Santolina chamaecyparissus L. (cotton-lavender) is receiving increasing attention due to its potential for modern medicine and is considered both a functional food and nutraceutical. In this work, the phytochemical profile of its flower hydromethanolic extract was investigated by gas chromatography-mass spectrometry, and its applications as a biorational for crop protection were explored against Neocosmospora spp., both in vitro and in planta. The phytochemical profiling analysis identified several terpene groups. Among sesquiterpenoids, which constituted the major fraction (50.4%), compounds featuring cedrane skeleton (8-cedren-13-ol), aromadendrene skeleton (such as (-)-spathulenol, ledol, alloaromadendrene oxide, epiglobulol, and alloaromadendrene), hydroazulene skeleton (ledene oxide, isoledene, and 1,2,3,3a,8,8a-hexahydro-2,2,8-trimethyl-,(3a α ,8 β ,8a α )-5,6-azulenedimethanol), or copaane skeleton ( cis -α-copaene-8-ol) were predominant. Additional sesquiterpenoids included longiborneol and longifolene. The monoterpenoid fraction (1.51%) was represented by eucalyptol, (+)-4-carene, endoborneol, and 7-norbornenol. In vitro tests against N. falciformis and N. keratoplastica , two emerging soil phytopathogens, resulted in effective concentration EC 90 values of 984.4 and 728.6 μg·mL -1 , respectively. A higher dose (3000 μg·mL -1 ) was nonetheless required to achieve full protection in the in planta tests conducted on zucchini ( Cucurbita pepo L.) cv. 'Diamant F1' and tomato ( Solanum lycopersicum L.) cv. 'Optima F1' plants inoculated with N. falciformis by root dipping. The reported data indicate an antimicrobial activity comparable to that of fosetyl-Al and higher than that of azoxystrobin conventional fungicides, thus making the flower extract a promising bioactive product for organic farming and expanding S. chamaecyparissus potential applications.

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Puupehenone and puupehedione are natural products isolated from marine organisms. These compounds display a broad spectrum of biological activities, the in vitro antitubercular activity of puupehenone being a stand out, and are equipped with an interesting structural complexity. These products have served to stimulate the continual interest of the synthetic community. The first part of this article is a review of their total synthesis, using natural compounds which have the potential to be transformed into these marine compounds as starting materials; the synthetic routes employed to generate the basic skeleton; and the advances made to synthesize the pyran C ring with the required diastereoselectivity to obtain the natural products. Finally, this perspective shows a personal reflection of the authors on a possible unified and efficient retrosynthetic route that could allow easy access to these natural products, as well as their epimers at the C8 carbon and which could be used to address future biological issues in the production of pharmacologically active compounds.

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Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few. In view of these, we developed a robust synthetic method that allows the assembly of 36 novel sclareolide-indole conjugates and their derivatives. The synthetic method was based on TiCl 4 -promoted nucleophilic substitution of sclareolide-derived hemiacetal 4 , while electron-rich aryles including indoles, polyphenol ethers, and pyrazolo [1,5-a]pyridine were good substrates. The stereochemistry of the final products was confirmed by single-crystal X-ray diffraction analysis, while the antiproliferative activities of selected final products were tested in K562 and MV4-11 cancer cell lines. Cytometric flow analysis shows that lead compounds 8k - and 10 -induced robust apoptosis in MV4-11 cancer cells, while they exhibited weak impact on cell cycle progression. Taken together, our study suggests that sclareolide could be a good template and substrate for the synthesis of novel antiproliferative compounds.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease which confers to patients a poor prognosis at short term. PDAC is the fourth leading cause of death among cancers in the Western world. The rate of new cases of pancreatic cancer (incidence) is 10 per 100,000 but present a 5-year survival of less than 10%, highlighting the poor prognosis of this pathology. Furthermore, 90% of advanced PDAC tumor present KRAS mutations impacting in several oncogenic signaling pathways, many of them associated with cell proliferation and tumor progression. Different combinations of chemotherapeutic agents have been tested over the years without an improvement of significance in its treatment. PDAC remains as one the more challenging biomedical topics thus far. The lack of a proper early diagnosis, the notable mortality statistics and the poor outcome with the available therapies urge the entire scientific community to find novel approaches against PDAC with real improvements in patients' survival and life quality. Natural compounds have played an important role in the process of discovery and development of new drugs. Among them, terpenoids, such as sesquiterpene lactones, stand out due to their biological activities and pharmacological potential as antitumor agents. In this review, we will describe the sesquiterpene lactones with in vitro and in vivo activity against pancreatic tumor cells. We will also discuss the mechanism of action of the compounds as well as the signaling pathways associated with their activity.

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Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc‑1 and ASPC‑1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine‑resistant cells (GR‑HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR‑HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR‑HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR‑HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine‑induced EMT through the TWIST1/Slug pathway in the GR‑HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma‑associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug‑hENT1/RRM1 signaling and resensitized GR‑HPCCs to gemcitabine. Finally, sclareolide resensitized GR‑HPCCs to gemcitabine through inducing apoptosis; in vivo, the co‑administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine‑resistant pancreatic cancer, which resensitizes GR‑HPCCs to gemcitabine through mediating NICD and Gli1.

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