2-Substituted hydrazinecarbothioamides and N ,2-disubstituted hydrazinecarbothioamides react in high yield with dimethyl acetylenedicarboxylate (DMAD) to give 4-oxo-Z-(thiazolidin-5-ylidene) acetate derivatives. Several mechanistic options involving interaction are presented. The structures of thiazolidin-4-ones have been unambiguously confirmed by single crystal X-ray crystallography. (C) 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.

ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 mu M range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 mu M, 1.56 mu M, 0.78 mu M and 0.72 mu M, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 mu M on both strains, and MIC value of 32 mu M against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. (C) 2019 Elsevier Masson SAS. All rights reserved.

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61 alpha (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61 alpha from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61 alpha forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61 alpha provides compelling evidence that Sec61 alpha is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61 alpha is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61 alpha function and to further investigate its potential as a therapeutic target for drug discovery.

Covering: up to the end of 2019 Diverse natural product small molecules have allowed critical insights into processes that govern eukaryotic cells' ability to secrete cytosolically synthesized secretory proteins into their surroundings or to insert newly synthesized integral membrane proteins into the lipid bilayer of the endoplasmic reticulum. In addition, many components of the endoplasmic reticulum, required for protein homeostasis or other processes such as lipid metabolism or maintenance of calcium homeostasis, are being investigated for their potential in modulating human disease conditions such as cancer, neurodegenerative conditions and diabetes. In this review, we cover recent findings up to the end of 2019 on natural products that influence protein secretion or impact ER protein homeostasis, and serve as powerful chemical tools to understand protein flux through the mammalian secretory pathway and as leads for the discovery of new therapeutics.

Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.

Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones la-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL Et3N. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e, f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATPcompetitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor subpanels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI(50) and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.

Coibamide A is a potent cancer cell toxin and one of a select group of natural products that inhibit protein entry into the secretory pathway via a direct inhibition of the Sec61 protein translocon. Many Sec61 client proteins are clinically relevant drug targets once trafficked to their final destination in or outside the cell, however the use of Sec61 inhibitors to block early biosynthesis of specific proteins is at a pre-clinical stage. In the present study we evaluated the action of coibamide A against human epidermal growth factor receptor (HER, ErbB) proteins in representative breast and lung cancer cell types. HERs were selected for this study as they represent a family of Sec61 clients that is frequently dysregulated in human cancers, including coibamide-sensitive cell types. Although coibamide A inhibits biogenesis of a broad range of Sec61 substrate proteins in a presumed substrate nonselective manner, endogenous HER3 (ErbB-3) and EGFR (ErbB-1) proteins were more sensitive to coibamide A, and the related Sec61 inhibitor apratoxin A, than HER2 (ErbB-2). Despite this rank order of sensitivity (HER3 > EGFR > HER2), Sec61-dependent inhibition by coibamide A was sufficient to decrease cell surface expression of HER2. We report that coibamide Aor apratoxin A-mediated block of HER3 entry into the secretory pathway is unlikely to be mediated by the HER3 signal peptide alone. HER3 (G11L/S15L), that is fully resistant to the highly substrate-selective cotransin analogue CT8, was more resistant than wild-type HER3 but only at low coibamide A (3 nM) concentrations; HER3 (G11L/S15L) expression was inhibited by higher concentrations of either natural product. Timeand concentration-dependent decreases in HER protein expression induced a commensurate reduction in AKT/MAPK signaling in breast and lung cancer cell types and loss in cell viability. Coibamide A potentiated the cytotoxic efficacy of small molecule kinase inhibitors lapatinib and erlotinib in breast and lung cancer cell types, respectively. These data indicate that natural product modulators of Sec61 function have value as chemical probes to interrogate HER/ErbB signaling in treatment-resistant human cancers.