Novel Sesquiterpenoid Skeletons by Wagner-Meerwein Rearrangements of Longipinane-9,13-diol-1-one Derivatives.

The partial or total hydrolysis of (3R,4S,5S,6S,9R,10R,11R)-9,13-diangeloyloxylongipinan-1-one (1), isolated from the roots of Stevia viscida, gave alcohols 2 or 3, respectively, which were subjected to molecular rearrangements with boron trifluoride etherate. Compound 2 afforded (3R,4R,5R,6S,9R,10S,11S)-11,13-oxyneomorelian-1-one (10) and (4S,5R,6S,8S,10R)-10,13-oxyneojiquilp-2-en-1-one (11), both possessing novel sesquiterpenoid skeletons. In turn, 3 provided (3R,4R,5S,6S,9R,11R)-13-hydroxymoreli-10(14)-en-1-one (7) and 10. Acetylation of 3 gave 4, thus allowing reduction of the C-1 carbonyl group to yield 5, which was rearranged to (1S,3R,4S,5S,6S,9R,10R,11R)-13-acetoxy-9,11-epoxyjiquilpane (6), while an attempt to mesylate 3 directly gave rearranged (3R,4R,5S,6S,9R,11R)-13-mesyloxymoreli-10(14)-en-1-one (8) through expulsion of the C-9 mesylate group by the antiperiplanar C-4-C-10 bond migration to C-4-C-9. In addition, treatment of 1 with boron trifluoride etherate generated (3R,4R,5S,6S,9R,11R)-13-angeloyloxymoreli-10(14)-en-1-one (9). The structures of 2-11 were elucidated by 1D and 2D NMR experiments and those of 2, 3, 8, 10, and 11 were confirmed by single-crystal X-ray diffraction analysis.

Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus.

The often-overlooked dorsal diencephalic conduction system (DDCS) is a highly conserved pathway linking the basal forebrain and the monoaminergic brainstem. It consists of three key structures; the stria medullaris, the habenula and the fasciculus retroflexus. The first component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fibers from the basal forebrain that terminate in the triangular eminence of the stalk of the pineal gland, known as the habenula. The habenula acts as a relay hub where incoming signals from the stria medullaris are processed and subsequently relayed to the midbrain and hindbrain monoaminergic nuclei through the fasciculus retroflexus. As a result of its wide-ranging connections, the DDCS has recently been implicated in a wide range of behaviors related to reward processing, aversion and motivation. As such, an understanding of the structure and connections of the DDCS may help illuminate the pathophysiology of neuropsychiatric disorders such as depression, addiction and pain. This is the first review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retroflexus, with particular focus on their anatomy, function and development.

Novel Sesquiterpene Skeletons by Multiple Wagner-Meerwein Rearrangements of a Longipinane-1,9-diol Derivative.

The tricyclic sesquiterpene (1R,3R,4S,5S,7S,8S,9S,10R,11R)-7,8-diangeloyloxylongipinan-1,9-diol, or rasteviol (7), underwent multiple Wagner-Meerwein molecular rearrangements and several hydride shifts when treated with Et2O-BF3 to generate the six new compounds (1R,3R,4S,5R,7S,8S,9S,10R,11S)-7,8-diangeloyloxy-1,9-epoxyjiquilpane (8), (1R,3R,4S,5R,7R,8S,9S,11S)-8-angeloyloxy-1,7-epoxyzamor-10(14)-ene (11), (2S,3R,4R,5R,6R,7R,8S,9S,10S)-7,8-diangeloyloxy-6,9-epoxyjanitziane (14), (4R,5R,7S,8S,9S,10S,11S)-7,8-diangeloyloxy-9-hydroxyjiquilp-3(15)-ene (16), (2S,3S,5R,7S,8R,10S,11R)-7,8-diangeloyloxyiratzian-9-one (18), and (2S,3S,5R,10S,11R)-8-angeloyloxyiratzi-7-en-9-one (22), of which 8, 11, 14, and 18 possess new hydrocarbon skeletons. Their structures were determined by 1D and 2D NMR in combination with single-crystal X-ray diffraction analyses of derivatives 10, 15, 20, and 21, which allowed confirmation of their absolute configurations by means of the Flack and Hooft parameters. In addition, some reaction mechanism information was gained from deuterium labeling experiments.

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan.

Chitosan is a natural polymer revealing an increased potential to be used in different biomedical applications, including drug delivery systems, and tissue engineering. It implies the evaluation of the organism response to the biomaterial implantation. Low-molecular degradation products, the chito-oligomers, are resulting mainly from the influence of enzymes, which are found in the organism fluids. Within this study, we have performed the computational assessment of pharmacological profiles and toxicological effects on human health of small chito-oligomers with distinct molecular weights, deacetylation degrees, and acetylation patterns. Our approach is based on the fact that regulatory agencies and researchers in the drug development field rely on the use of modeling to predict biological effects and to guide decision making. To be considered as valid for regulatory purposes, every model that is used for predictions should be associated with a defined toxicological endpoint and has appropriate robustness and predictivity. Within this context, we have used FAF-Drugs4, SwissADME, and PreADMET tools to predict the oral bioavailability of chito-oligomers and SwissADME, PreADMET, and admetSAR2.0 tools to predict their pharmacokinetic profiles. The organs and genomic toxicities have been assessed using admetSAR2.0 and PreADMET tools but specific computational facilities have been also used for predicting different toxicological endpoints: Pred-Skin for skin sensitization, CarcinoPred-EL for carcinogenicity, Pred-hERG for cardiotoxicity, ENDOCRINE DISRUPTOME for endocrine disruption potential and Toxtree for carcinogenicity and mutagenicity. Our computational assessment showed that investigated chito-oligomers reflect promising pharmacological profiles and limited toxicological effects on humans, regardless of molecular weight, deacetylation degree, and acetylation pattern. According to our results, there is a possible inhibition of the organic anion transporting peptides OATP1B1 and/or OATP1B3, a weak potential of cardiotoxicity, a minor probability of affecting the androgen receptor, and phospholipidosis. Consequently, these results may be used to guide or to complement the existing in vitro and in vivo toxicity tests, to optimize biomaterials properties and to contribute to the selection of prototypes for nanocarriers.

Absolute configuration of phomactatriene diterpenoids obtained by Wagner-Meerwein rearrangement of epimeric verticillols.

The epimeric diterpenes (+)-(1S,3E,7E,11S,12S)-verticilla-3,7-dien-12-ol (1), isolated from Bursera suntui, and (+)-(1S,3E,7E,11S,12R)-verticilla-3,7-dien-12-ol (2), isolated from Bursera kerberi, gave the same Wagner-Meerwein rearrangement product (-)-(1E,4Z,8Z,11S,12R)-phomacta-1,(15)4,8-triene (3). The Et2 O:BF3 -induced transformations evidence that verticillenes and phomactanes, both containing the bicyclo[9.3.1]pentadecane skeleton, are biogenetically related through the verticillen-12-yl cation (A+ ), which also is a key intermediate in the biosynthetic pathways to generate antitumor taxanes. Molecular modeling using the Monte Carlo protocol, followed by density functional theory (DFT) geometry optimization employing the hybrid functionals B3LYP and B3PW91, both with the DGDZVP basis set, secured the configuration of 3 as followed from the good agreement between the calculated and experimental vibrational circular dichroism spectra. Similar DFT calculations allowed determining the absolute configuration of (+)-(1R,4R,5R,8S,9S,11S,12R,15R)-1,15:4,5:8,9-triepoxyphomactane (9), which surprisingly derives from epoxidation of the second minimum energy conformer of 3.

Veneno de escorpión: Una nueva promesa en el tratamiento del cáncer / Scorpion venom: new promise in the treatment of cancer

ABSTRACT Cancer is a public health problem due to its high worldwide morbimortality. Current treatment protocols do not guarantee complete remission, which has prompted to search for new and more effective antitumoral compounds. Several substances exhibiting cytostatic and cytotoxic effects over cancer cells might contribute to the treatment of this pathology. Some studies indicate the presence of such substances in scorpion venom. In this review, we report characteristics of the principal scorpion venom components found in recent literature and their potential activity against tumor cells. There are different toxin groups present in the venom, and it seems that their mode of actions involves ionic channel blocking, disruption of the cell membrane integrity and damage to internal cell organelles. These properties make good prospects for studies on drugs and adjuvants in cancer treatment.

RESUMEN El cáncer es un problema de salud pública debido a su alta morbimortalidad mundial. Los protocolos de tratamiento actuales no garantizan la remisión completa lo que ha llevado a buscar compuestos antitumorales más efectivos. Varias sustancias que exhiben efectos citostáticos y citotóxicos sobre células tumorales pueden contribuir al diagnóstico y tratamiento de esta patología. Algunos estudios indican la presencia de tales sustancias en el veneno de escorpión. En esta revisión, se dan a conocer las características de los principales componentes del veneno de escorpión encontrados en la literatura reciente y su actividad potencial contra las células tumorales. Existen diferentes grupos de toxinas presentes en el veneno y parece que su modo de acción implica el bloqueo del canal iónico, la alteración de la integridad de la membrana celular y el daño a los orgánulos celulares internos. Estas propiedades ofrecen buenas perspectivas para estudios sobre medicamentos y adyuvantes en el tratamiento del cáncer.

Assessment of the properties of chitin deacetylases showing different enzymatic action patterns.

Chitin deacetylases are a group of enzymes catalysing the conversion of chitin to chitosan. Obtaining chitosan with established deacetylation degree and pattern is important for biomedical and biotechnological applications. Understandings of the structural properties of chitin deacetylases and the specificity of their interactions with chitin may conduct to the control of the pattern of deacetylation of chitosan. Our study is focused on the characterization and comparison of the structural and physicochemical properties of chitin deacetylases from fungi and marine bacteria. Despite the low sequences identity for the investigated chitin deacetylases, there are amino acids belonging to their active sites that are strongly conserved. Moreover, they reveal an increased structural similarity of their catalytic domains, reflecting the common biological function of these enzymes. The studied enzymes present dissimilar local physicochemical properties of their catalytic cavities that could be responsible of their distinct deacetylation patterns. Molecular docking studies reflect that deacetylation efficiency is also distinct for the chitin and partially deacetylated chitin oligomers and that N-acetylglucosamine units and some partially deacetylated chitin oligomers could have inhibitory effect against chitin deacetylases belonging to fungi and marine bacteria.

Computational Assessment of Pharmacokinetics and Biological Effects of Some Anabolic and Androgen Steroids.

PURPOSE: The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. METHODS: The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism. RESULTS: Investigated steroids usually reveal a high gastrointestinal absorption and a good oral bioavailability, may inhibit someof the human cytochromes involved in the metabolism of xenobiotics (CYP2C9 being the most affected) and reflect a good capacity for skin penetration. There are predicted numerous side effects of investigated steroids in humans: genotoxic carcinogenicity, hepatotoxicity, cardiovascular, hematotoxic and genitourinary effects, dermal irritations, endocrine disruption and reproductive dysfunction. CONCLUSIONS: These results are important to be known as an occupational exposure to anabolic and androgenic steroids at workplaces may occur and because there also is a deliberate human exposure to steroids for their performance enhancement and anti-aging properties.

Absolute configuration of cembrane diterpenoids from Bursera multijuga.

The stems of Bursera multijuga afforded (-)-(1S,3E,7R,8R,11E)-7,8-epoxycembra-3,11-dien-1-ol (1) and its acetate 2, together with cembrene A (3), nephthenol (4), and cembrenol (5). The structures of 1 and 2 were elucidated by 1D and 2D NMR, HRESIMS, and X-ray diffraction. The conformational preference of flexible 1 was studied by molecular modeling at the DFT B3LYP/DGDZVP level of theory. Good agreement between calculated and experimental vibrational circular dichroism curves established the absolute configuration of 1. This is the first time that cembrane derivatives have been isolated from the genus Bursera.

A new bisabolene from Stevia tomentosa.

The new sesquiterpene (1R,2R,3R,6R,7S)-1-acetoxy-2,3-dihydroxy-2,3-dihydrobisabolene (3) together with ten known terpenes and three known flavonoids were isolated from the aerial parts and from the roots of Stevia tomentosa. The structure of 3 follows from spectral studies, the relative chirality at C-3 follows from 1H NMR coupling constants comparison with the corresponding calculated values obtained by applying a generalized Karplus-type relationship to the dihedral angles of model compounds, and the absolute configuration is assumed in analogy to known (2R,3R,6R,7S)-2,3-epoxy-2,3-dihydrobisabolen-1-one (2).

Absolute configuration of podophyllotoxin related lignans from Bursera fagaroides using vibrational circular dichroism.

The ethanol extract from the dried exudate of Bursera fagaroides (Burseraceae) showed significant cytotoxic activity in the HT-29 (human colon adenocarcinoma) test system. The extract provided four podophyllotoxin related lignans, identified as (7'R,8R,8'R)-(-)-deoxypodophyllotoxin (3), (7'R,8R,8'R)-(-)-morelensin (4), (8R,8'R)-(-)-yatein (5), and (8R,8'R)-(-)-5'-desmethoxyyatein (6), whose spectroscopic and chiroptical properties were compared with those of (7R,7'R,8R,8'R)-(-)-podophyllotoxin (1) and its acetyl derivative (2). Their absolute configurations were assigned by comparison of the vibrational circular dichroism spectra of 1 and 3 with those obtained by density functional theory calculations.

Antifeedant and cytotoxic activity of longipinane derivatives.

The polyoxygenated longipinane derivatives 1- 8 were tested as antifeedant compounds against the herbivorous insects Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae. Compounds 1-3 and 8 exhibited significant antifeedant activity against S. littoralis and M. persicae. The antifeedant activity against S. littoralis increased moderately after the C-8 hydroxy group in 3 was removed to afford 1 and increased strongly after the remaining two hydroxy groups were acetylated to afford 2. Compound 1 was active on M. persicae. Compounds 1, 3, and 4, with an unsaturated six-membered ring, exhibited an increase in post-ingestive effects on S. littoralis ranging from antifeedant in the case of 1 to toxic for compounds 3 and 4. These compounds did not have any phytotoxic effect on Lactuca sativa. When tested on a panel of tumoral cells, compounds 2 and 6 exhibited moderate selective cytotoxic effects on the p53 null lung carcinoma cells H1299, which were not affected by the drug paclitaxel. In addition, vibrational circular dichroism (VCD) was applied to the representative longipinene derivative 2 to verify its absolute configuration, and the sensitivity of the VCD methodology was evaluated by comparing spectra of the three diastereoisomers (4 R,5 S,7 R,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one (2), (4 R,5 S,7 S,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one, and (4 R,5 S,7 R,9 S,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one.

Oxygenated verticillene derivatives from Bursera suntui.

Medium polarity fractions of the hexane extracts of the stems of Bursera suntui afforded six previously known (1-6) and four hitherto unknown verticillane derivatives: (1S,3Z,7S,8S,11S,12S)-(+)-7,8-epoxyverticill-3-en-12,20-diol (7), (1S,3Z,7S,8S,11S,12S)-(+)-7,8-epoxyverticill-3-en-12,20-diol 20-acetate (8), (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol (9), and (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol 20-acetate (10). Acetylation of 9 and 10 yielded (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol 7,20-diacetate (11), while hydrolysis of 8 gave 7. The structures and stereochemistry of 7-11 were established by spectroscopic analyses, particularly by 1D and 2D NMR spectra and HRESIMS. The conformational preferences of 7-11 were studied by molecular mechanics modelling employing the Monte Carlo protocol followed by B3LYP/DGDZVP DFT calculation, thus supporting the observed (1)H NMR NOESY cross peaks.

Absolute configuration of verticillane diterpenoids by vibrational circular dichroism.

Good agreement between theoretical and experimental vibrational circular dichroism curves of (1S,11S,12S)-(+)-verticilla-3E,7E-dien-12-ol (1) established the absolute configuration of this natural diterpene isolated from Bursera suntui. Molecular modeling of 1 was carried out using the Monte Carlo protocol followed by geometry optimization at the B3LYP 6-31G(d,p) level of theory. The 12-membered ring of 1 was found in a single preferred chair-chair-chair-chair conformation. In the six-membered ring a chair prevails over a distorted boat, and the C-OH bond rotation generates three predominant rotamers. Validation of the minimum energy conformation for 1 was achieved by comparison of theoretical and experimental infrared frequencies, vicinal 1H NMR coupling constants, and X-ray diffraction data. This study confirms that (+)-verticillol 1 isolated from Bursera species has the 1S,11S,12S absolute configuration that corresponds to the same enantiomeric series as verticillanes from Sciadopitys and Taxus, while verticillanes from Jackiella and Jungermannia have antipodal structures.

Verticillane derivatives from Bursera suntui and Bursera kerberi.

The stems of Bursera suntui afforded two new verticillane derivatives, (1S,3Z,7E,11S,12S)-(+)-verticilla-3,7-dien-12,20-diol (1) and (1S,3Z,7E,11S,12S)-(+)-verticilla-3,7-dien-12,20-diol 20-acetate (2), together with (1S,3E,7E,11R)-(+)-verticilla-3,7,12(18)-triene (3), (1R,3E,7E,11R,12Z)-(+)-verticilla-3,7,12-triene (4), (1R,7E,11Z)-(-)-verticilla-4(20),7,11-triene (5), and (1S,3E,7E,11S,12S)-(+)-verticilla-3,7-dien-12-ol (6). Compounds 3 and 4 are new enantiomerically pure natural products whose racemic mixtures, derived from synthetic approaches toward the taxane skeleton, were obtained previously. The stems of Bursera kerberi afforded the new (1S,3E,7E,11S,12R)-(+)-verticilla-3,7-dien-12-ol (7) together with 3-5. This is the first time that verticillane derivatives have been isolated from the genus Bursera. Their structures and stereochemistry were elucidated by 1D and 2D NMR data, including COSY, NOESY, HSQC, and HMBC experiments, while the absolute configuration was determined by comparison of the optical rotatory dispersion data with that of recently revised (1S,3E,7E,11S,12S)-(+)-verticilla-3,7-dien-12-ol (6), obtained from Sciadopitys verticillata, and those of (1R,3E,7E,11R,12R)-(-)-verticilla-3,7-dien-12-ol (8) and (1R,3E,7E,11R,12S)-(-)-verticilla-3,7-dien-12-ol (9), isolated from the liverwort Jackiella javanica. The conformational preferences of 1-7 were studied by molecular mechanics modeling employing the Monte Carlo protocol.