Nitrogen-containing andrographolide derivatives with multidrug resistance reversal effects in cancer cells.

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3-25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1-25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 µM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 µM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

Unlocking the Potential of Bio-Based Nitrogen-Rich Furanic Platforms as Biomass Synthons.

The demand for new biomass-derived fine and commodity chemicals propels the discovery of new methodologies and synthons. Whereas furfural and 5-hydroxymethylfurfural are cornerstones of sustainable chemistry, 3-acetamido-5-acetyl furan (3A5AF), an N-rich furan obtained from chitin biomass, remains unexplored, due to the poor reactivity of the acetyl group relative to previous furanic aldehydes. Here we developed a reactive 3-acetamido-5-furfuryl aldehyde (3A5F) and demonstrated the utility of this synthon as a source of bio-derived nitrogen-rich heteroaromatics, carbocycles, and as a bioconjugation reagent.

Design, synthesis, and biological evaluation of new arjunolic acid derivatives as anticancer agents.

Arjunolic acid (AA) is a pentacyclic triterpenoid with promising anticancer properties. A series of novel AA derivatives containing a pentameric A-ring with an enal moiety, combined with additional modifications at C-28, were designed and prepared. The biological activity on the viability of human cancer and non-tumor cell lines was evaluated in order to identify the most promising derivatives. Additionally, a preliminary study of the structure-activity relationship was carried out. The most active derivative, derivative 26, also showed the best selectivity between malignant cells and non-malignant fibroblasts. For compound 26, the anticancer molecular mechanism of action in PANC-1 cells was further studied and the results showed that this derivative induced a cell-cycle arrest at G0/G1 phase and significantly inhibited the wound closure rate of PANC-1 cancer cells in a concentration-dependent manner. Additionally, compound 26 synergistically increased the cytotoxicity of Gemcitabine, especially at a concentration of 0.24 µM. Moreover, a preliminary pharmacological study indicated that at lower doses this compound did not demonstrate toxicity in vivo. Taken together, these findings suggest that compound 26 may be a valuable compound for the development of new pancreatic anticancer treatment, and further studies are needed to explore its full potential.

High-Throughput Production of Microsponges from Platelet Lysate for Tissue Engineering Applications.

Cell-based therapies require a large number of cells, as well as appropriate methods to deliver the cells to damaged tissue. Microcarriers provide an optimal platform for large-scale cell culture while also improving cell retention during cell delivery. However, this technology still presents significant challenges due to low-throughput fabrication methods and an inability of the microcarriers to recreate the properties of human tissue. This work proposes, for the first time, the use of methacryloyl platelet lysates (PLMA), a photocrosslinkable material derived from human platelet lysates, to produce porous microcarriers. Initially, high quantities of PLMA/alginate core-shell microcapsules are produced using coaxial electrospray. Subsequently, the microcapsules are collected, irradiated with ultraviolet light, washed, and freeze dried yielding PLMA microsponges. These microsponges are able to support the adhesion and proliferation of human adipose-derived stem cells, while also displaying potential in the assembly of autologous microtissues. Cell-laden microsponges were shown to self-organize into aggregates, suggesting possible applications in bottom-up tissue engineering applications. Impact Statement Microcarriers have increasingly been used as delivery platforms in cell therapy. Herein, the encapsulation of human-derived proteins in alginate microcapsules is proposed as a method to produce microcarriers from photopolymerizable materials. The capsules function as a template structure, which is then processed into spherical microparticles, which can be used in cell culture, cell delivery, and bottom-up assembly. As a proof of concept, this method was combined with lyophilization to process methacryloyl platelet lysates into injectable microsponges for cell delivery.

Momordica balsamina: phytochemistry and pharmacological potential of a gifted species.

Momordica balsamina L. (Cucurbitaceae), frequently named balsam apple, southern balsam pear or African pumpkin, is a vegetable with high nutritional value, being mostly used as food in sub-Saharan Africa. It has also been largely used in traditional medicine to treat several diseases, such as malaria fevers and diabetes. As a member of the Cucurbitaceae family, the main constituents are cucurbitane-type triterpenoids, with different oxidation patterns, named cucurbitacins. This review aims at summarizing our contribution to the phytochemical study of M. balsamina and the evaluation of the isolated cucurbitacins and derivatives as multidrug resistance reversers in cancer cells and bacteria. In this way, the selective antiproliferative activity against multidrug resistant cancer cells of cucurbitacins obtained from M. balsamina, their ability as P-glycoprotein inhibitors in cancer cells overexpressing this ABC transporter, as well as efflux pump inhibitors in resistant bacteria strains are reviewed. Moreover, the in vitro antimalarial activity of cucurbitacins and acyl derivatives against the blood and liver-stages of Plasmodium strains, and the in vivo activity of selected compounds is also reviewed. Besides our work, edible and medicinal uses, and other studies mainly reporting the biological activities of M. balsamina extracts, such as antidiabetic, antibacterial, anti-inflammatory, and antioxidant properties are also addressed.

Cationic Pyrrolidine/Pyrroline-Substituted Porphyrins as Efficient Photosensitizers against E. coli.

New porphyrin-pyrrolidine/pyrroline conjugates were prepared by revisiting 1,3-dipolar cycloaddition reactions between a porphyrinic azomethine ylide and a series of dipolarophiles. Cationic conjugates obtained by alkylation of the pyrrolidine/pyrroline cycloadducts showed ability to generate singlet oxygen and to produce iodine in presence of KI when irradiated with visible light. Some of the cationic derivatives showed photobactericidal properties towards a Gram-negative bioluminescent E. coli. In all cases, these features were significantly improved using KI as coadjutant, allowing, under the tested conditions, the photoinactivation of the bacterium until the detection limit of the method with a drastic reduction of the required photosensitizer concentration and irradiation time. The obtained results showed a high correlation between the ability of the cationic porphyrin derivative to produce singlet oxygen and iodine and its E. coli photoinactivation profile.

Smart Artificial Markers for Accurate Visual Mapping and Localization.

Artificial marker mapping is a useful tool for fast camera localization estimation with a certain degree of accuracy in large indoor and outdoor environments. Nonetheless, the level of accuracy can still be enhanced to allow the creation of applications such as the new Visual Odometry and SLAM datasets, low-cost systems for robot detection and tracking, and pose estimation. In this work, we propose to improve the accuracy of map construction using artificial markers (mapping method) and camera localization within this map (localization method) by introducing a new type of artificial marker that we call the smart marker. A smart marker consists of a square fiducial planar marker and a pose measurement system (PMS) unit. With a set of smart markers distributed throughout the environment, the proposed mapping method estimates the markers' poses from a set of calibrated images and orientation/distance measurements gathered from the PMS unit. After this, the proposed localization method can localize a monocular camera with the correct scale, directly benefiting from the improved accuracy of the mapping method. We conducted several experiments to evaluate the accuracy of the proposed methods. The results show that our approach decreases the Relative Positioning Error (RPE) by 85% in the mapping stage and Absolute Trajectory Error (ATE) by 50% for the camera localization stage in comparison with the state-of-the-art methods present in the literature.

A Versatile Method for Depth Data Error Estimation in RGB-D Sensors.

We propose a versatile method for estimating the RMS error of depth data provided by generic 3D sensors with the capability of generating RGB and depth (D) data of the scene, i.e., the ones based on techniques such as structured light, time of flight and stereo. A common checkerboard is used, the corners are detected and two point clouds are created, one with the real coordinates of the pattern corners and one with the corner coordinates given by the device. After a registration of these two clouds, the RMS error is computed. Then, using curve fittings methods, an equation is obtained that generalizes the RMS error as a function of the distance between the sensor and the checkerboard pattern. The depth errors estimated by our method are compared to those estimated by state-of-the-art approaches, validating its accuracy and utility. This method can be used to rapidly estimate the quality of RGB-D sensors, facilitating robotics applications as SLAM and object recognition.

Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment.

Natural pentacyclic triterpenoids (PTs) have been often reported to exhibit a wide range of biological activities. Among them, the anticancer and anti-inflammatory activities are the most studied. Over the last two decades, the number of publications reporting the anticancer effects of PTs has risen exponentially, reflecting the increasing interest in these natural products for the development of new antineoplastic drugs. Among of the most investigated PTs regarding their anticancer properties are oleanane-, ursane and friedelane-types, including oleanolic, glycyrrhetinic, ursolic and asiatic acids, and celastrol, among others. The extensive research in this field shows that the anticancer effects of PTs are mediated by several mechanisms, as they modulate a diverse range of molecular targets and signaling pathways, involved in cancer cell proliferation and survival. Considering the anticancer potential of this class of compounds, a number of semisynthetic derivatives has been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity. Some of these new semisynthetic derivatives have shown improved anticancer activity in various cancer cell lines and animal models compared with the parent compound. Moreover, some of these compounds have been assessed in clinical trials, proving to be safe for human use. This review updates the most recent findings on the semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity. A brief introduction concerning the PTs and their anticancer activity is given, and the main semisynthetic modifications that have been performed between 2012 and early 2017 are reviewed and discussed.

Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives.

A series of novel fluorinated Asiatic Acid (AA) derivatives were successfully synthesized, tested for their antiproliferative activity against HeLa and HT-29 cell lines, and their structure activity relationships were evaluated. The great majority of fluorinated derivatives showed stronger antiproliferative activity than AA in a concentration dependent manner. The most active compounds have a pentameric A-ring containing an α,ß-unsaturated carbonyl group. The compounds with better cytotoxic activity were then evaluated against MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ cell lines. Derivative 14 proved to be the most active compound among all tested derivatives and its mechanism of action was further investigated in HeLa cell line. The results showed that compound 14 induced cell cycle arrest in G0/G1 stage as a consequence of up-regulation of p21(cip1/waf1) and p27(kip1) and down-regulation of cyclin D3 and Cyclin E. Furthermore, compound 14 was found to induce caspase driven-apoptosis with activation of caspases-8 and caspase-3 and the cleavage of PARP. The cleavage of Bid into t-Bid, the up-regulation of Bax and the down-regulation of Bcl-2 were also observed after treatment of HeLa cells with compound 14. Taken together, these mechanistic studies revealed the involvement of extrinsic and intrinsic pathways in the apoptotic process induced by compound 14. Importantly, the antiproliferative activity of this compound on the non-tumor BJ human fibroblast cell line is weaker than in the tested cancer cell lines. The enhanced potency (between 45 and 90-fold more active than AA in a panel of cancer cell lines) and selectivity of this new AA derivative warrant further preclinical evaluation.

Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs.

This review highlights the potential of natural and semisynthetic ursane-type triterpenoids as candidates for the design of multi-target bioactive compounds, with focus on their anticancer effects. A brief illustration of the biosynthesis, sources, and general biological effects of the main classes of naturally occurring pentacyclic triterpenoids (PTs) are provided.

Treatment of non-small cell lung cancer with ifosfamide (IFO)+ 4'-epiadriamycin (EPI)+platinum vs. IFO+EPI: a GETLAC Study. Grupo de Estudio y Tratamiento Latinoamericano del Cáncer Study.

203 patients with inoperable non-small cell lung cancer (NSCLC) were randomized to receive ifosfamide (IFO) 2.5 g/m2 days 1-2 + epirubicin (EPI) 70 mg/m2 day 1 with cisplatin (DDP) 70 mg/m2 day 1 (arm IEP), or without cisplatin (arm IE). For uroprophylaxis, mesna i.v. 20% of IFO dose, hour 0 and 3, and oral, 40% of IFO dose, hour 6 and 9, days 1-2 was given. Cycles were repeated every 28 days. Four cycles were required for evaluation purposes. After completion of chemotherapy, external beam irradiation 40 Gy was given over 4 weeks for stage III B responders. Most of the patients with stable disease, partial response or complete response (CR) received 6 cycles. The median follow-up of the trial is 30 months. There were no differences in overall response rates: arm IEP: 52% (2% CR); arm IE: 51% (13.5% CR). Median time to progression was 6 months (arm IEP) and 4 months (arm IE) (p = 0.4844). Toxicity ranged from mild to moderate. Nephrotoxicity was not seen; only 6 patients had neurotoxic side effects of short duration. Median survival according to treatment was 12 months for IEP arm (12% at 2 years) and 10 months for IE arm (21% at 2 years). IFO/mesna+EPI or IFO/mesna, EPI plus DDP appeared to be an active and well tolerated combination for the treatment of NSCLC, with a good survival time.

Combination of surgery and chemotherapy for small-cell bronchial carcinoma.

In several test model systems using spontaneous metastasizing experimental tumours, convincing data indicate the importance of the tumour burden left after surgery for the efficacy of the combination of surgery and chemotherapy. Early removal of the primary tumour by radical surgery for cure seems to improve the conditions for chemotherapy. Since 1979, in nine different departments of thoracic surgery, patients with small-cell carcinoma of the lung (SCCL) have been randomized after surgery for cure to receive a new sequential intermittent polychemotherapy (sq.CT) of 3 different alternating drug combinations given intermittently over 1 year, or one 4-drug combination chemotherapy (CT) given intermittently over 3 years. The calculation of their life table curves at 1 August 1984 indicated an improvement in the 4-year survival rate of 23 patients receiving sq.CT to about 50%, compared with a survival rate of about 30% for 29 patients receiving CT. The number of patients is still too small for firm conclusions to be drawn, but it is concluded that surgery for SCCL seems to be an advisable measure for the efficacy of aggressive intermittent long-term polychemotherapy. However, this can only be proved in large cooperative studies.

Uso del DTIC en dosis no convencionales en el tratamiento adyuvante del melanoma cutaneo. / Use of unusual doses of DTIC in the adjuvant treatment of cutaneous melanoma

Nueve pacientes con melanoma maligno(Clark III, IV y V y Breslow mayor a 0,75 mm),sin metastasis macroscopicas detectables, fueron tratados con cirugia (consistente en escision amplia del tumor), mas quimioterapia adyuvante con altas dosis de DTIC.Los primeros controles no mostraron recaidas. El seguimiento de los pacientes lleva entre los siete y los veintidos meses. Los efectos toxicos mas severos consisten en mielosupresion (leucopenia y trombocitopenia), nauseas, vomitos y hepatotoxicidad manifestados por un aumento de la TGP y TGO circulantes

Uso del DTIC en dosis no convencionales en el tratamiento adyuvante del melanoma cutaneo. / Use of unusual doses of DTIC in the adjuvant treatment of cutaneous melanoma

Nueve pacientes con melanoma maligno(Clark III, IV y V y Breslow mayor a 0,75 mm),sin metastasis macroscopicas detectables, fueron tratados con cirugia (consistente en escision amplia del tumor), mas quimioterapia adyuvante con altas dosis de DTIC.Los primeros controles no mostraron recaidas. El seguimiento de los pacientes lleva entre los siete y los veintidos meses. Los efectos toxicos mas severos consisten en mielosupresion (leucopenia y trombocitopenia), nauseas, vomitos y hepatotoxicidad manifestados por un aumento de la TGP y TGO circulantes