Near-Infrared Hypocrellin Derivatives for Synergistic Photodynamic and Photothermal Therapy.

Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600-900 nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near-infrared (NIR) region, NIR emission (peaked at 805 nm), and singlet oxygen quantum yields of 0.27/0.31. HE-PEG-NPs were also prepared using 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE-PEG-NPs not only retained their 1 O2 -generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and in vivo therapeutic results revealed that the synergetic effect of HE-PEG-NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE-PEG-NPs could be regarded as a promising phototheranostic agent.

Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light.

Quinones and quinones-like compounds are potential candidates for the inhibition of CDC25 phosphatases. The combination of MALDI-MS analyses and biological studies was used to develop a rapid screening of a targeted library of indeno[1,2-b]indoloquinone derivatives. The screening protocol using MALDI-TOFMS and MALDI-FTICRMS highlighted four new promising candidates. Biological investigations showed that only compounds 5c-f inhibited CDC25A and -C phosphatases, with IC50 values around the micromolar range. The direct use of a screening method based on MALDI-MS technology allowed achieving fast scaffold identification of a new class of potent inhibitors of CDC25 phosphatases. These four molecules appeared as novel molecules of a new class of CDC25 inhibitors. Assessment of 5c-e in an MRC5 proliferation assay provided an early indicator of toxicity to mammalian cells. Compound 5d seems the most promising hit for developing new CDC25 inhibitors.

The Role of Spongia sp. in the Discovery of Marine Lead Compounds.

A comprehensive review on the chemistry of Spongia sp. is here presented, together with the biological activity of the isolated compounds. The compounds are grouped in sesquiterpene quinones, diterpenes, C21 and other linear furanoterpenes, sesterterpenes, sterols (including secosterols), macrolides and miscellaneous compounds. Among other reports we include studies on the intraspecific diversity of a Mediterranean species, compounds isolated from associated sponge and nudibranch and compounds isolated from S. zimocca and the red seaweed Laurentia microcladia. Under biological activity a table of the reported biological activities of the various compounds and the biological screening of extracts are described. The present review covers the literature from 1971 to 2015.

Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivo.

Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clinical use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepared by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new preparation were found to remain nearly constant over 1 year. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concentration at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg(-1) along with yellow laser irradiation; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.

Diterpenylquinone hybrids: synthesis and assessment of gastroprotective mechanisms of action in human cells.

A modern approach in the search for new bioactive molecules is the synthesis of novel chemical entities combining molecules of different biosynthetic origin presenting biological effects as single compounds. Gastroprotective compounds from South American medicinal plants, namely quinones and diterpenes, were used as building blocks to obtain hybrid diterpenylquinones. Starting from the labdane diterpene junicedric acid and two isomers, as well as from three quinones, including lapachol, 18 hybrid molecules were synthesized. Six of them are described for the first time. The potential gastroprotective mechanisms of action of the compounds were assessed in dose-response experiments using human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). The following studies were carried out: stimulation of cell proliferation, cytoprotection against sodium taurocholate (NaT)-induced damage, synthesis of PGE2 and total reduced sulfhydryl (GSH) content. The antioxidant capacity of the compounds was determined on the inhibition of the lipoperoxidation in human erythrocyte membranes. Hybrid compounds presented activities different from those shown by the starting compounds, supporting the potential of this approach in the search for new bioactive molecules. The effects might be modulated by selective modification in the terpene or quinone moieties of the new molecules. Structure-activity relationships are discussed.

[Recent advances in the study of new antifungal lead compounds].

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

Semisynthesis of justicidone and a 1,2-quinone lignan. Cytotoxic activity of some natural and synthetic lignans.

The dioxo-lignans of the arylnaphthalene-type named justicidone (2) and elenodione (3) were obtained from elenoside (1) through a short and efficient semisynthetic process. Justicidone (2), one of its synthetic precursors, 4-(benzo[d][1,3]dioxol-5-yl)-5,6,8-trimethoxy-3a,4-dihydronaphtho[2,3-c]furan-1(3H)-one (9), and the aglycone of elenoside (5) showed cytotoxic activity towards the HL-60 cell line (IC50 = 7.25 miroM, 5.41 microM and 2.06 miroM, respectively).

A novel hypocrellin B derivative designed and synthesized by taking consideration to both drug delivery and biological photodynamic activity.

For making hypocrellins clinically applicable for phototherapy to vascular diseases, it is mainly focused onto finding a derivative which can be transported fluently in blood system but without serious loss of the inherent activity of its parents. Based on this consideration, a novel 17-3-amino-1-propane-sulfonic acid-HB Schiff-base (NSHB) was designed and synthesized in this work. As expected, NSHB is readily dissolved in phosphate buffered saline (PBS) or any other aqueous solvent in a concentration which is suitable for intravenous injection, while the quite higher partition coefficient (5:1) is beneficial to the affinity to biological targets. Based on EPR measurements, it is proved that the photosensitization activity of NSHB to photo-generate semiquinone anion radicals and superoxide anion radical (O*(2)(-)) is even higher than its parent HB, while the ability to generate singlet oxygen ((1)O(2)) is not seriously reduced. In addition, nearly comparable PDT activity to A549 cells for NSHB and HB confirms that the molecular design is successful and NSHB is readily delivered into target tissues via blood circulation after intravenous injection. Furthermore, the quantum yield of (1)O(2) for NSHB is as 12.5 times as that for HB under red light (600-700 nm), which is beneficial to phototherapy to solid tumors.

Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol.

Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity.

Computational design, synthesis and biological evaluation of para-quinone-based inhibitors for redox regulation of the dual-specificity phosphatase Cdc25B.

Quinoid inhibitors of Cdc25B were designed based on the Linear Combination of Atomic Potentials (LCAP) methodology. In contrast to a published hypothesis, the biological activities and hydrogen peroxide generation in reducing media of three synthetic models did not correlate with the quinone half-wave potential, E(1/2).

Cytotoxic calanquinone A from Calanthe arisanensis and its first total synthesis.

Calanquinone A (1) was isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Its structure was identified by spectroscopic methods. Compound 1 showed potent cytotoxicity (EC(50)<0.5microg/mL) against lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines, and interestingly, showed an improved drug resistance profile compared to paclitaxel. The total synthesis of 1 was also achieved and is reported herein.

Chemical synthesis and biological evaluation of a NAD(P)H:quinone oxidoreductase-1 targeted tripartite quinone drug delivery system.

NAD(P)H:quinone oxidoreductase-1 (NQO1) is a potential target for therapeutic intervention but attempts to exploit NQO1 using quinone-based bioreductive prodrugs have been largely compromised by toxicity to organs that inherently express high levels of NQO1. In an attempt to circumvent this problem, this study describes the development of a tripartite quinone-based drug delivery system, the ultimate objective of which is to release a targeted therapeutic agent following the reduction of a quinone "trigger" by NQO1. Molecular modeling of drug/NQO1 interactions were conducted prior to the synthesis of N-{4-[bis-(2-chloroethyl)-amino]-phenyl}-beta,beta,2,4,5-pentamethyl-3,6-dioxo-1,4-cyclohexadiene-1-propanamide (prodrug 1). Prodrug 1 is a good substrate for purified NQO1 (V(max) and K(m) values of 11.86 +/- 3.09 micromol/min/mg and 2.70 +/- 1.14 micromol/L, respectively) and liquid chromatography-mass spectrometry analysis of the metabolites generated showed that lactone 3 and aniline mustard 4 were generated in a time- and NQO1-dependent manner. Chemosensitivity studies showed that prodrug 1 is selectively toxic to cells that overexpress NQO1 under aerobic conditions, and comet assay analysis confirmed the presence of elevated interstrand cross-links in NQO1-rich compared with NQO1-deficient cells. Hypoxic sensitization (hypoxic cytotoxicity ratio = 15.8) was observed in T47D cells that overexpress cytochrome P450 reductase. In conclusion, the results of this study provide mechanistic proof of principle that a tripartite benzoquinone drug delivery system is enzymatically reduced to release an active therapeutic agent. Further development of this concept to fine-tune substrate specificity for specific reductases and/or the inclusion of alternative therapeutic agents is warranted.

Regioselective intramolecular reactions of 2-indolylacyl radicals with pyridines: a direct synthetic entry to ellipticine quinones.

[reaction: see text] 2-Indolylacyl radicals generated from the corresponding selenoesters under hexabutylditin-hnu conditions undergo regioselective intramolecular reaction with unprotonated pyridines to give polycyclic indolylpyridyl ketones. For substrates bearing a (3-pyridyl)methyl moiety connected to the 3-position of the indole ring, the cyclization provides easy access to ellipticine quinones.

First total synthesis of justicidone, a p-quinone-lignan derivative from Justicia hyssopifolia.

The first synthesis of justicidone (4-(1',3'-Benzodioxol-5'-yl)-6-methoxynaphtho[2,3-c]furan-1,5,8(3H)-trione) was carried out from piperonal, as a starting compound, through a lineal process using well known reactions.

Biotinylated geldanamycin.

Inhibition of the 90 kDa heat shock proteins (Hsp90) represents a promising new chemotherapeutic approach for the treatment of several cancers. Hsp90 is essential to the survival of cancer cells and is inhibited by members of the ansamycin family of antibiotics. In particular, the quinone-containing antibiotics geldanamycin (GDA) and herbimycin A inhibit Hsp90 function in vitro at low micromolar concentrations via interaction with an ATP binding domain. Many proteins bind ATP, and the discovery of selective Hsp90 inhibitors requires the identification of other proteins that bind GDA and may cause undesired effects. Biotinylated analogues of GDA with varying tether lengths have been synthesized to elucidate other proteins that competitively bind GDA. Analogues containing a photolabile tether have also been prepared as a complementary method for the removal of GDA-bound proteins from neutravidin-containing resin. Preliminary studies indicate several proteins other than Hsp90 are isolated with biotinylated GDA.

Trypanocidal activity of synthetic heterocyclic derivatives of active quinones from Tabebuia sp.

Continuing a program on the chemistry and biological activity of compounds from the Brazilian flora, the lytic activity against bloodstream forms of T. cruzi of nine new heterocyclic naphthooxazole and naphthoimidazole derivatives obtained from the reaction of naphtoquinones isolated from Tabebuia sp. (Tecoma) with amino-containing reagents has been studied. Also for the first time the biological activity of allyl derivatives of lawsone, a natural quinone from Lausonia alba inactive against T. cruzi, is reported. The introduction of an allyl group in lawsone gives rise to O-allyl-lawsone and C-allyl-lawsone that showed activity against the parasite, with ID50 values of 420.7 +/- 71.1 and 330.7 +/- 62.4 mumol/l, respectively. The trypanocidal activity of the naphtho heterocyclics synthesized from the original quinones showed no concordant behavior in relation to the parent compound. Six of nine of the synthesized compounds presented lower ID50 values than crystal violet, indicating a general trend of activity among naphthalenic heterocyclics of the oxazole/imidazole type. However, their chemical structures do not endow them with the capacity of free radical generation by biological reduction as the quinoidal moiety, nor do they have chemical reducible appendage like the nitro group of nifurtimox and benznidazole, responsible for such behaviour. As a hypothesis, the pattern of their biological actions should be focused in other aspects of their chemical structures. Because of their polycyclic planar topology, these derivatives are potential candidates for experimental tests as DNA intercalating agents.

[The effect of low doses of a synthetic analog of a quinoid radiotoxin on the viability of normal and gamma-irradiated animals]. / Vliianie malykh doz sinteticheskogo analoga khinoidnogo radiotoksina na zhiznesposobnost' normal'nykh i gamma-obluchennykh zhivotnykh.

The method for a production of synthetic quinoid radiotoxins in vitro has been developed and described. Synthetic quinoid radiotoxins like quinoid radiotoxins (qRT) which are being produced from irradiated tissues of the organisms have demonstrated high toxicity at relatively high qRT concentrations. However, when synthetic qRT is introduced into the organisms in ultra-small concentrations, one can observe the opposite action: the resistance of the organism increases and a number of essential functions are activated. Quinoid radiotoxins are assumed to take part in regulatory processes responsible for radiation hormesis.

Synthesis and biological activity of thiazolylindolequinones, analogues of the natural product BE 10988.

A number of analogues of the naturally occurring thiazolylindolequinone BE 10988, a reported potent inhibitor of topoisomerase II, have been prepared and evaluated. The compounds were synthesized from 4-(benzyloxy)-5-methoxy-1-methylindole by appropriate substitution at the indole 3-position followed by standard thiazole ring-forming reactions. The toxicity of these potentially bioreductively activated indolequinones was measured in Chinese hamster V79 cells under aerobic and hypoxic conditions. In addition, toxicity was measured in a human breast cancer cell line that shows amplification of the topo II alpha gene and hypersensitivity to known topo II inhibitors such as mAMSA and mitoxantrone. Using a DNA decatenation assay, a comparison was also made of the inhibitory effects of BE 10988 and mitoxantrone on topo II activity.

Isolation, structural elucidation, and chemical synthesis of 2-hydroxy-3-octadecyl-5-methoxy-1,4-benzoquinone (irisoquin), a cytotoxic constituent of Iris missouriensis.

As part of a continuing effort to provide novel agents of potential value in cancer chemotherapy, 2-hydroxy-3-octadecyl-5-methoxy-1,4-benzoquinone (irisoquin) was identified as a component of Iris missouriensis. This novel species demonstrated cytotoxic activity with cultured KB and P-388 cells (ED50 = 1.8 and 0.03 microgram/mL, respectively). The structure was assigned on the basis of spectral analyses and The structure was assigned on the basis of spectral analyses and confirmed by chemical synthesis. The latter provides a facile method for the production of irisoquin and structural derivatives that may be of value for the examination of structure-activity relationships. A closely related compound, 3-octadecyl-5-methoxy-1,4-benzoquinone (deoxyirisoquin), was also isolated from Iris missouriensis, prepared synthetically, and found to be devoid of cytotoxic activity.