Insights into podophyllotoxin lactone features: New cyclolignans as potential dual tubulin-topoisomerase II inhibitors.

Chemomodulation of natural cyclolignans as podophyllotoxin has been a successful approach to obtain semisynthetic bioactive derivates. One example of this approach is the FDA-approved drug etoposide for solid and hematological tumors. It differs from the antimitotic activity of the natural product in its mechanism of action, this drug being a topoisomerase II inhibitor instead of a tubulin antimitotic.

Podophyllic Aldehyde, a Podophyllotoxin Derivate, Elicits Different Cell Cycle Profiles Depending on the Tumor Cell Line: A Systematic Proteomic Analysis.

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling.

Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan.

Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles.

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity.

Improving Properties of Podophyllic Aldehyde-Derived Cyclolignans: Design, Synthesis and Evaluation of Novel Lignohydroquinones, Dual-Selective Hybrids against Colorectal Cancer Cells.

New lignohydroquinone conjugates (L-HQs) were designed and synthesized using the hybridization strategy, and evaluated as cytotoxics against several cancer cell lines. The L-HQs were obtained from the natural product podophyllotoxin and some semisynthetic terpenylnaphthohydroquinones, prepared from natural terpenoids. Both entities of the conjugates were connected through different aliphatic or aromatic linkers.

In Vitro Cytotoxic Activity of African Plants: A Review.

In African countries, cancer not only is a growing problem, but also a challenge because available funding and resources are limited. Therefore, African medicinal plants play a significant role in folk medicine and some of them are traditionally used for the treatment of cancer. The high mortality rate and adverse effects associated with cancer treatments have encouraged the search for novel plant-based drugs, thus, some African plants have been studied in recent years as a source of molecules with proven cytotoxicity.

New Antineoplastic Naphthohydroquinones Attached to Labdane and Rearranged Diterpene Skeletons.

Terpenylquinones are mixed biogenesis primary or secondary metabolites widespread in Nature with many biological activities, including the antineoplastic cytotoxicity, that have inspired this work. Here, we present a cytotoxic structure-activity relationship of several diterpenylhydroquinone (DTHQ) derivatives, obtained from the natural labdane diterpenoid myrceocommunic acid used as starting material. Different structural modifications, that changed the functionality and stereochemistry of the decalin, have been implemented on the bicyclic core through epoxidation, ozonolysis or decarboxylation, and through induction of biomimetic breaks and rearrangements of the diterpene skeleton.

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor.

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.

[High-risk drug use: epidemiological pattern through hair testing in the forensic context].

Objective: The basic sources of information on drug use are epidemiological surveys, although they have some limitations: their results may be conditioned by the lack of veracity of the responses and the sampling method makes it difficult to detect lowprevalence behaviours in target populations. This study aimed to establish the epidemiological pattern of drug use in the population undergoing drug testing in hair, in the framework of judicial investigations, in order to provide an additional approach to the knowledge of high-risk drug use.

Methods: A cross-sectional study on drug use was conducted on the population subjected to drug testing in hair (N=5,292) in the forensic context.

Anti-Herpetic, Anti-Dengue and Antineoplastic Activities of Simple and Heterocycle-Fused Derivatives of Terpenyl-1,4-Naphthoquinone and 1,4-Anthraquinone.

Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested.

Bioactive Prenyl- and Terpenyl-Quinones/Hydroquinones of Marine Origin .

The sea is a rich source of biological active compounds, among which terpenyl-quinones/hydroquinones constitute a family of secondary metabolites with diverse pharmacological properties. The chemical diversity and bioactivity of those isolated from marine organisms in the last 10 years are summarized in this review. Aspects related to synthetic approaches towards the preparation of improved bioactive analogues from inactive terpenoids are also outlined.

New Hybrids Derived from Podophyllic Aldehyde and Diterpenylhydroquinones with Selectivity toward Osteosarcoma Cells.

A new family of molecular hybrids, between cyclolignans related to podophyllic aldehyde and several diterpenylnaphthohydroquinones (DNHQ), was prepared and its biological activity evaluated in several human solid tumor cell lines, which are representative of the most prevalent solid tumors in the Western world. Both cyclolignan and quinone fragments were linked through aliphatic or aromatic spacers. The new hybrid family was evaluated for its cytotoxicity, and it was found that the hybrids were several times more potent against the osteosarcoma cell line MG-63 than against MCF-7 and HT-29 cell lines.

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum.

Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites.

Cytotoxic Terphenyl Neolignans from Fungus Terana coerulea: New Natural Corticins D and E. and Revised Structure for Corticin A.

The cobalt crust fungus Terana coerulea (Phanerochaetaceae family) was selected for a bio-guided study after an ethnobotanical survey at the Irati's Forest (Navarra, Spain) for its local use as antibiotic. Six extracts of increasing polarity, from hexane to hot water, were obtained from powdered dry fungi and tested for cytotoxicity against four human tumour cell lines and one non-tumour primary cell culture. From the most cytotoxic, EtOAc extract, we isolated and identified three terphenyl neolignans: two of them new natural products, named corticins D and E, and one previously described as corticin A, whose earlier structure has been revised.

Phylogeny and Phylogeography of a Recent HIV-1 Subtype F Outbreak among Men Who Have Sex with Men in Spain Deriving from a Cluster with a Wide Geographic Circulation in Western Europe.

We recently reported the rapid expansion of an HIV-1 subtype F cluster among men who have sex with men (MSM) in the region of Galicia, Northwest Spain. Here we update this outbreak, analyze near full-length genomes, determine phylogenetic relationships, and estimate its origin. For this study, we used sequences of HIV-1 protease-reverse transcriptase and env V3 region, and for 17 samples, near full-length genome sequences were obtained.

Synthesis and antifungal activity of terpenyl-1,4-naphthoquinone and 1,4-anthracenedione derivatives.

The antifungal evaluation of twenty seven simple and heterocycle-fused prenyl-1,4-naphthoquinones and 1,4-anthracenediones was performed in vitro against human pathogenic yeasts (Candida spp.) and filamentous fungi (Aspergillus spp., Fusarium spp.

Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives.

This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs.

Lignopurines: a new family of hybrids between cyclolignans and purines. Synthesis and biological evaluation.

A new family of hybrids between cyclolignans related to podophyllic aldehyde, a non-lactonic cyclolignan, and purines were prepared and evaluated against several human tumour cell lines. Both fragments, cyclolignan and purine, were linked through aliphatic and aromatic chains. The influence on the cytotoxicity of the purine substitution and the nature of the linker is analyzed.

Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C.

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.

iso-Kaurenoic acid from Wedelia paludosa D.C.

A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.

Synthesis and biological evaluation of new podophyllic aldehyde derivatives with cytotoxic and apoptosis-inducing activities.

Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below.

Synthesis and cytotoxic evaluation of 6-(3-pyrazolylpropyl) derivatives of 1,4-naphthohydroquinone-1,4-diacetate.

Several new 6-(3-pyrazolylpropyl) derivatives of 1,4-naphthohydroquinone-1,4-diacetate (NHQ-DA) have been prepared by chemical modifications of the Diels-Alder adduct of alpha-myrcene and 1,4-benzoquinone. All these new compounds and precursors have been evaluated in vitro for their cytotoxicity against cultured human cancer cells of MB-231 breast-adeno carcinoma, A-549 lung carcinoma, and HT-29 colon carcinoma. GI(50) values ranged in and below the micromolar concentration level.

Cytotoxic-antineoplastic derivatives of prenyl-1,2-naphthohydroquinone.

Several new prenyl-1,2-naphthohydroquinone derivatives have been prepared by chemical modifications of Diels-Alder products which were obtained from cycloaddition of alpha-myrcene to 1,2-benzoquinone and then evaluated in vitro for their cytotoxic activity against A-549 lung carcinoma, HT-29 colon carcinoma, and MB-231 breast adeno-carcinoma culture cells. Most of them exhibited GI50 values in the microM-concentration level.