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

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum 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. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017-mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

Halimanes and cancer: ent-halimic acid as a starting material for the synthesis of antitumor drugs.

The development of new anti-cancer agents is an urgent necessity nowadays, as it is one of the major causes of mortality worldwide. Many drugs currently used are derived from natural products. Halimanes are a class of bicyclic diterpenoids present in various plants and microorganisms. Many of them exhibit biological activities such as antitumor, antimicrobial, or anti-inflammatory. Among them, ent-halimic acid is an easily accessible compound, in large quantities, from the ethyl acetate extract of the plant Halimium viscosum, and it has been used as a starting material in a number of bioactive molecules. In this work, we review all the natural halimanes with antitumor and related activities until date as well as the synthesis of antitumor compounds using ent-halimic acid as a starting material.

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. Among the evaluated hybrids, the L-HQ with the aromatic spacer clearly displayed the in vitro dual cytotoxic effect derived from each starting component, retaining the selectivity and showing a high cytotoxicity at short (24 h) and long (72 h) incubation times (4.12 and 0.0450 µM, respectively) against colorectal cancer cells. In addition, the cell cycle blockade observed by flow cytometry studies, molecular dynamics, and tubulin interaction studies demonstrated the interest of this kind of hybrids, which docked adequately into the colchicine binding site of tubulin despite their large size. These results prove the validity of the hybridization strategy and encourage further research on non-lactonic cyclolignans.

Reactive perforating collagenosis: a rare side effect associated with sorafenib.

We present the case of a patient with a debut of reactive perforating collagenosis associated with the use of Sorafenib for stage IV hepatocarcinoma, very successfully controlled with local corticotherapy and systemic antihistamines. This is an extremely rare side effect associated with this treatment, as only another eleven cases of acquired perforating dermatoses associated with Sorafenib or other multi-kinase inhibitors have been found in the medical literature. Given the unusual nature of this presentation, high clinical suspicion and a correct histopathological study are indispensable for its correct filiation and treatment.

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.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.

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. The presence of an aromatic ring in the linker gave the most potent and selective agent, improving the cytotoxicity of the parent compounds. Cell cycle studies demonstrated that this hybrid induces a strong and rapid apoptotic effect and arrests cells at the G2/M phase of the cell cycle, in the same way that the parent compound podophyllic aldehyde does.

Halimane diterpenoids: sources, structures, nomenclature and biological activities.

Covering: 1970 to 2017 Diterpenes with a halimane skeleton constitute a small group of natural products that can be biogenetically considered as being between labdane and clerodane diterpenoids. Some of these compounds show biological activities, such as antitumour, mosquito repellency, germination inhibition and antimicrobial, as well as being biomarkers for tuberculosis. To the best of our knowledge, there are no reviews on these compounds. In this review, halimane skeleton diterpenoids are classified according to their biogenetic origin, characterization and/or the enzymes involved in their biosynthesis. Herein, a review of their synthesis or synthetic approaches is communicated.

Acceptability and effectiveness of using mobile applications to promote HIV and other STI testing among men who have sex with men in Barcelona, Spain.

OBJECTIVE: To evaluate the acceptability and effectiveness of a pilot intervention programme using gay geosocial mobile applications (apps) to offer rapid HIV and other STI tests to men who have sex with men (MSM) in Barcelona between December 2015 and March 2016. METHODOLOGY: We offered rapid HIV, syphilis and hepatitis C testing by sending private messages on apps for sexual and social encounters. Acceptance was defined as the proportion of users who favourably responded to the message and effectiveness was defined as the proportion of users who attended our facilities among those who were interested in attending. To identify variables associated with the response to the messages, multivariate logistic regression was used. Adjusted OR (ORa) and 95% CIs were calculated. We collected information on sociodemographics, sexual behaviours and app usage from the contacted user profiles and from users who attended our facilities. A descriptive analysis was carried out. RESULTS: 2656 individual messages were sent. Overall, a 38.4% response rate was obtained, 83.0% of them found it acceptable to receive the unsolicited message, and 73.2% effectiveness was obtained. Responders had higher odds of being 45 years or older (ORa=1.48; 95% CI 1.06 to 2.08), being connected at the moment the message was sent or during the previous hour (ORa=1.92; 95% CI 1.38 to 2.68), having a profile photo not exposing bare chest or abdomen (ORa=1.44; 95% CI 1.07 to 1.92) and using the Grindr app (ORa=1.39; 95% CI 1.12 to 1.73). Of those who were tested and took the survey (n=77), 45.5% had not taken an HIV test in over a year, 24.7% had had a previous STI diagnosis, 51.4% had reported anal sex without condom and 52% had consumed alcohol or drugs for sex. CONCLUSIONS: The response rate, acceptance and effectiveness observed in this study indicate that this strategy could be a useful tool for promoting STI testing among high-risk MSM population.

Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-epi-Luffarin I and Luffarin A.

Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from 2.8-15µM, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure-activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with [Formula: see text] values in the range 2.8-15 M.

NOMAD spectrometer on the ExoMars trace gas orbiter mission: part 1--design, manufacturing and testing of the infrared channels.

NOMAD is a spectrometer suite on board ESA's ExoMars trace gas orbiter due for launch in January 2016. NOMAD consists of two infrared channels and one ultraviolet and visible channel allowing the instrument to perform observations quasi-constantly, by taking nadir measurements at dayside and nightside, and during solar occultations. In this paper, the design, manufacturing, and testing of the two infrared channels are described. We focus upon the optical working principle in these channels, where an echelle grating, used as a diffractive element, is combined with an acousto-optical tunable filter, used as a diffraction order sorter.

Synthesis and bioactivity of Luffarin I.

The first synthesis of Luffarin I, sesterterpenolide isolated from sponge Luffariella geometrica, has been accomplished from commercially available sclareol. The key strategy involved in this synthesis is the diastereoselective reduction of an intermediate ketone. Luffarin I against human solid tumor cell lines showed antiproliferative activities (GI50) in the range 12-17 µM.

Biomimetic synthesis of two salmahyrtisanes: salmahyrtisol A and hippospongide A.

Sesterterpenes with a salmahyrtisane skeleton have been synthesized for the first time. (-)-Sclareol has been selected as a precursor for the synthesis of two novel natural products: salmahyrtisol A (1) and hippospongide A (2). Our results represent a biomimetic approach to obtaining salmahyrtisanes from hyrtiosanes. Salmahyrtisol A has shown an activity comparable to that of the standard anticancer drugs in the cell lines A549, HBL-100, HeLa, and SW1573.

Synthesis of Bioconjugate Sesterterpenoids with Phospholipids and Polyunsaturated Fatty Acids.

A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) are obtained varying the sesterterpenoid in position 1 or 2 of the glycerol or a phosphocholine or PUFA unit in position 3. Simple bioconjugates of sesterterpenoids and eicosapentaenoic acid (EPA) have been obtained too. All synthetic derivatives were tested against the human tumour cell lines HeLa (cervix) and MCF-7 (breast). Some compounds showed good IC50 (0.3 and 0.2 µM) values against these cell lines.

Synthesis and biological activity of polyalthenol and pentacyclindole analogues.

A series of indole sesquiterpenes analogues of polyalthenol and pentacyclindole have been synthesized starting from ent-halimic acid in order to test their biological activity. These analogues include diverse oxidation levels at the sesquiterpenyl moiety and different functionalization on the indole ring. All synthetic derivatives were tested against a representative panel of Gram positive and Gram negative bacterial strains, and the human solid tumour cell lines A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon). Overall, the compounds presented activity against the cancer cell lines. The resulting lead, displaying a polyalthenol scaffold, showed GI50 values in the range 1.2-5.7 µM against all cell lines tested.

Synergistic antibacterial activity of the essential oil of aguaribay (Schinus molle L.).

Schinus molle L. (aguaribay, aroeira-falsa, "molle", family Anacardiaceae), a native of South America, produces an active antibacterial essential oil extracted from the leaves and fruits. This work reports a complete study of its chemical composition and determines the antibacterial activity of Schinus molle L. essential oil and its main components. The results showed that the crude extract essential oil has a potent antibacterial effect on Staphylococcus aureus ATCC 25923, a strong/moderate effect on Escherichia coli ATCC 25922 and moderate/weak one on Pseudomonas aeruginosa ATCC 27853.

Comprehensive smoking bans and acute myocardial infarction among Medicare enrollees in 387 US counties: 1999-2008.

Restrictions on smoking in public places have become increasingly widespread in the United States, particularly since the year 2005. National-scale studies in Europe and local-scale studies in the United States have found decreases in hospital admissions for acute myocardial infarction (AMI) following smoking bans. The authors analyzed AMI admission rates for the years 1999-2008 in 387 US counties that enacted comprehensive smoking bans across 9 US states, using a study population of approximately 6 million Medicare enrollees aged 65 years or older. Effects of smoking bans on AMI admissions were estimated by using Poisson regression with linear and nonlinear adjustment for secular trend and random effects at the county level. Under the assumption of linearity in the secular trend of declining AMI, smoking bans were associated with a statistically significant ban-associated decrease in admissions for AMI in the 12 months following the ban. However, the estimated effect was attenuated to nearly zero when the assumption of linearity in the underlying trend was relaxed. This analysis demonstrates that estimation of potential health benefits associated with comprehensive smoking bans is challenged by the need to adjust for nonlinearity in secular trend.