Activity of resveratrol triesters against primary acute lymphoblastic leukemia cells.

Resveratrol is a common polyphenol of plant origin known for its cancer prevention and other properties. Its wider application is limited due to poor water solubility, low stability, and weak bioavailability. To overcome these limitations, a series of 13 novel resveratrol triesters were synthesized previously. In this paper, we describe the synthesis of 3 additional derivatives and the activity of all 16 against primary acute lymphoblastic leukemia cells. Of these, 3 compounds were more potent than resveratrol (IC50=10.5µM) namely: resveratryl triacetate (IC50=3.4µM), resveratryl triisobutyrate (IC50=5.1µM), and resveratryl triisovalerate (IC50=4.9µM); all other derivatives had IC50 values of >10µM. Further studies indicated that the active compounds caused G1 phase arrest, increased expression of p53, and induced characteristics of apoptotic cell death. Moreover, the compounds were only effective in cycling cells, with cells arrested in G1 phase being refractory.

Double helix quinine-based supergelator.

10,11-Didehydroquinine is a simple, low molecular weight supergelator which forms, in nonpolar media, stable chiral organogels composed of unique double-helix nano-sized fibers. A novel gelation mechanism involves a hydrogen bonding network formed by an acidic alkyne proton of the Cinchona gelator and the carbonyl group of ethyl acetate used as a solvent.

Synthesis and anticancer activity of some 5-fluoro-2'-deoxyuridine phosphoramidates.

Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-O-(t-butoxycarbonyl)-5-fluoro-2'-deoxyuridine (3'-BOC-FdU) (9a-9j) and 5-fluoro-2'-deoxyuridine (FdU) (10a-10j) were synthesized by means of phosphorylation of 3'-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a-9j were converted to the corresponding 10a-10j by removal of the 3'-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a-9j and 10a-10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a-10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.

Role of Fisetin in Selected Malignant Neoplasms in Women.

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.

Synthesis of 3'-azido-3'-deoxythymidine (AZT)--Cinchona alkaloid conjugates via click chemistry: Toward novel fluorescent markers and cytostatic agents.

Novel nucleoside-Cinchona alkaloid conjugates were synthesized using 'click' chemistry approach based on the copper(I) catalyzed Huisgen azide-alkyne cycloaddition. Two series of conjugates were prepared employing 3'-azido-3'-deoxythymidine (AZT) as the azide component and the four 10,11-didehydro Cinchona alkaloids as well as their 9-O-propargyl ethers as the alkyne components. All obtained conjugates showed strong fluorescence emission and some of them exhibited marked cytotoxic activity in vitro.

Novel Pirkle-type quinine 3,5-dinitrophenylcarbamate chiral stationary phase implementing click chemistry.

A new Pirkle-anion exchange hybrid-type chiral stationary phase (CSP-1) has been synthesized by immobilizing 10,11-didehydroquinine 3,5-dinitrophenylcarbamate onto 3-azidopropyl silica gel using click chemistry (1,3-dipolar Huisgen cycloaddition). This chiral selector and CSP contain a strong π-accepting 3,5-dinitrophenyl residue besides the π-basic quinoline group and an ionizable tertiary amino group. In concert with ion pairing it offers π-donor-π-acceptor interactions resulting in an enhancement of the selectivity toward specific π-donating analytes such as aryloxypropionic acids and profens. A representative set of these analytes has been investigated under various chromatographic conditions (polar-organic, reversed- and normal-phase) leading to base-line enantioseparations with selectivity (α) values up to 1.8. Control experiments with related quinine tert-butylcarbamate phase grafted onto the surface either by thioether (Chiralpak QN-AX) or 1,2,3-triazole linker revealed the impact of the additional aromatic moiety in the chiral selector motif.

Unexpected enantioseparation of mandelic acids and their derivatives on 1,2,3-triazolo-linked quinine tert-butyl carbamate anion exchange-type chiral stationary phase.

Replacement of the flexible thioether linker for the novel, rigid 1,2,3-triazole spacer group in the course of immobilization of quinine tert-butyl carbamate onto a silica surface led to a chiral stationary phase (CSP) with enhanced enantioselectivity for the resolution of mandelic acid and derivatives thereof. These new CSPs allowed efficient resolution of a wide set of mandelic acids with α-values between 1.08 and 1.68. The high loadability of these chiral ion exchange type CSPs allows preparative separation in the milligram range on an analytical column of 100×4 mm id in a single run as it was demonstrated for 4-trifluoromethylmandelic, 2-naphthylglycolic and 3,4-methylenedioxymandelic acids. The chiral recognition process has been studied using a library of 25 diverse racemic probes. A tentative model suggests that the rigid 1,2,3-triazole group takes part in the formation of an enantioselective-binding pocket of the entire and immobilized selector moiety of the CSP. The primary interaction site is given by the ionizable quinuclidine group of the Cinchona alkaloid supported by possible π-π stabilization effects within the selector-selectand complex.

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives.

A series of 27 cinchona alkaloid derivatives (1f-w, 2a-e and 3a-d) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF-7, A-549, Hep-G2, U-87 and HL-60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds (1u, 1w, 2e and 3d) were identified with promising cytotoxic activity with 50% growth inhibition (GI50 ) values below 10 µM. Two (2e and 3d) of the four compounds also exhibited potent anti-trypanosomal activity with GI50 values of 0.3-0.4 µM. All four active compounds represented derivatives modified at their C-9 hydroxy group. With respect to anti-proliferative activity and selectivity, 2e (epi-N-quinidyl-N'-bis(3,5-trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u, 1w, 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti-cancer and anti-trypanosome drug candidates.

In vitro antimicrobial activity of extracts and compounds isolated from Cladonia uncialis.

Heptane (Hep), diethyl ether (Et2O), acetone (Me2CO) and methanolic (MeOH) extracts, as well as (-)-usnic acid and squamatic acid, were obtained from thallus of Cladonia uncialis (Cladoniaceae). The antimicrobial activities of these extracts, (-)-usnic acid and squamatic acid, were tested against reference strains: Staphylococcus aureus, Escherichia coli and Candida albicans. In addition, Me2CO extract was analysed against 10 strains of Methicillin-resistant S. aureus (MRSA) isolated from patients. All extracts exerted antibacterial activity against the reference strain S. aureus, comparably to chloramphenicol [minimum inhibitory concentration (MIC) = 5.0 µg/mL]. The Me2CO extract exhibited the strongest activity against S. aureus (MIC = 0.5 µg/mL), higher than (-)-usnic acid, whereas squamatic acid proved inactive. The Me2CO extract showed potent antimicrobial activity against MRSA (MIC 2.5-7.5 µg/mL). Also no activity of C. uncialis extracts against E. coli and C. albicans was observed.

Antiproliferative Activity of Polyether Antibiotic--Cinchona Alkaloid Conjugates Obtained via Click Chemistry.

A series of eight new conjugates of salinomycin or monensin and Cinchona alkaloids were obtained by the Cu(I)-catalysed 1,3-dipolar Huisgen cycloaddition (click chemistry) of respective N-propargyl amides of salinomycin or monensin with four different Cinchona alkaloid derived azides. In vitro antiproliferative activity of these conjugates evaluated against three cancer cell lines (LoVo, LoVo/DX, HepG2) showed that four of the compounds exhibited high antiproliferative activity (IC50 below 3.00 µm) and appeared to be less toxic and more selective against normal cells than two standard anticancer drugs.

Folding of aromatic oligoimides of trans-1,2-diaminocyclohexane.

Chiral oligomeric diimides prepared from pyromellitic dianhydride, (R,R)-1,2-diaminocyclohexane and phthalic anhydride fold into M or P helical conformers; trimer 1 folds into the P conformer in the crystal but the M conformer dominates in solution; longer chain oligomers 2 and 3 form preferentially P conformers in solution, as a result of intermolecular interactions.

Synthesis of novel 2',3'-didehydro-2',3'-dideoxyinosine phosphoramidate prodrugs and evaluation of their anticancer activity.

An efficient synthesis of 4-chlorophenyl N-alkyl phosphoramidates of 2 ',3 '-didehydro-2 ',3 '-dideoxyinosine employing 4-chlorophenyl phosphoroditetrazolide as a phosphorylating agent is reported. Improved method for the synthesis of 2 ',3 '-didehydro-2 ',3 '-dideoxyinosine starting from inosine is also described. The synthesized phosphoramidates 11-18 were examined for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB), and breast (MCF-7) employing sulforhodamine B assay. The highest activity in all investigated cancer cell lines was displayed by phosphoramidate 13 with N-n-propyl substituent.

Triazolo-linked cinchona alkaloid carbamate anion exchange-type chiral stationary phases: Synthesis by click chemistry and evaluation.

Immobilization strategy based on Huisgen 1,3-dipolar cycloaddition (click chemistry) of 10,11-didehydrocinchona tert-butylcarbamates to azido-grafted silica gels has been evaluated for preparation of novel chiral stationary phases (CSP 1-3). The resultant 1,2,3-triazole-linked CSPs were tested under various mobile phase conditions (polar organic and reversed phase mode) with a representative set of structurally diverse racemic acids including N-protected aminoacids, aromatic and aryloxycarboxylic acids as well as binaphthol phosphate. The chiral recognition performance of the C3-triazole-linked CSPs was found to mirror largely that of the known C3-thioether-linked CSP in terms of elution order, enantioselectivity and retention behavior. In an effort to assess the non-specific binding expressed as retention increment of these triazole-linked CSPs, the parent azidopropyl- and triazole-modified silica materials (thus not containing the chiral head ligand) were studied independently. Compared with the corresponding CSPs, the analyte retention on the azidopropyl control column was very low, and practically negligible on the corresponding triazole-modified reference column. Only minor losses in analyte retention behavior (<5%) were observed with triazole-linked CSPs after two month of continuous use with polar-organic and reversed-phase-type mobile phases, highlighting the excellent stability of the 1,2,3-triazole linker.

An improved synthesis of 10,11-didehydro Cinchona alkaloids.

A revised procedure for the conversion of the four major Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) into their respective 10,11-didehydro derivatives is described. The reported protocol offers several advantages over a recently published synthetic route. These include (i) enhanced robustness (ii) ready scalability (iii) reduced operational complexity and number of steps (iv) chromatography-free work-up. In addition, toxic solvents were replaced by environmentally less problematic alternatives.

Structure and unexpected chiroptical properties of chiral 4-pyrrolidinyl substituted 2(5H)-furanones.

Planar 2(5H)-furanones substituted at C4 with a chiral pyrrolidinyl group show CD spectra which are apparently due to the distortion of the C4-N1 bond of sp2 character from the plane defined by the 2(5H)-furanone ring atoms and/or due to the presence of substituents in the pyrrolidine ring. This is a new, previously not encountered structural factor determining the chiroptical properties of 2(5H)-furanones and emerging from the analysis of X-ray diffraction data and quantum mechanical DFT computations. In the presence of a C5 pseudoaxial substituent in the furanone ring, the sign of the furanone n-pi* and pi-pi* transition Cotton effects is determined primarily by the previously postulated allylic helicity rule.