Evaluation of Interactions of Selected Olivacine Derivatives with DNA and Topoisomerase II

Olivacine and ellipticine are model anticancer drugs acting as topoisomerase II inhibitors. Here, we present investigations performed on four olivacine derivatives in light of their antitumor activity. The aim of this study was to identify the best antitumor compound among the four tested olivacine derivatives. The study was performed using CCRF/CEM and MCF-7 cell lines. Comet assay, polarography, inhibition of topoisomerase II activity, histone acetylation, and molecular docking studies were performed. Each tested compound displayed interaction with DNA and topoisomerase II, but did not cause histone acetylation. Compound 2 (9-methoxy-5,6-dimethyl-1-({[1-hydroxy-2-(hydroxymethyl)butan-2-yl]amino}methyl)-6H-pyrido[4,3-b]carbazole) was found to be the best candidate as an anticancer drug because it had the highest affinity for topoisomerase II and caused the least genotoxic damage in cells.

Advances in Cancer Treatment by Targeting the Neddylation Pathway

Developmental down-regulation protein 8 (NEDD8), expressed by neural progenitors, is a ubiquitin-like protein that conjugates to and regulates the biological function of its substrates. The main target of NEDD8 is cullin-RING E3 ligases. Upregulation of the neddylation pathway is closely associated with the progression of various tumors, and MLN4924, which inhibits NEDD8-activating enzyme (NAE), is a promising new antitumor compound for combination therapy. Here, we summarize the latest progress in anticancer strategies targeting the neddylation pathway and their combined applications, providing a theoretical reference for developing antitumor drugs and combination therapies.

DOMESTIC ANTITUMOR COMPOUND 2-[3-(2-CHLOROETHYL)-3-NITROSOUREIDO]-1,3- PROPANEDIOL (CHLONISOL). ACUTE TOXICITY

2-[3-(2-Chloroethyl)-3-nitrosoureido]-1,3-propanediol (Сhlonisol) is a representative of a separate group of derivatives of the class of nitrosoalkylureas – alkylnitrosoureidopropanediols, which are characterized by high antitumor activity on a wide range of experimental tumors. Chlonisol LD50 in male mice for intravenous administration was 35 mg/kg, intraperitoneal – 39 mg/kg, in female mice – 34 mg/kg and 36 mg/kg, respectively. In rats of males with intraperitoneal administration, LD50 was 30 mg/kg, in rats of females – 32 mg/kg. The maximum tolerated dose in mice, rats, guinea pigs and rabbits was 20 mg/kg. The tolerated dose for dogs was a dose of 2 mg/kg. Myelo-depression was a dose-limiting side effect. Lethal and sublethal doses of Chlonisol caused aplasia of the bone marrow and lymphoid organs, damage to the mucous membrane of the gastrointestinal tract, and dystrophic changes in the myocardium, lungs, liver, kidneys, pancreas, and reproductive organs. In the late stages after intraperitoneal administration of sublethal doses of Chlonisol, chylothorax and chyloperitoneum were found in some rats.

Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs

Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of sugar metabolites in organisms and in model cells and identified novel low abundant nucleotide sugars in human cells, such as ADP-glucose and UDP-arabinose, and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Dynamic tracing of propargyloxycarbonyl (Poc) labeled analogs, commonly used for MOE, revealed that ManNPoc is metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, combined treatment of B16-F10 melanoma cells with antitumor compound 3Fax-NeuNAc and 13C-labeled GlcNAc revealed that endogenous CMP-NeuNAc levels started to decrease before a subsequent decrease of ManNAc 6-phosphate was observed. This implicates 3Fax-NeuNAc first acts as a substrate for cytosolic CMP-sialic acid synthetase and subsequently its product CMP-3Fax-NeuNAc functions as a feed-back inhibitor for UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Thus, dynamic analysis of sugar metabolites provides key insights into the time-dependent metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects.

Sulforaphane: Expected to Become a Novel Antitumor Compound

Natural products are becoming increasingly popular in a variety of traditional, complementary, and alternative systems due to their potency and slight side effects. Natural compounds have been shown to be effective against many human diseases, especially cancers. Sulforaphane (SFE) is a traditional Chinese herbal medicine. In recent years, an increasing number of studies have been conducted to evaluate the antitumor effect of SFE. The roles of SFE in cancers are mainly through the regulation of potential biomarkers to activate or inhibit related signaling pathways. SFE has exhibited promising inhibitory effects on breast cancer, lung cancer, liver cancer, and other malignant tumors. In this review, we summarized the reports on the activity and functional mechanisms of SFE in cancer treatment and explored the efficacy and toxicity of SFE.

Isolation Detection and Characterization of Syringolin A produced from the Probiotic Strain Bacillus Cereus Isolated from Donkey Milk

Syringolin A is a non-ribosomal virulence factor secreted by few Pseudomonas strains. Syringolin A is an well known irreversible proteasome inhibitor and antitumor compound. The present study is focused on the extraction of Syringolin A through a non-tedious and economical process. Syringolin A is extracted from culture supernatants by the immiscible organic layer by mixing of dichloromethane or chloroform (trichloromethane). Syringolin A was identified by the characteristic peak at 350 nm by UV spectra. The compound was further characterized by Thin Layer Chromatography (TLC) with the retention value, Rf was found to be in the range of 0.78-0.83 run using a combination of solvent systems water and methanol. The molecular weight of the compound was found to be 492.2614 g mol-1 identified and analyzed by UHPLC–QTOF-MS analysis. Due to its significant pharmacological importance in proliferative diseases, further studies on production and optimization of these compounds are necessary.