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The triterpenoid natural products have played an important role in understanding mechanistic models of human diseases. These natural products are diverse, but many have been characterized as reactive oxygen species (ROS) modulators. ROS can regulate cell survival and function, which ultimately affects biological processes leading to disease. The triterpenoids offer an untapped source of creativity to generate tool compounds with high selectivity to regulate ROS. This brief Review highlights the diverse complexity by which these secondary metabolites induce many cell death modalities (apoptosis, autophagy, ferroptosis, etc.) that can affect various complex cell signaling pathways through ROS and ultimately lead to evading or accelerating cell death.

The abietane diterpenoids ferruginol (1), tanshinone IIA (3), and carnosol (4) are well-known for their interesting pharmacological properties, including antitumor, similar to other natural and semisynthetic abietanes. In this study, a pair of semisynthetic C18-functionalized analogues of 3 and 4 were prepared from the commercially available (+)-dehydroabietylamine or readily obtained methyl dehydroabietate. Semisynthetic ferruginol (1) and some selected analogues, together with the synthesized analogues, were tested in vitro for the inhibition of proliferation in four breast cancer cell lines, SUM149, MDA-MB231, T47D, and MCF07. As a result, several tested abietane analogues decreased cell proliferation and enhanced cell death, with IC50 in the range 1.3–18.7 μM. This work demonstrates the antitumor activities of two tested compounds, making these molecules interesting for the development of new anticancer agents., The funds were granted by the Universitat Politècnica de Valencia (grant ADSIDEO AD 1902 to M.A.G.-C) and the Board of Regents Support Fund Award LEQSF-RD-A-05 to F.R.

Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.

Pentacyclic triterpenes, such as oleanolic acid (I), are promising scaffolds for diversification through the use of combinatorial methods to obtain derivatives that improve their biological properties, increasing their bioavailability and enhancing their therapeutic efficacy. The purpose of this study was to evaluate the influence that derivatives of oleanolic acid, conjugated with one or two amino acids and an acyl group, might exert on HIV-1 protease inhibition. The in vitro studies conducted suggested that the presence of a carboxyacyl group generally improves the inhibition of HIV-1 protease, especially when a phthaloyl group is present, with IC50 concentration values below 5 μM. The gain in activity of three 3-phthaloyl derivatives, with sub-micromolar IC50 values, was between 60- and 100-fold more active than oleanolic acid. A molecular docking study has also been performed to elucidate the mode of binding to the protease by these oleanolic acid derivatives. In general, the derivatives that exhibited the highest inhibitory activity of HIV-1 protease also showed the highest binding energies in docking simulations. The overall results suggest that the coupling of one or two amino acids and a phthaloyl group to oleanolic acid improves HIV-1 protease inhibition, implying that these triterpene derivatives may be promising antiviral agents against HIV.

The natural product colletoic acid (CA) is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11β-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11β-HSD1 bound to CA at 2.6 Å resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11β-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11β-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.

Natural products continue to provide a platform to study biological systems. A bioguided study of cancer cell models led us to a new member of the jatrophane natural products from Jatropha gossypiifolia, which was independently identified and characterized as jatrogossone A (1). Purification and structure elucidation was performed by column chromatography and high-performance liquid chromatography-mass spectrometry and NMR techniques, and the structure was confirmed via X-ray crystallography. The unique molecular scaffold of jatrogossone A prompted an evaluation of its mode of action. Cytotoxicity assays demonstrated that jatrogossone A displays selective antiproliferative activity against cancer cell models in the low micromolar range with a therapeutic window. Jatrogossone A (1) affects mitochondrial membrane potential (ΔΨm) in a time- and dose-dependent manner. This natural product induces radical oxygen species (ROS) selectively in cancer cellular models, with minimal ROS induction in noncancerous cells. Compound 1 induces ROS in the mitochondria, as determined by colocalization studies, and it induces mitophagy. It promotes also in vitro cell death by causing cell arrest at the G2/M stage, caspase (3/7) activation, and PARP-1 cleavage. The combined findings provide a potential mechanism by which 1 relies on upregulation of mitochondrial ROS to potentiate cytotoxic effects through intracellular signaling.

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (−)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure–activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10–16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species (L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1β2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks., Financial support by the Spanish Government [Consejo Superior de Investigaciones Científicas (201680I008)] is gratefully acknowledged. M.S. thanks the support by the doctoral program “Molecular Drug Targets” (Austrian Science Fund FWF W 1232). F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC). M.A.D.-A. thanks the Santander Bank for the support for her project in consolidable groups of CEU-UCH.

Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.

Ergosterol peroxide selectively displays biological activity against a wide range of diseases, however, its mode of action remains unknown. Here we present an efficient synthesis of ergosterol peroxide chemical probes for in vitro anticancer evaluation, live cell studies and proteomic profiling. The ergosterol peroxide analogues show promising anti-proliferation activity against triple negative breast cancer cellular models, revealing information on the structure-activity-relationship of this natural product in order to develop superior analogues. The combined cellular studies demonstrate that ergosterol peroxide is distributed across the cytosol with significant accumulation in the endoplasmic reticulum (ER). These chemical probes support our efforts towards uncovering the potential target (s) of ergosterol peroxide against triple negative breast cancer cell lines.

[EN] The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs are reported. The compounds were generated from the readily available methyl callitrisate (7), which was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was conducted to determine the effects of the different functional groups present in these molecules, providing basic structure-activity relationship (SAR) elements. In particular, the ferruginol and sugiol analogs compounds 10-16 were characterized by the presence of a phenol moiety, higher oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. The biological profiling of these compounds was investigated against a panel of six human solid tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABA(A)) receptors (alpha(1)beta(2)gamma(2s)) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted., This research was funded by Spanish National Research Council: 201680I008; Austrian Science Fund: FWF W 1232; American Lebanese Syrian Associated Charities. Santander Bank. Spanish Ministry of Science: PGC2018-094503-B-C22 and "The APC was funded by MDPI".

A base-mediated cascade reaction between malonate esters and acrolein was developed to access complex polycyclic systems. This novel tandem reaction enables the simultaneous generation of up to seven new bonds and at least three new stereogenic centers. Mechanistic studies indicate a series of nucleophilic 1,4 and 1,6 Michael addition reactions occur, followed by an aldol condensation reaction, culminating in the formation of three fused rings. The compounds were characterized by NMR studies and the stereochemistry was confirmed by X-ray analysis. The ability to generate multigram quantities of such complex molecular scaffolds renders the method promising for medicinal chemistry campaigns. Herein, we also demonstrate that the lead compounds display promising anti-proliferative activities against human cancer cell models.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening., Canvass, a crowd-sourced library of natural products, was evaluated through HTS in a spectrum of disease-relevant assays to survey the broad biological potential of natural products in drug discovery.

The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid natural products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal natural products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that natural products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant cancer cell models.

La incorporación de grasa en la dieta podría mejorar la performance reproductiva de cerdos en producción, principalmente durante las épocas más calurosas. Para comprobar esta hipótesis se evaluó el efecto de la inclusión de grasa a diferentes niveles sobre variables reproductivas de cerdas primíparas en condiciones de subtrópico. Se utilizaron 3 grupos de 6 animales (n=18) a los cuales se les suministraron 3 dietas con diferentes niveles de inclusión de grasa (0%, 3,5% y 7%) desde el día 90 de gestación y durante la lactación (21 días). Las variables medidas fueron el número de lechones nacidos totales, nacidos vivos, muertos y peso de la camada al nacimiento y al destete, mientras que sobre las hembras se registró el intervalo de retorno al celo. Se empleó un diseño completamente aleatorizado y los datos fueron analizados mediante ANOVA con el software estadístico Infostat®. No se encontraron diferencias al incorporar grasa, en relación al número de lechones nacidos vivos, muertos, totales, peso al nacimiento e intervalo-destete celo (p>0,05) mientras que el número y peso de lechones al destete se vio influenciado de manera significativa (p, Adding fat to sow diets may improve reproductive performance during the warm season. Therefore, the objective of this study was to evaluate the effect of fat addition at different levels on reproductive variables of primiparous sows in subtropical conditions. Three groups of six animals (n=18) were fed with three diets with different fat levels (0%, 3.5% and 7%) from day 90 of gestation until the end of lactation (21 days). Litter size, weight and number of piglets born alive and stillborn were recorded, as well as weight and number of pigs at weaning, along with weaning-to-estrus interval. Completely random design was used, and collected data were analyzed using Infostat® statistical software. ANOVA was used for means comparison. No differences between treatments were observed among number and weight of pig born alive, stillborn, litter size and weaning-to-estrus interval (p>0.05), whereas number and weight of pigs at weaning were increased by the addition of fat (p, Facultad de Ciencias Veterinarias

We previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds. We report the structures of the seven most abundant GLE compounds and their selective efficacy against triple negative (TNBC) and inflammatory breast cancers (IBC) and other human cancer cell types (solid and blood malignancies) to illustrate their potential as anti-cancer agents. Three of the seven compounds (ergosterol, 5,6-dehydroergosterol and ergosterol peroxide) exhibited significant in vitro anti-cancer activities, while we report for the first time the structure elucidation of 5,6-dehydroergosterol from Ganoderma lucidum. We also show for the first time in TNBC/IBC cells that ergosterol peroxide (EP) displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation, and PARP cleavage. EP decreased migratory and invasive effects of cancer cells while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc in the tested IBC cells. Our investigation also indicates that these compounds induce reactive oxygen species, compromising cell fate. Furthermore, we generated a superior derivative, ergosterol peroxide sulfonamide, with improved potency in IBC cells and ample therapeutic index (TI > 10) compared to normal cells. The combined studies indicate that EP from Ganoderma lucidum extract is a promising molecular scaffold for further exploration as an anti-cancer agent.

Liquidambar formosana (also known as maple) is a tall deciduous tree widely distributed in various regions of the South of the Qinling Mountains and Huaihe River in China, and also found in Northern Vietnam, Laos and South Korea. L. formosana is a famous ornamental plant for leaves are green in spring and summer, and red in autumn. Different plant parts of L. formosana, such as leaf, fruit, bark, and resin, are proved to be treasures as natural medicinal plant resources [1]. Among the bioactive constituents, several diterpenoid acids of the abietane family have been identified. Abietic acid (1) occurs in plants of the genus Abies and is the first member of a class of plant metabolites, the abietane-type diterpenoids. They are characterized by a tricyclic ring system and have shown a wide range of chemical diversity and biological activity.[2,3] Medicinal chemists have studied derivatives of two readily available materials such as dehydroabietic acid (2) and dehydroabietylamine (3, DHAA).[3] To date, there is only one commercial drug, Ecabet® [ecabet sodium (4)], based on abietanes, which is used for the treatment of reflux esophagitis and peptic ulcer disease. Ferruginol (5) exhibits anticancer effects in human ovarian cancer and inhibition of cancer cell migration. Recent studies of sugiol (6) demonstrated in vivo antitumor activity in DU145 prostate xenografts. These biological reports and the simultaneous isolation, (in 2014) by Hua and co-workers, of the new abietane liquiditerpenoic acid A (7), a sugiol analogue, from the resin of Liquidambar formosana [4] and from Pinus massoniana,[5] by Kuo and co-workers named independently as abietopinoic acid, prompted us to synthesize it and study its biological properties along with some analogues. References [1] Ouyang, X. L.; Yi, S.; Lu, H. Y.; Wu, S. M.; Zhao, H. Q. Eur. J. Med. Plants 2016, 17, 1-11. [2] For a review on this topic, see: Gonzalez, M. A. Nat. Prod. Rep. 2015, 32, 684-704. [3] For a review on this topic, see: Gonzalez, M. A. Eur. J. Med. Chem. 2014, 87, 834-842. [4] Shang, H.-J.; Li, D.-Y.; Wang, W.-J.; Li, Z.-L.; Hua, H.-M. Nat. Prod. Res. 2014, 28, 1-6. [5] Mohamed, H. A.; Hsieh, C.-L.; Hsu, C.; Kuo, C.-C.; Kuo, Y.-H. Helv. Chim. Acta 2014, 97, 1146-1151.

Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.

Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/β-catenin signaling pathway.

Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/β-catenin signaling pathway.

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Up to a quarter of ALL patients relapse and face poor prognosis. To identify new compound leads, we conducted a phenotypic screen using terrestrial natural product (NP) fractions against immortalized ALL cellular models. We identified vitexin, a flavonoid, as a promising hit with biological activity (EC50 = 30 μM) in pre-B cell ALL models with no toxicity against normal human tissue (BJ cells) at the tested concentrations. To develop more potent compounds against ALL and elucidate its potential mode of action, a vitexin-inspired compound library was synthesized. Thus, we developed an improved and scalable protocol for the direct synthesis of 4-quinolone core heterocycles containing an N-sulfonamide using a one-pot condensation reaction protocol. The newly generated compounds represent a novel molecular scaffold against ALL as exemplified by compounds 13 and 15, which demonstrated EC50 values in the low micromolar range (0.3–10 μM) with little to no toxicity in normal cellular models. Computational studies support the hypothesis that these compounds are potential CDK inhibitors. The compounds induced apoptosis, caused cell arrest at G0/G1 and G2/M, and induced ROS in cancer cells.

Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

Ganoderma lucidum extract (GLE), an extensively studied mushroom for its anti-cancer and anti-inflammatory properties, has been shown to possess physiologically active compounds such as polysaccharides, triterpenoids and sterols. In our previous studies, we reported that commercially available GLE whole mushroom extract selectively inhibits cancer cell viability, induces apoptosis, reduces invasion, and regulates key signaling molecules in various cell models of breast cancer. Hence, we sought to elucidate the compounds responsible for the observed anti-cancer activity. Among the isolated compounds from GLE, we identified a steroidal compound, Ergosterol Peroxide (EP), which has shown antiproliferative activity against cancer. EP is a member of natural endoperoxides, featuring the peroxy- warhead that can lead to hydroxyperoxy radicals or be activated and react as nucleophile, leading to significant biological cytotoxicity against various cancer models (e.g. ovarian, liver, colon). We hypothesized that EP would promote cell death mechanisms in the aggressive breast cancer phenotype. Thus, in this study, we evaluated EP’s anti-cancer potential using immunoblotting, colony formation, cell motility, cell cycle and reactive oxygen species (ROS) production assays against human breast cancer SUM-149, MCF-7, MDA-MB-231 cellular models. We show that EP displays anti-proliferative effects through cell arrest in G1 phase, and apoptosis induction via caspase 3/7 activation. EP induced ROS and decreased the migratory and invasive phenotype of these cancer cells. Moreover, it inhibited the expression of total AKT1, AKT2, BCL-2, BCL-XL, Cyclin D1 and c-Myc. Our combined results indicate that EP from GLE is a promising molecular scaffold for further exploration as an anti-cancer agent,particularly in aggressive breast cancer models. Citation Format: Camille L. Santiago, Fatima Rivas, Taotao Ling, Ivette J. Suarez-Arroyo, Gabriela Ortiz, Mercedes Y. Lacourt, Anibal Valentin, Walter H. Lang, Michelle M. Martínez-Montemayor. Mechanistic evaluation of ergosterol peroxide onin vitrobreast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1869.

Protozoal diseases such as malaria are a leading world health concern. We screened a library of fractionated natural products to identify new potential therapeutic leads and discovered that jatrophone (a product of Jatropha isabelli) exerts significant activity against Plasmodium falciparum strains 3D7 and K1. A focused jatrophone-scaffold library was synthesized to evaluate jatrophone's mode of action and identify more selective analogs. Compounds 25 and 32 of this natural product–inspired compound library exhibited micromolar EC50 values against strains 3D7 and K1, thus providing a new antimalarial molecular scaffold. Our report describes an efficient derivatization approach used to evaluate the structure–activity relationship of jatrophone analogs in search of potential new antimalarial agents.

In this paper the Enhanced Normalized Normal Constrained method is applied to find the optimal tuning of second order PID controllers. This tuning takes into account both the servo and regulatory modes simultaneously, as well as a closed loop robustness criterion. The methodology is successfully applied to a high order linear plant and to a non linear continuous stirred tank reactor model, showing the effectiveness of the optimization methodology to solve control related problems. Also, the method is applied to a benchmark control system that takes into account three different sources of disturbances. Universidad de Costa Rica [Vicerrectoría de Investigación de la Universidad de Costa Rica.] 322-B4-218 UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ingeniería::Instituto Investigaciones en Ingeniería (INII) UCR::Vicerrectoría de Docencia::Ingeniería::Facultad de Ingeniería::Escuela de Ingeniería Eléctrica

Lactams represent an important group of molecules due to their industrial and medicinal applications.1 Highly functionalized γ-lactams are present in biologically relevant natural products (NPs) wi...

Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

Maitotoxin (1) continues to fascinate scientists not only because of its size and potent neurotoxicity but also due to its molecular architecture. To provide further support for its structure and facilitate fragment-based biological studies, we developed an efficient chemical synthesis of the ABCDEFG segment 3 of maitotoxin. (13)C NMR chemical shift comparisons of synthetic 3 with the corresponding values for the same carbons of maitotoxin revealed a close match, providing compelling evidence for the correctness of the originally assigned structure to this polycyclic system of the natural product. The synthetic strategy for the synthesis of 3 relied heavily on our previously developed furan-based technology involving sequential Noyori asymmetric reduction and Achmatowicz rearrangement for the construction of the required tetrahydropyran building blocks, and employed a B-alkyl Suzuki coupling and a Horner-Wadsworth-Emmons olefination to accomplish their assembly and elaboration to the final target molecule.

Dysregulation of protein synthesis can lead to aberrant cellular proliferation and survival, a hallmark of cancer. Protein synthesis is a multistep process tightly controlled by specific translation factors. In eukaryotes, at the initiation point, the 43S preinitiation complex is formed by the association of several factors [eukaryotic initiation factor 2 (eIF2), GTP and methionyl initiator tRNA] with the 40S ribosomal subunit and the eukaryotic initiation factor 3 (eIF3). Over expression of eIFs has been reported in breast cancer, particularly in the most aggressive subtype, triple negative breast cancer (TNBC). More than one million global cases of breast cancer are diagnosed yearly and approximately 15% are characterized as triple negative breast cancer (TNBC), a subtype that lacks effective targeted therapy modalities. Recently, we generated a library of cell permeable abietane natural product derivatives (i.e. SJ6038) and showed that these compounds are more potent against TNBC over the estrogen receptor positive cellular models. These compounds were tagged with biotin for affinity enrichment and with a fluorescent chromophore to facilitate protein target(s) identification. A SILAC proteomics approach was used to distinguish specific binding targets from the non-specific ones. Gene Ontology analysis showed the targets identified were affiliated with regulation of protein synthesis. Ingenuity Pathway Analysis suggested that abietanes may exert their anticancer effects on critical biological pathways such as the eIF2, eIF4/p70S6K, and mTOR signaling pathways. Live cell experiments utilizing fluorescent abietane derivatives demonstrate that these probes localize to subsections of the ER, supporting the SILAC findings. Time of Exposure and Dose Response experiments further demonstrate that Abietane derivatives affect the eIF2 signaling axis. Using chemical biology and medicinal chemistry approaches, we show that abietane natural products preferentially promote cell death in TNBC cellular models by targeting the eIF2 signaling axis. These compounds will serve as unique chemical tools targeting the eIF2/eIF4 signaling axis and advance from hit- to lead for further preclinical development as a targeted therapy against aggressive solid tumors. Citation Format: Walter Lang, Taotao Ling, Jangsoon Lee, Naoto T. Ueno, Fatima Rivas. Abietane natural products as novel therapeutics against solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B28.

application/pdf, We have developed two loop-mediated isothermal amplification (LAMP) assays for specific detection of Trypanosoma cruzi and Trypanosoma rangeli based on the 18S ribosomal RNA (rRNA) and the small nucleolar RNA (snoRNA) genes, respectively. The detection limit of the assays is 100 fg and 1 pg for T. cruzi and T. rangeli, respectively, with reactions conducted in 60 minutes. The two LAMP assays were used in detection of T. cruzi and T. rangeli infections in comparison with polymerase chain reaction (PCR) for DNA samples extracted from Rhodnius pallescens bugs collected from palm trees in Panama. Out of a total of 52 DNA samples from R. pallescens bugs 17 (33%) and 14 (27%) were T. cruzi-positive by LAMP and PCR, respectively, while, 7 (13%) and 4 (8%) were T. rangeli-positive by LAMP and PCR, respectively. Further evaluation of these LAMP assays is needed, especially with specimens collected from human patients as well as blood kept for transfusion purposes. Copyright © 2010 by The American Society of Tropical Medicine and Hygiene.

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).

The cure rate of pediatric acute lymphoblastic leukemia (ALL) has significantly improved in the past thirty years, however not all patient cohorts respond well to current chemotherapy regimens. Among the high risk patient cohort is infants with MLL-rearranged (MLL-r) B-ALL, which remains dismal with an overall survival rate

Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11β-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11β-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11β-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11β-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11β-HSD1 and will serve for further biological evaluation.

Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 μM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate.

Natural products (NPs) are nature’s evolutionarily product, containing complex and diverse molecular structures. For the past two decades, pharmaceutical companies have focused on developing targeted therapeutic agents by screening libraries of small synthetic molecules. However, recent development of new technologies that improve the extraction/characterization process as well as new synthetic methodologies that render NP derivatization possible have ignited a revival in the field of NPs. NPs are now being used as a rich repository for drug discovery. Here we review recent work on the bioactive NPs derived from Jatropha isabelli along with their corresponding derivatives. Most of these NPs are sesquiterpenoids with unique molecular architectures. They display activity against various disease models and therefore may offer early compound leads for drug discovery programs.