Cyclopeptide alkaloids: stereochemistry and synthesis of the precursors of discarines C and D and myrianthine A.

The stereochemistry of discarines C (1) and D (2) and myrianthine A (3), three cyclopeptide alkaloids isolated from Discaria febrifuga, was determined by a combination of NMR studies of 1-3, enantioselective gas chromatography, and comparison of NMR data with those of synthetic tripeptides. For the synthesis of peptides, the nonproteinogenic amino acid 3-phenylserine was also obtained in its four diastereoisomeric forms (l and d threo, obtained by recrystallization of the diastereoisomeric tripeptide, and l and d erythro, obtained by a Mitsunobu reaction with the threo-tripeptides). The general synthetic strategy described in this paper allows the tripeptide to be obtained with the free N-terminal extremity protected or dimethylated. This strategy also allows the synthesis of the corresponding peptide with an imidazolidinone ring.

Absolute configuration of franganine.

The absolute configuration of franganine (1), a cyclopeptide alkaloid isolated from the methanol root bark extract of Discaria americana, was established on the basis of detailed NMR spectroscopic data and X-ray diffraction analysis of its salt (2).

New cyclopeptide alkaloid of Condalia buxifolia and the absolute stereochemistry of Condaline A.

During the course of a study of Condalia buxifolia (Rhamnaceae), one new cyclopeptide alkaloid condaline B (1), together with six known cyclopeptide alkaloids, condaline A (2), and the scutianines B (3), - D (4) and -E (5), frangulanine (6), and 3,4,28-tris-epi-scutianene N (7), were isolated from the rind bark of Condalia buxifolia. Their structures have been confirmed through spectroscopic analyses such as 1D and 2D NMR experiments. The absolute stereochemistry of condaline A (2), was elucidated by X-ray crystal structure determination of its HI salt. In addition, condaline B (1) was obtained synthetically through a structural transformation of condaline A. Meanwhile, the crude methanol extract, the basic ether fraction, and alkaloids 1-7 were tested against various strains of Gram-positive and Gram-negative bacteria and fungus, showing promising antimicrobial activity.

New cytotoxic cucurbitacins from Wilbrandia ebracteata Cogn.

Chemical investigation of the roots of Wilbrandia ebracteata Cogn. (Cucurbitaceae) led to the isolation of two new (1- 2) and four known (3- 6) cucurbitacins. Their structures were elucidated by NMR and MS and compared with related compounds. The in vitro cytotoxicity of isolated compounds was evaluated against RD, KB, HCT-8, and A549 cell lines showing strong activity.

Influence of melatonin on the order of phosphatidylcholine-based membranes.

The effect of melatonin was evaluated on three phosphatidylcholine-based membrane models. Changes in liposome dynamics were monitored by fluorescence, following the response of the probe merocyanine-540, as well as by differential scanning calorimetry (DSC). Langmuir monolayers were investigated using molecular area measurements, as well as by Brewster angle microscopy (BAM). Mica-supported bilayers were observed via atomic force microscopy (AFM). Fluorescence results demonstrating that melatonin increases the affinity between MC-540 and lipid molecules possibly because of an increase in the membrane fluidity in liposomes. DSC analyses showed that melatonin promoted a reduction in enthalpy in the lipid nonpolar chains. Melatonin also promoted an increase in the molecular area of Langmuir monolayers, as well as a decrease in membrane thickness. Consequently, melatonin appeared to induce re-ordering effects in liposome and Langmuir monolayers. AFM images of bilayers immobilized on mica suggested that melatonin induced a gel state predominance or a delay in the main phase transition. At experimental conditions, melatonin interacted actively with all membranes models tested and induced changes in their physico-chemical properties. The data presented here may contribute to the understanding of melatonin physiologic properties, as well as the development of therapeutic advanced systems, such as drug delivery systems and biosensors.

In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B.

Lung cancer is the most deadly type of cancer in humans, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer showing high resistance to radiation and chemotherapy. Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task. Here we describe a new semisynthetic derivative of cucurbitacin B (DACE) as a potent inhibitor of NSCLC cell proliferation. DACE arrested the cell cycle of lung epithelial cells at the G2/M phase and induced cell apoptosis by interfering with EGFR activation and its downstream signaling, including AKT, ERK, and STAT3. Consistent with our in vitro studies, intraperitoneal application of DACE significantly suppressed the growth of mouse NSCLC that arises from type II alveolar pneumocytes due to constitutive expression of a human oncogenic c-RAF kinase (c-RAF-1-BxB) transgene in these cells. Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.

Multivariate SAR and QSAR of cucurbitacin derivatives as cytotoxic compounds in a human lung adenocarcinoma cell line.

This article describes structure-activity relationship (SAR/QSAR) studies on the cytotoxic activity in a human lung adenocarcinoma cell line (A549) of 43 cucurbitacin derivatives. Modeling was performed using the methods partial least squares with discriminant analysis (PLS-DA) and PLS. For both studies, the variables were selected using the ordered predictor selection (OPS) algorithm. The SAR study demonstrated that the presence or absence of cytotoxic activity of the cucurbitacins could be described using information derived from their chemical structures. The QSAR study displayed suitable internal and external predictivity, and the selected descriptors indicated that the observed activity might be related to electrophilic attack on cellular structures or genetic material. This study provides improves the understanding of the cytotoxic activity of cucurbitacins and could be used to propose new cytotoxic agents.