Assembly of an unprecedented metal-pipemidic acid complex modifying octamolybdates containing like DNA spiral chain

By introducing antibacterial drugs pipemidic acid into the octamolybdates, an unprecedented compound, [Zn(PPA)₂(H₂O)]₂·[Mo₈O₂₆]·3.5H₂O (1) (PPA = pipemidic acid), has been synthesized and characterized by routine physical methods. Single-crystal X-ray diffraction analysis reveals that the title compound contains the right- and left-double-stranded like DNA helical chains, which are assembled together via sharing the β-Mo₈ clusters forming the fascinating double intertwined inverted helices. The result of the antitumor activities shows that the title compound possesses higher antitumor activity and selectivity.     

FR900482, a close cousin of mitomycin C that exploits mitosene-based DNA cross-linking

Background: The class of antitumor antibiotics that includes FR900482 has a very close structural analogy to the mitomycins, one of which, mitomycin C, has been in widespread clinical use for more than 20 years. Like mitomycin C, these antitumor antibiotics are reductively activated in vivo and covalently cross-link DNA as a result of activity of the mitosene moiety generated on reduction. Owing to differences in structure and the attendant mechanistic differences in bioreductive activation between the mitomycins and FR900482, FR900482 does not produce an adventitious superoxide radical anion during reductive activation and thus does not exhibit oxidative strand scission of DNA. It is postulated that the low clinical toxicity of FR900482 relative to mitomycin C is a direct manifestation of the mechanistic differences of bioreductive activation leading to the highly reactive DNA cross-linking mitosenes.Results: Using Fe(II)-EDTA footprinting, we showed that the two natural products FR900482 (1) and dihydro, FR66979 (3), and the semi-synthetically derived triacetate FK973 (2), display remarkable selectivity for 5′ deoxy-CG sequences of DNA, and that this selectivity is abolished upon deletion of the exocyclic N2 amine of either participating guanosine residue. In addition, we investigated the mono alkylation abilities of FR66979 with respect to a number of inosine-substituted oligonuclectides and observed that the FR900482 class of compounds were able to give rise to easily separable orientation isomers of their respective cross-links.Conclusions: The FR900482 class of antitumor antibiotics cross-link DNA in a fashion analogous to the mitomycins. The cross-linking reaction yields two orientation, isomers which are of vastly different electrophoretic mobility and which also exhibit radically different DNA-protein recognition properties upon reaction with Alul restriction endonuclease. In addition, mono-alkylation of DNA by FR66979 shows little, if any, dependence upon pre-covalent interactions deemed necessary for the mitomycins. These insights support the proposal that the FR900482 class of compounds represents a compelling clinical replacement for mitomycin C, given its greatly reduced host toxicity and superior DNA interstrand cross-linking efficacy.     

An unusual indole alkaloid with anti-adenovirus and anti-HSV activities from Alstonia scholaris

A novel alkaloid, 17-nor-excelsinidine (1), possessing an unusual 1-azoniatricyclo [4.3.3.0] undecane moiety was isolated from the twigs and leaves of Alstonia scholaris alongside its biogenetically related strictamine (2). The structure and absolute stereochemistry of compound 1 were rigorously determined by a combination of NMR spectroscopy and X-ray crystallography. The 17-nor-excelsinidine (1) and strictamine (2) showed significant inhibitory activity against herpes simplex virus (HSV) and adenovirus (ADV).     

The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA)₂]H₄[SiW₁₂O₄₀]}·HPPA·3H₂O (1), and {[Zn(PPA)₂]₂H₄[SiW₁₂O₄₀]}·3H₂O (2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.     

Ligation of the quinolone antibacterial agent pipemidic acid to Keggin polyoxotungstates

Three new drug molecules modifying Keggin polyoxometallate compounds have been synthesized under hydrothermal conditions and structurally characterized by routine techniques. Single-crystal X-ray diffraction analysis shows that compound 1 is constructed by a Keggin cluster and two [Cu(PPA)₂] drug complexes, formulated as [Cu(PPA)₂]₂·[PW₁₂O₄₀]·6H₂O. Compound 2 consists of a Cd substituted Keggin cluster [PW₁₁CdO₃₉] and five isolated HPPA drug molecules, formulated as [HPPA]₅·[PW₁₁CdO₃₉]·2H₂O. Compound 3 consists of a full oxidised Keggin [PW₁₂O₄₀] cluster and three isolated HPPA drug molecules, formulated as [HPPA]₃·[PW₁₂O₄₀]·2H₂O. Additionally, the antitumor activity of the three new compounds and their parent components in vitro were studied by a MTT experiment. The results show that introduction of TM-PPA/PPA into the polyoxoanion surface could increase their antitumor activity and make the compounds penetrate into the cells easily. Furthermore, the antitumor activity of the compounds can be modulated by their different structures.     

Nagelamides M and N, new bromopyrrole alkaloids from sponge Agelas species

Two new bromopyrrole alkaloids, nagelamides M (1) and N (2), have been isolated from an Okinawan marine sponge Agelas species, and the structures and stereochemistry were elucidated from the spectroscopic data. Nagelamide M (1) is a novel bromopyrrole alkaloid possessing a 2-amino-octahydropyrrolo[2,3-d]imidazole ring with a taurine unit, while nagelamide N (2) is a new bromopyrrole alkaloid possessing a 2-amino-tetrahydroimidazole-4-one ring with a taurine unit and 3-(dibromopyrrole-2-carboxamido)propanoic acid moiety. Nagelamides M (1) and N (2) exhibited antimicrobial activity.     

Synthesis and properties of PI polyamide-SAHA conjugate

We have designed and synthesized new types of pyrrole (P)-imidazole (I) polyamide conjugates 1 and 2 possessing a suberoylanilide hydroxamic acid (SAHA) moiety that is a strong inhibitor of histone deacetylase (HDAC). SAHA conjugate 2 was designed to target the promoter region of the p16 tumor suppressor gene. The DNA binding affinity of SAHA conjugate 2 to its target sequence was examined using surface plasmon resonance. HDAC inhibition activity of conjugates 1 and 2 was evaluated using a colorimetric assay. The results demonstrated that even though it possesses the relatively large SAHA moiety, conjugate 2 has high DNA sequence-specific binding properties and moderate HDAC inhibitory activity in vitro. SAHA conjugate 2 was found to cause morphological changes in HeLa cells and to induce selective Histone H3 lysine 9 acetylation.     

Rational design,synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Heat shock protein 90 (Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin (GA) is the first identified Hsp90 inhibitor that exhibited potent anti-cancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1 (C6-ethyl) and 2 (C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds 1 and 2 bind to Hsp90 protein with the IC₅₀ of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.     

Aminopyridyl derivative of thiacalix[4]arene-carboxylic acid as ionizable highly selective Ag+ ionophore

A novel mono-ionizable receptor 2 possessing three aminopyridyl and one carboxylic group in 1,3-alternate conformation based on thiacalix[4]arene, confirmed by single crystal X-ray analysis, was prepared. For competitive solvent extraction of alkali metal (Na⁺, K⁺ and Cs⁺) and some transition metal (Cu²⁺, Zn²⁺, TI⁺, Ag⁺) cations from aqueous solutions into chloroform, it was found that the introduction of proton-ionizable group (carboxylic acid moiety) into the aminopyridyl-thiacalix[4]arene derivative could further improve its Ag⁺ extractability with high selectivity.     

Design,synthesis and evaluation of novel dehydroabietic acid-dithiocarbamate hybrids as potential multi-targeted compounds for tumor cytotoxicity

In the present study, novel representatives of the important group of biologically-active, dehydroabietic acid-bearing dithiocarbamate moiety, were synthesized and characterized by ¹H NMR, ¹³C NMR, HR-MS. The in vitro antiproliferative activity evaluation (MTT) indicated that these compounds exhibited potent inhibitory activities in various cancer cell lines (HepG-2, MCF-7, HeLa, T-24, MGC-803). Particularly, compound III-b possessed extraordinary cytotoxicity with low micromolar IC₅₀ values ranging from 4.07 to 38.84 µM against tested cancer cell lines, while displayed weak cytotoxicity on two normal cell lines (LO-2 and HEK 293 T). Subsequently, the potential mechanisms of representative compound III-b were elementarily investigated by Transwell experiment, which showed III-b can inhibit cancer cells migration. Annexin-V/PI dual staining showed that the compound can induce HepG-2 cells apoptosis in a dose-dependent manner. Meanwhile this apoptosis may be related to the upregulated protein expression of cleaved-caspase 3, cleaved-caspase 9, Bax and downregulated of Bcl-2 indicated by Western Blot. Later study further confirmed that ROS levels in HepG-2 cells increased significantly with the rise of concentrations. In addition, through the network pharmacology data analyzing, the core targets and signaling pathways of compound III-b for treatment of liver neoplasms were forecasted. Molecular docking model showed that compound III-b had high affinity with hub targets (CASP3, EGFR, HSP90AA1, MAPK1, ERBB2, MDM2), suggesting that compound III-b might target the hub protein to modulate signaling activity. Taken together, these data indicated that dehydroabietic acid structural modification following the “Molecular hybridization” principle is a feasible way to discover the potential multi-targeted antitumor compounds.     

Absolute configuration of 2-methoxy-2-(2-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

2-Methoxy-2-(2-naphthyl)propionic acid 1 and 2-hydroxy-2-(2-naphthyl)propionic acid 2 were prepared by the Grignard reaction of 2-naphthylmagnesium bromide with (1R,2S,5R)-(−)-menthyl pyruvate. The absolute configurations of (+)-1 and (+)-2 were determined to be S by the ¹H NMR anisotropy method.     

Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer

Eight new water-soluble amino acid derivatives of chlorin p₆ ethers 6a-h were designed and synthesized using purpurin-18 (2) as key intermediate. All target compounds exhibited better phototoxicity than talaporfin and the most phototoxic compound 6d showed IC₅₀ values of 0.20 μmol/L against A549 cell and 0.41 μmol/L against B16-F10 cell, which represented 31- and 24-fold increase of PDT antitumor efficacy compared to talaporfin.     

Prenylated sulfonyl amides from the leaves of Glycosmis pentaphylla and their potential anti-proliferative and anti-inflammatory activities

Six previously undescribed sulfur-containing amides were isolated from the leaves of Glycosmis pentaphylla. Their structures were delineated by HRESIMS, 1D and 2D NMR, electronic circular dichroism (ECD) calculations, and DP4+ analyses based on gauge-independent atomic orbital (GIAO) NMR calculations. Compounds 1–4 belong to the type of methylsulfonylpropenoic acid amides. Through different cyclization pathways of geranyloxy, compounds 1 and 2 carry uncommon cyclohexane-1, 3-diol and cyclohex-3-en-1-ol moiety, respectively. Compound 3 is the oxidation product of the double bond Δ^{6′′(7′′)} of geranyloxy. Compound 5 is elucidated as the type of methylsulfonylpropanoic acid amide. Compound 6 represents a rare sulfur-containing amide possessing a morpholin-3-one moiety. All isolated compounds were evaluated for their anti-inflammatory and anti-proliferative activities. Compound 4 significantly inhibited lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells with the IC₅₀ value of 0.55 µM. Moreover, compounds 3 and 4 exhibited different anti-proliferative activities against HepG-2 with IC₅₀ values ??of 11.52 and 9.41 µM, respectively.     

Pseudodimorphism of the Trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic Acid Clathrates with Acetic and Propionic Acids

The versatile host compound trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid (1) forms under ambient conditions isostructural complexes with acetic and propionic acids being true clathrates without host-guest type H-bonds. A new modification of the clathrate between 1 and acetic acid (1a) is obtained at sub-room temperature (5 °C) while for preparation of the new crystal form of the clathrate with propionic acid (1b) crystallization temperature should be increased up to 50 °C. Crystal structures of the pseudodimorphs show that homo carboxylic acid dimers existing in the conventional phases are also observed here, demonstrating the new compounds to be of same clathrate type. Crystal data: for 1a: triclinic P-1, a = 8.626(2) Å, b = 9.073(2) Å, c = 12.042(2) Å, α = 76.34(3)°, β = 77.41(3)°, γ = 84.13(3)°, V = 892.5(4) ų, Z = 2, R = 0.0446 for 3171 reflections; for 1b: monoclinic C2/c, a = 13.268(3) Å, b = 12.636(3) Å, c = 21.786(4) Å, β = 90.56(3)°, V = 3652.3(14) ų, Z = 8, R = 0.0618 for 2365 reflections.     

Chemical constituents of the lichen Usnea baileyi (Stirt.) Zahlbr

Investigation of the chemical constituents of the lichen Usnea baileyi (Stirt.) Zahlbr led to the isolation of a new dimeric xanthone, bailexanthone (1), and a novel depsidone, bailesidone (2), along with twenty-five known metabolites (3–27). Their structures were established by means of extensive spectroscopic analysis and comparison with data reported in the literatures. Compound 1 derives from secalonic acid scaffold with C-8/8′ reduction and compound 2 represents the first example of menegazziaic acid derivative with an unprecedented B-ring moiety. Two new compounds 1–2 were evaluated for their cytotoxic activities against A549 (human lung carcinoma) and HT29 (human colorectal adenocarcinoma) cell lines. All of them showed weak or no activity against two cell lines.     

Conformational consequences of intramolecular cyclopropanation within small bicyclic systems. : Synthesis and desymmetrization of 1-methyltricyclo[2.2.2.02,6]Octane-3,5-dione

Diketone 3, available by cyclization of keto acid 2 with PPA/HOAc, undergoes intramolecular oxidative cyclization to 4 by exposure of its dienolate to FeCl₃ in DMF at −78 °C. Convenient monomethylenation of 4 with optical resolution to give optically pure (+) - and (−) - 12 is described.     

Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II) complexes with pyridine–pyrazole ligands: Influence of ligands’ structure on cytotoxic activity

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-phosphonic acid dimethyl ester (2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) complexes (3a–7a) as potential anticancer compounds. The molecular structures of the platinum(II) and copper(II) complexes 3a and 6a have been determined by X-ray crystallography. The cytotoxicity of the phosphonic ligand 2a and its carboxylic analog 2b as well as their complexes has been evaluated on leukemia and melanoma cell lines. Copper(II) complexes were found to be more efficient in the induction of melanoma cell death than the platinum(II) or palladium(II) complexes. Cytotoxic effectiveness of compound 7b against melanoma WM-115 cells was two times better than that of cisplatin. The reaction of compound 5b with 9-methylguanine has been studied.     

A practical total synthesis of gelastatins

The first and practical total synthesis of gelastatins 1, a novel matrix metalloproteinase inhibitor possessing antitumor activity, was accomplished in nine steps starting from Meldrum's acid.     

Stereoselective synthesis of the hydroxy amino acid moiety of Al-77-B,a gastroprotective substance from Bacillus pumilus Al-77

The hydroxy amino acid moiety of Al-77-B (1) has been prepared as its protected form 2 from the (R)-glyceric acid derivative 3 in an efficiently stereoselective manner through the direct C-acylation using diphenyl phosphorazidate and the hydroxy-directed hydrogenation.