Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizing C.elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Enzymatic Benzofuranoindoline Formation in the Biosynthesis of the Strained Bridgehead Bicyclic Dipeptide (+)-Azonazine A.

We uncovered and reconstituted a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A from marine-derived Aspergillus insulicola. Formation of the hexacyclic benzofuranoindoline ring system from cyclo-(l-Trp-N-methyl-l-Tyr) is catalyzed by a P450 enzyme through an oxidative cyclization. Supplementing the producing strain with various indole-substituted tryptophan derivatives resulted in the generation of a series of azonazine A analogs.

Distribution and diversity of 'Tectomicrobia', a deep-branching uncultivated bacterial lineage harboring rich producers of bioactive metabolites.

Genomic and functional analyses of bacterial sponge symbionts belonging to the uncultivated candidate genus 'Entotheonella' has revealed them as the prolific producers of bioactive compounds previously identified from their invertebrate hosts. These studies also suggested 'Entotheonella' as the first members of a new candidate phylum, 'Tectomicrobia'. Here we analyzed the phylogenetic structure and environmental distribution of this as-yet sparsely populated phylum-like lineage. The data show that 'Entotheonella' and other 'Tectomicrobia' are not restricted to marine habitats but widely distributed among terrestrial locations. The inferred phylogenetic trees suggest several intra-phylum lineages with diverse lifestyles. Of these, the previously described 'Entotheonella' lineage can be more accurately divided into at least three different candidate genera with the terrestrial 'Candidatus Prasianella', the largely terrestrial 'Candidatus Allonella', the 'Candidatus Thalassonella' comprising sponge-associated members, and the more widely distributed 'Candidatus Entotheonella'. Genomic characterization of 'Thalassonella' members from a range of sponge hosts did not suggest a role as providers of natural products, despite high genomic similarity to 'Entotheonella' regarding primary metabolism and implied lifestyle. In contrast, the analysis revealed a correlation between the revised 'Entotheonella' 16S rRNA gene phylogeny and a specific association with sponges and their natural products. This feature might serve as a discovery method to accelerate the identification of new chemically rich 'Entotheonella' variants, and led to the identification of the first 'Entotheonella' symbiont in a non-tetractinellid sponge, Psammocinia sp., indicating a wide host distribution of 'Entotheonella'-based chemical symbiosis.

Suppression of MAPK/NF-kB and activation of Nrf2 signaling by Ajugarin-I in EAE model of multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neurodegenerative autoimmune disease of the central nervous system (CNS). The current study aimed to investigate the neuroprotective properties of Ajugarin-I (Aju-I) against the experimental autoimmune encephalomyelitis (EAE) model of MS and explored the underlying mechanism involved. The protective potential of Aju-I was first confirmed against glutamate-induced HT22 cells and hydrogen peroxide (H2 O2 )-induced BV2 cells. Next, an EAE model has been established to investigate the mechanisms of MS and identify potential candidates for MS treatment. The behavioral results demonstrated that Aju-I post-immunization treatment markedly reduced the EAE-associated clinical score, motor impairment, and neuropathic pain. Evans blue and fluorescein isothiocyanate extravasation in the brain were markedly reduced by Aju-I. It effectively restored the EAE-associated histopathological changes in the brain and spinal cord. It markedly attenuated EAE-induced inflammation in the CNS by reducing the expression levels of p-38/JNK/NF-κB but increased the expression of IkB-α. It suppressed oxidative stress by increasing the expression of Nrf2 but decreasing the expression of keap-1. It suppressed EAE-induced apoptosis in the CNS by regulating Bax/Bcl-2 and Caspase-3 expression. Taken together, this study suggests that Aju-I treatment exhibits neuroprotective properties in the EAE model of MS via regulation of MAPK/NF-κB, Nrf2/Keap-1, and Bcl2/Bax signaling.

Reevaluation of a Bicyclic Pyrazoline as a Selective 15-Lipoxygenase V-Type Activator Possessing Fatty Acid Specificity.

Regulation of lipoxygenase (LOX) activity is of great interest due to the involvement of the various LOX isoforms in the inflammatory process and hence many diseases. The bulk of investigations have centered around the discovery and design of inhibitors. However, the emerging understanding of the role of h15-LOX-1 in the resolution of inflammation provides a rationale for the development of activators as well. Bicyclic pyrazolines are known bioactive molecules that have been shown to display antibiotic and anti-inflammatory activities. In the current work, we reevaluated a previously discovered bicyclic pyrazoline h15-LOX-1 activator, PKUMDL_MH_1001 (written as 1 for this publication), and determined that it is inactive against other human LOX isozymes, h5-LOX, h12-LOX, and h15-LOX-2. Analytical characterization of 1 obtained in the final synthesis step identified it as a mixture of cis- and trans-diastereomers: cis-1 (12%) and trans-1 (88%); and kinetic analysis indicated similar potency between the two. Using compound 1 as the cis-trans mixture, h15-LOX-1 catalysis with arachidonic acid (AA) (AC50 = 7.8 +/- 1 µM, A max = 240%) and linoleic acid (AC50 = 5.3 +/- 0.7 µM, A max = 98%) was activated, but not with docosahexaenoic acid (DHA) or mono-oxylipins. Steady-state kinetics demonstrate V-type activation for 1, with a ß value of 2.2 +/- 0.4 and an K x of 16 +/- 1 µM. Finally, it is demonstrated that the mechanism of activation for 1 is likely not due to decreasing substrate inhibition, as was postulated previously. 1 also did not affect the activity of the h15-LOX-1 selective inhibitor, ML351, nor did 1 affect the activity of allosteric effectors, such as 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12S-HETE) and 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid (14S-HpDHA). These data confirm that 1 binds to a distinct activation binding site, as previously postulated. Future work should be aimed at the development of selective activators that are capable of activating h15-LOX-1 catalysis with DHA, thus enhancing the production of DHA-derived pro-resolution biomolecules.

Appraising California Zinfandel Exposure to Wildfire Smoke Using Natural Product Phenolic Diglycoside Biomarkers.

Zinfandel grapes are ubiquitous in California and its wine quality could be negatively impacted from wildfire smoke. Thus, the occurrence of fires prior to grape harvest presents a persistent problem to both viticulture and enology processes. This is the first broad study on Zinfandel to investigate wine quality defects produced by natural wildfires. The project, guided by UHPLC separations and MS2 multiple reaction monitoring, involved measuring natural product phenolic diglycosides (PDs) bioaccumulated in grapes, and expands outcomes published in 2022 by our team (called the Santa Cruz Campaign, SCC). The plan was implemented by exploiting a panel of six marker PDs 1-6 and their deuterated analogues. Examined in the study were 24 different Zinfandel wines obtained from 2016 to 2021 vintages of nine different American Viticulture Areas (AVAs) that were also within five of the eight California Zinfandel viticulture zones. The goal was to extend understanding on PD variations using patterns that possibly change as a function of appellation and fire intensity. Preliminary data was obtained to examine the relative amounts of PDs localized in berry skin versus pulp. The baseline of <15 ppb was proposed by surveying 18 distinct unsmoked Zinfandel wines. It was proposed to estimate the smoke impact on other Zinfandel wines by using seven PD ppb concentrations categories. A pilot study was also launched to assess conclusions by comparing ppb-based ratings versus sensory evaluation quality estimates. General findings presented herein should provide an important foundation to build understanding of using PD patterns to forecast possible Zinfandel wine wildfire damage.

In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (-)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (-)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.

Tandem high resolution mass spectrometry based phytochemical composition of Sauromatum guttatum tubers and its enzyme inhibitory potential with molecular docking.

Sauromatum guttatum has been traditionally used in the treatment of snakebite and tumors in India, Pakistan, and China. However, it lacks detailed phytochemical composition like other members of the family Araceae. Therefore, the aim of the present study was to investigate the phytochemical composition of crude methanolic extract and subsequent fractions from S. guttatum tubers and to determine their enzyme inhibitory potentials. The phytochemical profile was studied through tandem high-resolution mass-based phytochemical analysis and Global Natural Product Social (GNPS) molecular networking. Similarly, crude extract and fractions were also investigated for enzyme inhibitory activity against urease and α-glucosidase. Twenty-six compounds were dereplicated belonging to flavone C-glycosides, flavone O-glycosides, phenolic acids, phenolic acid glycosides, and iridoid glycosides. The n-butanol fraction was particularly found rich in flavone di-C-glycosides including schaftoside, isoschaftoside, neoschaftoside, and vicenin-2. The n-butanol fraction exhibited the highest in vitro inhibition against urease and α-glucosidase with IC50 values of 113.7 µg/mL and 155.3 µg/mL, respectively. The results of enzyme inhibition potential were also supported by in silico molecular docking studies against the above-mentioned enzymes. This is the first report on the detailed phytochemical profile of S. guttatum tubers, and these results will contribute to the chemosystematic knowledge of the Araceae family. The results of this study also suggest that S. guttatum may find possible applications in the treatment of gastrointestinal disorders and diabetes.

Natural Product Phenolic Diglycosides Created from Wildfires, Defining Their Impact on California and Oregon Grapes and Wines.

Forest fires produce malodorous phenols, bioaccumulated in grapes as odorless phenol glycosides (mono- to tri-), and produce unpleasant smoke tainted wines when these complexes are transformed by glycosidases in saliva. Metabolomic analyses were used to further understand smoke taint by quantitating marker phenolic diglycosides via UHPLC separations and MS/MS multiple reaction monitoring. A collection of grapes and wines provided data to forecast wine quality of grapes subjected to wildfire smoke infestations; the analytics used a panel of reference compounds (1-6). Overall, eight different Vitis vinifera varietals were examined from 2017-2021 vintages involving >218 distinct samples (wines and/or grapes) from 21 different American Viticulture Areas. Results acquired allowed correlation of phenolic diglycoside levels as a function of grape cultivar, varietal clones, and intensity of wildfire smoke. Baseline data were tabulated for nonsmoked samples (especially, Cabernet Sauvignon having a sum 1-6 of <6 µg/L) and then compared to those exposed to six other levels of smoke. Outcomes established that (1) analyzing paired samples (bottled wines versus smoke-exposed grapes) can provide diagnostic metabolomic data, (2) phenolic diglycosides are stable in wines aged for >2.5 years, and (3) major gaps exist in our current understanding of this pool of metabolites.

Re-evaluation of the Fijianolide/Laulimalide Chemotype Suggests an Alternate Mechanism of Action for C-15/C-20 Analogs.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (3), fijianolide B di-acetate (4), and two new semisynthetic analogs of 3, which include fijianolide J (5) and fijianolide L (6). Similar to paclitaxel, compound 3 demonstrated classic microtubule stabilizing activity with potent (GI50 = 0.7-17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines. Alternatively, compounds 5 or 6, generated from oxidation of C-20 or C-15 and C-20 respectively, resulted in a unique profile with reduced potency (GI50 = 4-9 µM), but improved efficacy in some lines, suggesting a distinct mechanism of action. The C-15, C-20 di-acetate, and dioxo modifications on 4 and 6 resulted in compounds devoid of classic microtubule stabilizing activity in biochemical assays. While 4 also had no detectable effect on cellular microtubules, 6 promoted a reorganization of the cytoskeleton resulting in an accumulation of microtubules at the cell periphery. Compound 5, with a single C-20 oxo substitution, displayed a mixed phenotype, sharing properties of 3 and 6. These results demonstrate the importance of the C-15/C-20 chiral centers, which appear to be required for the potent microtubule stabilizing activity of this chemotype and that oxidation of these sites promotes unanticipated cytoskeletal alterations that are distinct from classic microtubule stabilization, likely through a distinct mechanism of action.

Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.

Human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) is expressed in many tissues and has been implicated in atherosclerosis, cystic fibrosis and ferroptosis. However, there are few reported potent/selective inhibitors that are active ex vivo. In the current work, we report newly discovered molecules that are more potent and structurally distinct from our previous inhibitors, MLS000545091 and MLS000536924 (Jameson et al, PLoS One, 2014, 9, e104094), in that they contain a central imidazole ring, which is substituted at the 1-position with a phenyl moiety and with a benzylthio moiety at the 2-position. The initial three molecules were mixed-type, non-reductive inhibitors, with IC50 values of 0.34 ±â€¯0.05 µM for MLS000327069, 0.53 ±â€¯0.04 µM for MLS000327186 and 0.87 ±â€¯0.06 µM for MLS000327206 and greater than 50-fold selectivity versus h5-LOX, h12-LOX, h15-LOX-1, COX-1 and COX-2. A small set of focused analogs was synthesized to demonstrate the validity of the hits. In addition, a binding model was developed for the three imidazole inhibitors based on computational docking and a co-structure of h15-LOX-2 with MLS000536924. Hydrogen/deuterium exchange (HDX) results indicate a similar binding mode between MLS000536924 and MLS000327069, however, the latter restricts protein motion of helix-α2 more, consistent with its greater potency. Given these results, we designed, docked, and synthesized novel inhibitors of the imidazole scaffold and confirmed our binding mode hypothesis. Importantly, four of the five inhibitors mentioned above are active in an h15-LOX-2/HEK293 cell assay and thus they could be important tool compounds in gaining a better understanding of h15-LOX-2's role in human biology. As such, a suite of similar pharmacophores that target h15-LOX-2 both in vitro and ex vivo are presented in the hope of developing them as therapeutic agents.

Assessing the ethnobotanical potential of Carissa opaca berries by merging outcomes from metabolomics profiling, enzyme assays, and in silico docking studies.

The phytochemical profile of Carissa opaca fruit extract and fractions was established through dereplication strategies employing LC-MS/MS and global natural product social molecular networking (GNPS). Crude extract and fractions were evaluated for their potential to inhibit α-glucosidase and urease in vitro. Flavonoid-O-glycosides, flavonoid-C-glycosides, flavonoids, proanthocyanidin B2, phenolics, and triterpenoids were annotated as the major classes of secondary metabolites present in the extract and fractions. α-Glucosidase inhibition was associated with n-butanol and ethyl acetate fractions comparable to acarbose (IC50 = 120.43 µg/mL) with IC50 values of 123.67 and 131.72 µg/mL, respectively. The ethyl acetate fraction showed good urease inhibition comparable with thiourea (IC50 = 103.71 µg/mL) with an IC50 value of 109.14 µg/mL. Molecular docking studies of compounds observed in the crude extract and bioactive fractions had significant binding scores, which supported results for enzyme inhibition in vitro. This study provided a detailed phytochemical profile of C. opaca fruit and its enzyme inhibition potential.

Highlights of marine natural products having parallel scaffolds found from marine-derived bacteria, sponges, and tunicates.

Marine-derived bacteria are a prolific source of a wide range of structurally diverse natural products. This review, dedicated to Professor William Fenical, begins by showcasing many seminal discoveries made at the University of California San Diego from marine-derived actinomycetes. Discussed early on is the 20-year journey of discovery and advancement of the seminal actinomycetes natural product salinosporamide A into Phase III anticancer clinical trials. There are many fascinating parallels discussed that were gleaned from the comparative literature of marine sponge, tunicate, and bacteria-derived natural products. Identifying bacterial biosynthetic machinery housed in sponge and tunicate holobionts through both culture-independent and culture-dependent approaches is another important and expanding subject that is analyzed. Work reviewed herein also evaluates the hypotheses that many marine invertebrate-derived natural products are biosynthesised by associated or symbiotic bacteria. The insights and outcomes from metagenomic sequencing and synthetic biology to expand molecule discovery continue to provide exciting outcomes and they are predicted to be the source of the next generation of novel marine natural product chemical scaffolds.

An exon skipping screen identifies antitumor drugs that are potent modulators of pre-mRNA splicing, suggesting new therapeutic applications.

Agents that modulate pre-mRNA splicing are of interest in multiple therapeutic areas, including cancer. We report our recent screening results with the application of a cell-based Triple Exon Skipping Luciferase Reporter (TESLR) using a library that is composed of FDA approved drugs, clinical compounds, and mechanistically characterized tool compounds. Confirmatory assays showed that three clinical antitumor therapeutic candidates (milciclib, PF-3758309 and PF-562271) are potent splicing modulators and that these drugs are, in fact, nanomolar inhibitors of multiple kinases involved in the regulation the spliceosome. We also report the identification of new SF3B1 antagonists (sudemycinol C and E) and show that these antagonists can be used to develop a displacement assay for SF3B1 small molecule ligands. These results further support the broad potential for the development of agents that target the spliceosome for the treatment of cancer and other diseases, as well as new avenues for the discovery of new chemotherapeutic agents for a range of diseases.

Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8S Configuration.

Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 µM) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [α]D data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 µM, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-1-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.

Unraveling Structures Containing Highly Conjugated Pyrrolo[4,3,2-de]quinoline Cores That Are Deficient in Diagnostic Proton NMR Signals.

This study began with the goal of identifying additional constituents from Zyzzya fuliginosa extracts obtained from an Indo-Pacific sponge (coll. no. 06132). The previous work identified several red and green pyrroloiminiquinones (aka pyrrolo[4,3,2-de]quinolines), and this reinvestigation provided two additional analogues, a blue compound named zyzzamine A (1) and a green compound named zyzzamine B (2). The relatively low ratio of H/[sum(CNO)] = 0.71 or 0.76 of this pair greatly complicated the final steps of compound characterization and required the use of five 2D NMR strategies and MS2 data sets.

The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: .

The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells.

Our quest to isolate and characterize natural products with in vitro solid tumor selectivity is driven by access to repositories of Indo-Pacific sponge extracts. In this project an extract of a species of Haplosclerida sponge obtained from the US NCI Natural Products Repository displayed, by in vitro disk diffusion assay (DDA) and IC50 determinations, selective cytotoxicity with modest potency to a human pancreatic cancer cell line (PANC-1) relative to the human lymphoblast leukemia cell line (CCRF-CEM). Two brominated indoles, the known 6-bromo conicamin (1) and the new derivative, 6-Br-8-keto-conicamin A (2), were identified and 2 (IC50 1.5 µM for the natural product vs 4.1 µM for the synthetic material) was determined to be responsible for the cytotoxic activity of the extract against the PANC-1 tumor cell line. The new natural product and ten additional analogs were prepared for further SAR testing.