A seven-membered ring (7) isomeric to 1 and 2 is the result of the reaction of 6 with ^tBu₂SiF₂. Compound 7 contains one imine and one enamine unit in the ring skeleton.The comparable reaction of the (CH₃)₃Si-substituted dilithium-di(tert-butylmethyl)ketazide and ^tBu₂SiF₂ yields the five-membered ring compound 8 with one endocyclic imine and one exocyclic enamine unit.Quantum chemical calculations of 1, 2, 7 and the intermediate silene IV have been carried out and show a low energy difference between the cyclic silyl-ketazine isomers.     

New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium

Two new phlegmarane-type alkaloids, cermizines A (1) and B (2), three new quinolizidine alkaloids, cermizine C (3) and senepodines G (4) and H (5), and a new C₁₆N₂ type alkaloid consisting of a quinolizidine and a piperidine ring, cermizine D (6), as well as two new cernuane-type alkaloids, cernuine N-oxide (7) and lycocernuine N-oxide (8), have been isolated together with cernuine (9) and lycocernuine (10) from the club moss Lycopodium cernuum and L. chinense. The relative stereochemistry of 1-4 and 6, and the absolute stereochemistry of 5, 7, and 8 were elucidated by combination of NOESY correlations, modified Mosher's method, chemical transformations, and computational methods. Cermizine D (6) might be a biosynthetic intermediate of cernuane-type alkaloids such as 7-10.     

Synthesis and stability of 1,1-dialkyl-1H-azulenium cations

Starting from trimethylsilyl enol ether of 1-acetyl-1,3,5-cycloheptatriene, the title 1,1-dimethyl-, 1,1-diethyl-, and 1,1-dipropyl-1H-azulenium cations 6-8 were synthesized in five steps. The order of pK_R+ values of these cations was found to be 7>8>6. A comparison of the values between 1,1-dialkyl- and 1,1-spiroalkylated 1H-azulenium cations with the same number of carbon atoms at the 1-position provided the results of 7>1 and 8<3. The cation 8 shows a relatively lower pK_R+ value to those of 3 and 7 probably due to its slightly bulkier propyl groups from which solvation stabilization of 8 under the conditions suffers. An intermolecular charge-transfer interaction between the cations and dibenzo-24-crown-8 was also studied.