SP94 Peptide-Functionalized PEG-PLGA Nanoparticle Loading with Cryptotanshinone for Targeting Therapy of Hepatocellular Carcinoma.

To achieve improved drug delivery efficiency to hepatocellular carcinoma (HCC), biodegradable poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP), surface-modified with SP94 peptide, were designed for the efficient delivery of cryptotanshinone to the tumor for the treatment of HCC. Cryptotanshinone NP and SP94-NP were prepared by using nanoprecipitation. The physicochemical and pharmaceutical properties of the NP and SP94-NP were characterized, and the release kinetics suggested that both NP and SP94-NP provided continuous, slow release of cryptotanshinone for 48 h. The in vitro cellular experiment demonstrated that SP94-NP significantly enhanced the cellular uptake of cryptotanshinone and induced high cytotoxicity and cellular apoptosis of hepatocellular carcinoma (HepG2) cells. The in vivo detecting results of targeting effect using the Cy5.5 probe evidenced that SP94-NP showed an accumulation in tumor more efficiently than that of unconjugated ones. Meanwhile, SP94-NP exhibited the smallest tumor size than other groups and showed no toxicity to body. The results of this study provide a promising nanoplatform for the targeting of HCC.

Novel nitric oxide-releasing derivatives of triptolide as antitumor and anti-inflammatory agents: Design, synthesis, biological evaluation, and nitric oxide release studies.

A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD50 = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study.

Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide.

Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure-activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues.

Synthesis of highly functionalized 9,10-phenanthrenequinones by oxidative coupling using MoCl5.

The strong oxidative power of molybdenum pentachloride gives rise to an efficient oxidative C-C bond formation of benzil derivatives to the corresponding 9,10-phenanthrenequinones. A highly complementary method to previous approaches was developed. The required derivatives are accessible in a modular fashion and in excellent yields. By this approach the orchid-derived natural product cypripediquinone A was synthesized for the first time.

A novel protocol for the preparation of sodium tanshinone sulphonates by direct ultrasound-assisted sulphonation of the crude extract of the roots of Salvia miltiorrhiza Bunge and following counter-current chromatography purification.

INTRODUCTION: Sodium tanshinone sulphonates are water-soluble derivatives of tanshinones originated from Tanshen (or Danshen, Salvia miltiorrhiza Bunge), a famous Traditional Chinese Medicine, which have potent biological activities, especially in the treatment of cardiovascular disorders. However, the classical preparation processes of sodium tanshinone sulphonates often involve multiple time- and solvent-consuming steps after purification of tanshinones, resulting in relatively low yields. OBJECTIVE: To develop a simple protocol for direct preparation of sodium tanshinone sulphonates from the complex crude extract of the roots of S. miltiorrhiza without pre-purification of tanshinones. METHODOLOGY: The 100 mg crude tanshinone extract of S. miltiorrhiza was first sulphonated in a ultrasound bath with glacial acetic acid, acetic anhydride and concentrated sulphuric acid for 20 min, and then subjected to counter-current chromatography (CCC) separation using a optimum two-phase solvent system composed of n-hexane:ethylacetate:ethanol:5% sodium chloride aqueous solution (1:8:4:10, v/v). Based on the UV detection and HPLC analyses, the sulphonated fractions were collected. RESULT: Sodium tanshinone IIA sulphonate (7.1 mg) and sodium tanshinone I sulphonate (2.8 mg) with over 95% purity were obtained successfully for the first time by ultrasound-assisted sulphonation and following CCC purification. CONCLUSION: The study has shown that the method combining ultrasound-assisted sulphonation and CCC purification is an efficient way to prepare tanshinone sulphonates without pre-purification of tanshinones from the complex extracts of Tanshen, and can be explored as a new protocol for wide natural product modification directly from a crude complex extracts without pre-purification.

Biosynthesis, total syntheses, and antitumor activity of tanshinones and their analogs as potential therapeutic agents.

Tanshinones are a series of abietane diterpenes, isolated exclusively from Salvia miltiorrhiza and related species. More than 40 tanshinones and their analogs have been isolated since the 1930s. Their biosynthetic pathway correlates with the MEP/DOXP pathway, and many key enzymes, such as mCPS, are responsible for establishing their molecular scaffolds and stereospecificity. Because of their unique structural characteristics and promising biological activities, total syntheses of various tanshinones have attracted the interest of many synthetic chemists, including R. H. Thomson, H. Kakisawa, R. L. Danheiser, Y. Inouye and J. K. Snyder. Tanshinones and their analogs exhibit interesting and broad antitumor activity in various cell and animal models. Most recently, the tanshinone analog neo-tanshinlactone has shown potent and selective activity against breast cancer. This review will discuss the biosynthesis, total syntheses, and antitumor activities of tanshinones,especially neo-tanshinlactone and its analogs.

A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway.

A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth.

Total synthesis of aristolactams via a one-pot suzuki-miyaura coupling/aldol condensation cascade reaction.

A direct one-pot synthesis of phenanthrene lactams, which employs a Suzuki-Miyaura coupling/aldol condensation cascade reaction of isoindolin-1-one with 2-formylphenylboronic acid, has been developed. The approach is used to efficiently produce a number of natural aristolactams, such as aristolactam BII (cepharanone B), aristolactam BIII, aristolactam FI (piperolactam A), N-methyl piperolactam A, and sauristolactam.

Total synthesis of (+/-)-hasubanonine.

[reaction: see text] Total synthesis of the alkaloid (+/-)-hasubanonine is described. A key feature of the route is generation of a phenanthrene intermediate via a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence. Conversion of the phenanthrene into the target molecule required six steps including dearomatization by means of oxidative phenolic coupling, anionic oxy-Cope rearrangement, and a final acid-promoted cyclization. Production of an undesired rearranged product in the last step could be suppressed by moderating the acid strength.

Dihydrophenanthrenes from Bletilla formosana.

Three new dihydrophenanthrenes, 4-methoxy-9,10-dihydrophenanthrene-1,2,7-triol (1), 1-(4-hydroxybenzyl)-4,7-dimethoxy-9,10-dihydrophenanthrene-2-ol (2), and 1,3,6-tri(4-hydroxybenzyl)-4-methoxydihydrophenanthrene-2,7-diol (3) together with seven known phenanthrene derivatives, six known flavonoids, a bibenzyl and three phenolic compounds were isolated from the whole plant of Bletilla formosana. Their structures were elucidated by spectroscopic, mainly 2D NMR spectrometry and chemical methods.

Syntheses of ficuseptine, juliprosine, and juliprosopine by biomimetic intramolecular Chichibabin pyridine syntheses.

[structure: see text] Biomimetic intramolecular Chichibabin pyridine syntheses using two molecules of an aldehyde and 4-aminobutanal dimethyl acetal (6) proceed efficiently in AcOH at 95 degrees C to give 2,3-dihydro-1H-indolizinium salts. Reaction occurs at 25 degrees C if 1-pyrroline (5) is used instead of 6. This reaction has been used for a one-step synthesis of ficuseptine (1) and the first syntheses of juliprosine (2) and juliprosopine (17t), which is now assigned as the trans stereoisomer.

Semisynthesis of rosmanol and its derivatives. Easy access to abietatriene diterpenes isolated from the genus Salvia with biological activities.

The known diterpenes rosmanol (3), rosmaquinone (4), 7-methoxyrosmanol (5), 7-ethoxyrosmanol (6), galdosol (7), and epirosmanol (8) have been obtained by partial synthesis from carnosol (2), an abundant natural product present in Salvia species. The physical and spectroscopic data of these semisynthetic diterpenes were identical to those of authentic natural samples and with data reported in the literature. These abietane diterpenes have very interesting biological activities and are present in the genus Salviain low quantities; thus, the semisynthetic approach described here represents an efficient alternative method to obtain these compounds. Additionally, the known diterpene 16-hydroxyrosmanol (10) and a new aromatic diterpene 11 were obtained from 16-hydroxycarnosol (9) by reaction with Ph3P/NBS in CH2Cl2. The structure of the new compound 11 was established from its spectroscopic data as 12,16-epoxycarnosol.

Preparation and in vitro evaluation of solid dispersions of halofantrine.

The low aqueous solubility of halofantrine (HF) and its low bioavailability from commercially available tablets (Halfan) suggested the formulation of solid dispersions (SDs) of HF to reduce its particle size and improve its wettability and aqueous solubility. Preformulation studies involved the development of a high performance liquid chromatography (HPLC) method for the analysis of HF. In addition, solubility studies were conducted on HF in aqueous solutions containing different concentrations of various carriers. Formulation studies included the preparation of SDs and physical mixtures (PMs) of HF with different carriers and their physicochemical characterization using differential scanning calorimetry (DSC), Fourier-Transform infra-red (FT-IR) spectroscopy and dissolution studies. A 3-month stability study at elevated temperatures was conducted on representative SDs of HF with selected carriers.

Toxicity evaluation of natural and synthetic phenanthrenes in aquatic systems.

Seven natural 9,10-dihydrophenanthrenes were isolated from the common reed Juncus effusus by means of chromatographic processes and identified by spectroscopic means. Furthermore, mimics of natural isolated compounds were synthesized to try to evaluate the influence of functional groups on the dihydrophenanthrene skeleton. Syntheses of compounds were based on the cross-coupling of 1-(2-iodo-5-methoxy)phenyl-ethanol with variously substituted iodobenzenes by zerovalent nickel. All the chemicals were tested to evaluate their effects on freshwater organisms from different trophic levels. Toxicity tests were performed on reducers (the bacterium Escherichia coli); producers (the alga Raphidocelis subcapitata, previously known as Selenastrum capricornutum); and consumers including a rotifer (Brachionus calyciflorus), a cladoceran (Daphnia pulex), and an anostracan (Thamnocephalus platyurus). Results suggested no one organism was uniquely sensitive to the chemicals tested. Toxicity depended on the kind and position of substituents on the aromatic skeleton.

New potential antimalarial agents: synthesis and biological activities of original diaza-analogs of phenanthrene.

Several diaza-analogs of phenanthrene derived from 3-amino, 5-amino, 6-amino, 8-aminoquinolines, and 5-aminoisoquinoline were prepared to evaluate their antiplasmodial activities. All compounds showed mild to good activitiy in vitro, both on a Nigerian chloroquino-sensitive strain and on the chloroquino-resistant FcB1-Columbia and FcM29 strains. The position of the intracyclic nitrogen atom is shown to be crucial for the activities (best results are obtained with a 1,10-phenanthroline skeleton). In regard to the particular properties of this structure (metalloprotease inhibition activitiy by chelating divalent metal ions), the potential chelating site of the molecule was blocked. In this case, the biological activity of the compound was greatly enhanced, showing that the mechanism of action of such a compound is probably not correlated to metalloprotease inhibition activity.

Effects of tanshinone VI derivatives on post-hypoxic contractile dysfunction of perfused rat hearts.

The present study was undertaken to elucidate the effects of sodium tanshinone VI 1-phenolate (1), 1'-O-hydrogen succinyltanshinone VI 1-O-hydrogen succinate (2), and disodium 1'-O-succinyltanshinone VI 1-O-succinate (3), water-soluble derivatives of tanshinone VI, on post-hypoxic contractile recovery of isolated perfused rat hearts. The effects were compared with those of tanshinone VI as tested previously. The hearts were perfused for 20 min under hypoxic conditions, followed by 45 min reoxygenation, and their cardiac performance was determined. Changes in tissue sodium, potassium, calcium, and magnesium contents after reoxygenation, and release of creatine kinase and purines and bases (ATP metabolites) during hypoxia/reoxygenation were also examined. The derivatives were dissolved in a Krebs-Henseleit buffer and administered at concentrations of 42 nM into the buffer. Hypoxia/reoxygenation resulted in slight recovery of cardiac contractile force, significant alterations in tissue ion concentrations, and pronounced release of creatine kinase and ATP metabolites, suggesting hypoxia/reoxygenation-induced functional and morphological damage. The tanshinone VI derivatives improved post-hypoxic contractile recovery, which was associated with restoration of tissue ionic concentrations, and diminishment of the release of creatine kinase and ATP metabolites from the hypoxic/reoxygenated hearts. The efficacy of these compounds was similar to that of tanshinone VI. The results suggest that water-soluble tanshinone VI derivatives, like tanshinone VI itself, are beneficial for hypoxia/reoxygenation injury.

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen).

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).