Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product.

Monoterpenes and meroterpenes are two large classes of isoprene-based molecules produced by terrestrial plants and unicellular organisms as diverse secondary metabolites. The global rising incidence of cancer has led to a renewed interest in natural products. These monoterpenes and meroterpenes represent a novel source of molecular scaffolds that can serve as medicinal chemistry platforms for the development of potential preclinical leads. Furthermore, some of these natural products are either abundant, or their synthetic strategies are scalable as it will be indicated here, facilitating their derivatization to expand their scope in drug discovery. This review is a collection of representative updates (from 2016-2023) in biologically active monoterpene and meroterpenoid natural products and focuses on the recent findings of the pharmacological potential of these bioactive compounds as well as the newly developed synthetic strategies employed to access them. Particular emphasis will be placed on the anticancer and antioxidant potential of these compounds in order to raise knowledge for further investigations into the development of potential anti-cancer therapeutics. The mounting experimental evidence from various research groups across the globe regarding the use of these natural products at pre-clinical levels, renders them a fast-track research area worth of attention.

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus.

Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction in the antiviral effective concentration of drugs already approved by the FDA, such as ivermectin (IVM), ribavirin (RIBA), and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV), and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecules with broad-spectrum antiviral activity, the ferruginol analog 18-(phthalimid-2-yl)ferruginol (phthFGL), which presented an IC99 of 25.6 µM for the three types of virus. In general, the combination of IVM, phthFGL, and oregano EO showed the greatest synergism potential against CHIKV, ZIKV, and HHV-2. For instance, this combination achieved reductions in the IC99 value of each component up to ~8-, ~27-, and ~12-fold for CHIKV, respectively. The ternary combination of RIBA, phthFGL, and oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, and oregano EO, which indicates that IVM could contribute more to the differentiation of cell targets (for example via the inhibition of the host heterodimeric importin IMP α/ß1 complex) than ribavirin. Statistical analysis showed significant differences among the combination groups tested, especially in the HHV-2 and CHIKV models, with p = 0.0098. Additionally, phthFGL showed a good pharmacokinetic profile that should encourage future optimization studies.

Discovery of Novel Bioactive Tanshinones and Carnosol Analogues against Breast Cancer.

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.

Triterpenoids as Reactive Oxygen Species Modulators of Cell Fate.

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.

Changes on the health care of people with multiple sclerosis from Latin America during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in uncertain access to medical treatment for people with multiple sclerosis (pwMS) all over the world. However, there is no data regarding its impact on access to health care of pwMS from Latin America. OBJECTIVES: We investigated and described changes in health care delivery for pwMS from Latin America during the COVID-19 pandemic. METHODS: PwMS from 18 patient organizations of the region completed a web-based survey hosted from May to October 2020. RESULTS: A total of 602 pwMS completed the questionnaire. Changes in disease-modifying therapies (DMTs) use: 6.7% of pwMS on continuous DMTs claimed to stopped them; 14.1% of those on infusion therapies declared to postpone their dosing; 68.8% declared delaying the initiation of a DMT. Disruptions in accessing rehabilitation services were reported by 65.7%. Changes in laboratory and MRI monitoring were reported by 30% and 33%, respectively. In a multivariable-adjusted logistic regression model, changes in laboratory monitoring were significantly associated with increased odds of postponing MRI monitoring (OR 4.09 CI95% 2.79-6.00, p < 0.001). CONCLUSIONS: The COVID-19 pandemic has disrupted all aspects of the routine care for pwMS from Latin America. Consequences are yet to be determined.

Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues.

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 (GABAA) receptors (α1ß2γ2s) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted.

Surface periarterial spaces of the mouse brain are open, not porous.

Fluid-dynamic models of the flow of cerebrospinal fluid in the brain have treated the perivascular spaces either as open (without internal solid obstacles) or as porous. Here, we present experimental evidence that pial (surface) periarterial spaces in mice are essentially open. (1) Paths of particles in the perivascular spaces are smooth, as expected for viscous flow in an open vessel, not diffusive, as expected for flow in a porous medium. (2) Time-averaged velocity profiles in periarterial spaces agree closely with theoretical profiles for viscous flow in realistic models, but not with the nearly uniform profiles expected for porous medium. Because these spaces are open, they have much lower hydraulic resistance than if they were porous. To demonstrate, we compute hydraulic resistance for realistic periarterial spaces, both open and porous, and show that the resistance of the porous spaces are greater, typically by a factor of a hundred or more. The open nature of these periarterial spaces allows significantly greater flow rates and more efficient removal of metabolic waste products.

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition.

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.

Identification of rapid access to polycyclic systems via a base-catalyzed cascade cyclization reaction and their biological evaluation.

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.

Mechanistic Insight on the Mode of Action of Colletoic Acid.

The natural product colletoic acid (CA) is a selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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. 11ß-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 11ß-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 11ß-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 11ß-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.

Studies of Jatrogossone A as a Reactive Oxygen Species Inducer in Cancer Cellular Models.

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.

Cytostatic and Cytotoxic Natural Products against Cancer Cell Models.

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.

Development of ergosterol peroxide probes for cellular localisation studies.

Ergosterol peroxide selectively exhibits 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. 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.

Identification of Biologically Active Ganoderma lucidum Compounds and Synthesis of Improved Derivatives That Confer Anti-cancer Activities in vitro.

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.

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies.

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 (α1ß2γ2s) 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.

Identification of substituted 5-membered heterocyclic compounds as potential anti-leukemic agents.

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.

Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8.

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.

Seguimiento de un año de pacientes con úlceras venosas crónicas en pierna y pie, tratadas en la clínica de úlceras y heridas del Hospital Nacional Rosales, incidentes en el periodo de 1 de enero a 31 de diciembre 2017 / One-year follow-up of patients with chronic venous leg and foot ulcers, treated in the ulcer and wound clinic of the Rosales Nacional Hospital, incidents in the period from January 1 to December 31, 2017

Las ulceras crónicas venosas (UCVP) de la pierna se definen como "herida crónica de la pierna que muestra ninguna tendencia a sanar después de 3 meses de tratamiento apropiado o no está totalmente sana a 12 meses". Su prevalencia es del 1% al 5%, más frecuente en mujeres y añosas, con un tiempo de curación de 12 meses, carácter cíclico y crónico, con periodos de cicatrización seguidos de recurrencia con persistencia de años. Son una causa principal de morbilidad, sufrimiento y elevados costes sanitarios. Su manejo es integral, manejo del factor etiológico, medias de compresión y mantenimiento sin infección de las UCVP. Utilizamos un diseño observacional, longitudinal de seguimiento a un año de pacientes incidentes en el año 2017, con UCVP que requirieron curación en la Clínica de Ulceras y Heridas del HNR, seguidos hasta el cierre de la UCVP, o hasta cumplir un año de curación, utilizando fuentes documentales existentes, los expedientes de pacientes. Se identificaron 72 pacientes: 45 mujeres (62.5%) y 27 hombres (37.5%), relación femenina/masculino de 1.66:1. Edad media de 60.93 años (DS + 17.702). El área de ubicación de la ulcera fue distal en la pierna en 53 casos. Al 65.34% de pacientes no se les busco factor etiológico. Manejo: 38.9% se les indico medias compresivas, 81.9% se les coloco antibiótico tópico. Al 23.11% se les realizo cirugía sobre el factor etiológico. Tasa global de cierre del 11.1% y 25% de recidiva a 4 semanas. La tasa global de cierre de la UCVP en la clínica de ulceras y heridas del Hospital Nacional Rosales es baja

Correction: The natural compound Jatrophone interferes with Wnt/ß-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer.

[This corrects the article DOI: 10.1371/journal.pone.0189864.].

Novel vitexin-inspired scaffold against leukemia.

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.