Attempts to prepare aromatic O-acyl-hydroxylamines—I : Dehydrohalogenation of 1-bromo-4-acetoxyimino-1,2,3,4-tetrahydrophenanthrene by tetramethylammonium dimethylphosphate

The dehydrohalogenation of 1-bromo-4-acetoxyimino-1,2,3,4-tetrahydrophenanthrene by tetramethylammonium dimethylphosphate gave a mixture of products. Ten of these were identified and together account for 70% of the total yield. The proposed reaction mechanism implicates the corresponding O-acetyl-hydroxylamine 15 as an intermediate. Attempts to prepare O-esters or O-ethers of aromatic hydroxylamines by dehydrogenation, with quinones, of the corresponding oximino-derivatives of oxo-1,2,3,4-tetrahydro-naphthalene and oxo-1,2,3,4-tetrahydro-phenanthrene were without success.     

Synthesis and HIV-1 integrase inhibition of novel bis- or tetra-coumarin analogues

Present studies were undertaken on the preparation of synthetic analogues of bis- or tetra-coumarins and their activity against HIV-1 integrase (HIV-1 IN). Among these coumarin analogues, compounds 14, 16 and 18 were found to be potent molecules against HIV-1 IN at IC50 values of 0.96, 0.58, and 0.49 microM, respectively. The results provided a tool for guiding the further design of more potent antiviral agents and for predicting the affinity of related compounds.     

Mass spectrometric fragmentation of some lignans

Mass spectra of some lignans containing either γ-butyrolactone, 1,2,3,4-tetrahydro-naphthalene or the 3,7-dioxabicyclo[3. 3. 0]octane ring systems are reported. Probable structures are presented for the more abundant ions in the mass spectra of these lignans.     

Controlled Multi‐functionalization Facilitates Targeted Delivery of Nanoparticles to Cancer Cells

A major objective of nanomedicine is to combine in a controlled manner multiple functional entities into a single nanoscale device to target particles with great spatial precision, thereby increasing the selectivity and potency of therapeutic drugs. A multifunctional nanoparticle is described for controlled conjugation of a cytotoxic drug, a cancer cell targeting ligand, and an imaging moiety. The approach is based on the chemical synthesis of polyethylene glycol that at one end is modified by a thioctic acid for controlled attachment to a gold core. The other end of the PEG polymers is modified by a hydrazine, amine, or dibenzocyclooctynol moiety for conjugation with functional entities having a ketone, activated ester, or azide moiety, respectively. The conjugation approach allowed the controlled attachment of doxorubicin through an acid‐labile hydrazone linkage, an Alexa Fluor dye through an amide bond, and a glycan‐based ligand for the cell surface receptor CD22 of B‐cells using strain promoted azide‐alkyne cycloaddition. The incorporation of the ligand for CD22 led to rapid entry of the nanoparticle by receptor‐mediated endocytosis. Covalent attachment of doxorubicin via hydrazone linkage caused pH‐responsive intracellular release of doxorubicin and significantly enhanced the cytotoxicity of nanoparticles. A remarkable 60‐fold enhancement in cytotoxicity of CD22 (+) lymphoma cells was observed compared to non‐ targeted nanoparticles.     

Synthesis and antitumor evaluation of symmetrical 1,5-diamidoanthraquinone derivatives as compared to their disubstituted homologues

A series of symmetrical 1,5-diamidoanthraquinone derivatives with potentially bioreducible groups has been synthesized and their cytostatic activity against the panel of various cancer cell lines in vitro has been studied. Preliminary structure-activity relationships were established. The results indicated that compounds 5 and 18 exhibited significant potent cytotoxicity at 1.24-1.75 microM for Hepa G2 cell line; compounds 5, 16, and 18 exhibited cytotoxicity at 0.14-1.82 microM for 2.2.15 cell line as determined by XTT colorimetric assay. Two structurally related compounds, mitoxantrone and adriamycin, were tested in parallel as positive controls. In addition, it was found that compounds 5 and 18 were a more potent and specific human hepatoma cell line than mitoxantrone and showed comparable activity to adriamycin. Among them, compound 18 was the most potent for 2.2.15 cells. We have demonstrated that the anthraquinone moiety is essential for activity and that less sterically hindered substituents contribute to enhanced in vitro efficacy. Implications for amidoanthraquinone cytotoxicity as potential anticancer agents are discussed. We further delineate the nature of the pharmacophore for this class of compounds, which provides a rational basis for the structure-activity relationships.     

Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.     

Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.     

Synthesis and evaluation of novel aza-caged Garcinia xanthones

Inspired by the therapeutic potential of the simplified caged xanthones, we have developed a chemical strategy for synthesizing novel aza-caged Garcinia analogues through a regioselective Claisen/Diels-Alder cascade reaction. The origin of regioselectivity has been explained using the DFT method. We have further evaluated the cell proliferation and IKKβ inhibitory activities of these compounds and studied their binding mode with IKKβ by molecular docking. The results suggested that the aza-caged scaffold provides a suitable modification site and the introduction of a hydrophobic moiety leads to improvement in the cytotoxicity and IKKβ inhibitory activity. The aza-caged compound 6c exhibited an IC(50) value of 2.68, 2.10, 8.02 μM against the HepG2, A549 cells and IKKβ, respectively. Mechanism studies with 6c showed that the aza-caged compounds induce apoptosis and cell cycle S phase arrest in A549 cells.     

New 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidinium alkaloids (phloeodictynes) from the New Caledonian shallow-water haplosclerid sponge Oceanapia fistulosa. Structural elucidation from mainly LC-tandem-MS-soft-ionization techniques and discovery of antiplasmodial activity

We report here on new 6-hydroxy-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidinium alkaloids, belonging to the phloeodictyne family, isolated from the haplosclerid sponge Oceanapia[=Phloeodictyon]fistulosa(Bowerbank, 1873) from New Caledonian shallow waters. Online LC-ESI-MS analysis, coupled to tandem fragmentation experiments on the crude alkaloid mixture, allowed us to clarify their flat structures, including structural isomers. At least 25 different components, of which 17 are new members with variable terminus and length chains, were characterised, besides less abundant analogues bearing a thioethylguanidine side chain. Crude mixtures and HPLC enriched fractions proved active against chloroquine-resistant Plasmodium falciparum, with IC(50) values ranging from 0.6 to 6 microM, while cytotoxicity against human A-549 cell line was low. This makes these alkaloids a good prospect as leads for novel antimalarial agents.     

Depigmenting activity and low cytotoxicity of alkoxy benzoates or alkoxy cinnamte in cultured melanocytes

To obtain effective and safe topical depigmenting agents, we synthesized hydroxybenzoates, alkoxybenzoates, and 3,4,5-trimethoxycinnamate containing a thymol moiety and screened then for high-level inhibitory activity against melanin synthesis in cultured melanocytes. Eight compounds were tested for their depigmenting effect and cytotoxicity using a murine melanocyte cell line. We found that 3,4,5-trialkoxybenzoates and 3,4,5-trimethoxycinnamate, synthesized by conjugating 3,4,5-trialkoxybenzoic acids and 3,4,5-trimethoxycinnmic acid with thymol, showed a potent depigmenting effect and low cytotoxicity. Compound 4h, 5-methyl-2-(methylethyl)phenyl (2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoate, showed the most potent depigmenting effect (IC50=10 microM) with low cytotoxicity (IC50=200 microM).     

Isolation, biological significance, synthesis, and cytotoxic evaluation of new natural parathiosteroids A-C and analogues from the soft coral Paragorgia sp

Three unusual new steroid thioesters, parathiosteroids A-C (1a-3a), were isolated from the 2-propanol extract of the soft coral Paragorgia sp. collected in Madagascar. Their structures, determined by detailed spectroscopic analysis, were confirmed by synthesis and represent the first isolation of natural steroids bearing a C22 thioester in their side chain. These compounds displayed cytotoxicity against a panel of three human tumor cell lines at the micromolar level. The preparation of several analogues revealed structure/activity relationships in this type of steroids, for example, that the XCH2CH2NHCOCH3 moiety (X = S, O, NH) in the side chain is essential for the antiproliferative activity, and a low degree of oxidation in the A-ring results in higher bioactivity. These natural products could be biosynthetic intermediates in the steroid side chain degradation pathway involving activation with CoA and beta-oxidations.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

Macrolide Analogues of the Novel Immunosuppressant Sanglifehrin: New Application of the Ring-Closing Metathesis Reaction

Macrocycles containing a conjugated 1,3-diene moiety have been synthesized for the first time in good yields by the ring-closing metathesis reaction [Eq. (1)]. The new compounds represent cyclophilin-binding, simplified analogues of the macrocyclic core of sanglifehrin A, an immunosuppressant which binds with high affinity to cyclophilin.     

A Novel RP-LC Method for Determination of pK a Values of Some Anticancer Agents and Their Assay

A simple, reliable, and rapid RP-LC method has been developed for the determination of some anticancer drugs (daunorubicin, doxorubicin and vincristine sulfate) in their dosage forms and human urine. These compounds are well separated on a C18 column using the mobile phase consisting of a mixture of acetonitrile (50:50; v/v) at a flow rate of 1.5 mL min^?1. The analyte peaks were detected at 235 nm for doxorubicin and daunorubicin, and 220 nm for vincristine. Linearity was obtained in different concentration ranges between 0.10 and 12 μg mL^?1 for all compounds. Good sensitivity for all analytes was observed with DAD detection. LOD and LOQ of the method were found satisfying. The proposed method has been extensively validated in accordance with ICH guidelines and obtained results proved that the proposed method was precise, accurate, selective, and sensitive for simultaneous analysis of studied compounds. All analytical procedures including sample preparation, flow rate, and run time were at low levels. Also, pK _a values were determined using the dependence of the retention factor on the pH of the mobile phase. The effect of the mobile phase composition on the ionization constant was studied by measuring the pK _a at different methanol–water mixtures, ranging between 45 and 60 % (v/v).     

柔红霉素和阿霉素自旋标记衍生物的合成与抗肿瘤活性

合成了5个新的柔红霉素及阿霉素的氮氧自由基自旋标记衍生物(5_9),经元素分析,IR,MS和ESR分析确证了其组成和结构,并对它们进行了抑制小鼠白血病P388、小鼠黑色素癌B16、人胃腺癌MGC和人肝癌SMMC7721细胞的体外筛选.初步药理试验表明,化合物5_9对4种瘤株均有一定的抑制活性,其中化合物9的活性与阿霉素相当.     

Alkylation of Potassium 1-(N-Benzyloxycarbonylamino)alkylphosphonates and Phosphinates in the Presence of 18-Crown-6

During past several years we have been engaged in the synthesis of phosphono peptides, peptide analogues with phosphonic acid replacing C-terminal or N-terminal carboxylate moiety. These compounds are of interest not only because of their promise of direct practical applications^1,2 but also as a source of information about mechanisms of enzymatic reactions. ^1,3–5 Esters of N-blocked 1 -aminoalkylphosphonic and phosphinic acids are popularly used as starting substrates in multistep syntheses of phosphono peptides.^6–9 Although several methods for their preparation have been described ^6,10–13 the search for the new and useful methods of their synthesis is still in progress. In this paper we report that the use of complexes of potassium 1-(N- benzyloxycarbonylamiuo)alkylphosphonates and phosphates with 18-crown-6 as nucleophiles in the reaction with alkyl halides afforded the desired esters in good yields.     

Using a differential refractive index detector as a pressure transducer for online viscometry in exclusion chromatography

A macrocyclic glycopeptide, ristocetin A, was used as chiral stationary phase for the high-performance liquid chromatographic separation of enantiomers of 28 unnatural amino acids, such as analogues of phenylalanine, tyrosine and tryptophan, and analogues containing 1,2,3,4-tetrahydroisoquinoline, tetraline or 1,2,3,4-tetrahydro-2-carboline skeletons. Excellent resolutions were achieved for most of the investigated compounds by using reversed-phase or a new polar-organic mobile phase system. The conditions of separation were optimized by variation of the mobile phase composition, temperature and flow-rate.     

Total synthesis and biological evaluation of nannocystin analogues modified at the polyketide phenyl moiety

Total synthesis of a focused set of 10 nannocystin analogues 3a–3j modified at the polyketide phenyl moiety was reported. These compounds were evaluated against three cancer cell lines. Compared with the naturally occurring congener 3a, the other synthetic variants either preserved or lose antiproliferative activity at varying degrees. Moreover, the potent analogues also displayed comparable levels of cytotoxicity toward two normal cell lines.     

Synthesis of bridged aza-rebeccamycin analogues

The syntheses of rebeccamycin analogues possessing a 7-azaindole moiety instead of an indole unit, and with both indole and azaindole moieties linked to the carbohydrate are described. In these bridged aza compounds, the oxygen of the pyranose heterocycle is oriented towards either the indole, or the azaindole unit. In these series, compounds bearing a free imide nitrogen were synthesized by coupling the corresponding aglycones with a sugar pre-tosylated in 2-position via a Mitsunobu reaction. To obtain a precursor for bridged aza-rebeccamycin analogues substituted in 6-position on the sugar moiety, a 2,6-ditosylated sugar was used.     

Synthesis of benzophenone-containing analogues of phosphatidylcholine

As part of a collaborative study of cellular efflux of cholesterol and phospholipids, photoactivable analogues 4-8 of phosphatidylcholine (PC) having benzophenone groups in the choline moiety and at the end of the C2 and C1 alkyl chains have been synthesized. The efficient preparation via Suzuki coupling of the appropriate long-chain benzophenone-containing carboxylic acid and alcohol and their incorporation by adaptation of known approaches into the acyl- and ether-linked PC analogues 6-8 are described. Development of a method for radiolabeling these PC analogues, via hydrogenation of a double bond in modified side chains, is also described.