Novel Glycerophospholipid, Lipo- and N-acyl Amino Acids from Bacteroidetes: Isolation, Structure Elucidation and Bioactivity

The ‘core’ metabolome of the Bacteroidetes genus Chitinophaga was recently discovered to consist of only seven metabolites. A structural relationship in terms of shared lipid moieties among four of them was postulated. Here, structure elucidation and characterization via ultra-high resolution mass spectrometry (UHR-MS) and nuclear magnetic resonance (NMR) spectroscopy of those four lipids (two lipoamino acids (LAAs), two lysophosphatidylethanolamines (LPEs)), as well as several other undescribed LAAs and N-acyl amino acids (NAAAs), identified during isolation were carried out. The LAAs represent closely related analogs of the literature-known LAAs, such as the glycine-serine dipeptide lipids 430 (2) and 654. Most of the here characterized LAAs (1, 5–11) are members of a so far undescribed glycine-serine-ornithine tripeptide lipid family. Moreover, this study reports three novel NAAAs (N-(5-methyl)hexanoyl tyrosine (14) and N-(7-methyl)octanoyl tyrosine (15) or phenylalanine (16)) from Olivibacter sp. FHG000416, another Bacteroidetes strain initially selected as best in-house producer for isolation of lipid 430. Antimicrobial profiling revealed most isolated LAAs (1–3) and the two LPE ‘core’ metabolites (12, 13) active against the Gram-negative pathogen M. catarrhalis ATCC 25238 and the Gram-positive bacterium M. luteus DSM 20030. For LAA 1, additional growth inhibition activity against B. subtilis DSM 10 was observed.

COMPARATIVE ANTIBACTERIAL EFFICACY OF METHANOL AND AQUEOUS EXTRACT OF M. PANICULATA AGAINST X. CITRI AND X. CAMPESTRIS

In this study, Murraya paniculata was analysed for its antibacterial activity by using different solvents like methanol and aqueous against two plant pathogens i.e. X. citri and X. campestris and observed the growth inhibition activity ranging from 20 µl - 100 µl. The antibacterial potential of M. paniculata (leaf and stem) by using two different solvents was studied by agar well diffusion method and we observed that at 100 µl it’s showed significant result against both the tested bacteria. Highest antibacterial activity was observed by the methanolic leaf extract of M. paniculata against X. citri i.e.13.22±0.05 mm at 100 µl of concentration.

One-pot, multi-component synthesis of novel 2-amino-[1,2,4]triazolo[1,5-a] pyrimidine-6-carboxamide derivatives as antiproliferative agents

A novel series of 2-amino-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives has been achieved successfully via an efficient one-pot three-component Biginelli-like heterocyclization reaction between different benzaldehydes, 1H-1,2,4-triazole-3,5-diamine, and N-substituted acetoacetamides in the presence of p-toluenesulfonic acid as a catalyst. Moreover, the effects of different conditions on the reaction were well investigated. In addition, cancer cell growth inhibition activity for these target compounds was also explored, and analogue 5l demonstrated the most potent cytotoxic activity against different cancer cells. These finds indicat that 2-amino-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide core could be well worth further optimization as a potential scaffold for development of anticancer agents.

Evaluation of tumor growth inhibition activity of a novel multi-TRK inhibitor ABP-1119 on pancreatic tumor xenograft model.

e16741 Background: Owing to its high mortality and lack of effective treatments, there is therefore an urgent unmet need to develop novel and more effective treatments for pancreatic cancer (PC). ABP-1119 is a novel and potent multi-TRK Inhibitor for several PC-related prime tyrosine kinases (TRKs), such as EGFR, HER2, ALK, and BTK. Pre-clinical studies with ABP-1119, especially study to evaluate its tumor growth inhibition activity on pancreatic tumor xenograft model, are planned. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, ALK, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of Mia-Paca-2 Cell Line, (3) Anti-tumor inhibition study of ABP-1119 with the pancreatic cancer nude mice, (4) Safety studies of ABP-1119 for Ames, hERG, and maximum tolerated dose (MTD). Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1119 was 0.9nM to EGFR, 4.8nM to HER2, 0.9nM to ALK, and 2.1nM to BTK, respectively. Its inhibition activity for Cell Line Mia-Paca-2 was 0.06 µM. In anti-tumor inhibition study with the Mia-Paca-2 tumor nude mice for 14 days, the anti-tumor inhibition rate of ABP-1119 (50 mg/kg, QD) was over 82% (vs Erlotinib as a positive control, 50mg/kg, QD, inhibition rate: 48%), and no any death and other serious side effects were observed during the nude mice tests. Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in MTD studies with ABP-1119 (100mg/kg, QD) for 14 days. ABP-1119 also had very good metabolic stability in Human (T1/2 = 2.5hr). Conclusions: Based on our completed preclinical study results, ABP-1119 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and good tumor growth inhibition activity with tolerable toxicity in pancreatic tumor xenograft in nude mice model. It is warranted to continue further investigation in pancreatic cancer.

Syntheses and Structure–Activity Relationships in Growth Inhibition Activity against Human Cancer Cell Lines of 12 Substituted Berberine Derivatives

In this study, quaternary berberine chloride is used as a lead compound to design and synthesize a series of berberine-12-amine derivatives to evaluate the growth inhibition activity against human cancer cell lines. Forty-two compounds of several series were obtained. The quaternary berberine-12-N,N-di-n-alkylamine chlorides showed the targeted activities with the IC50 values of most active compounds being dozens of times those of the positive control. A significant structure–activity relationship (SAR) was observed. The activities of quaternary berberine-12-N,N-di-n-alkylamine chlorides are significantly stronger than those of the reduced counterparts. In the range of about 6-8 carbon atoms, the activities increase with the elongation of n-alkyl carbon chain of 12-N,N-di-n-alkylamino, and when the carbon atom numbers are more than 6-8, the activities decrease with the elongation of n-alkyl carbon chain. The activities of the tertiary amine structure are significantly higher than that of the secondary amine structure.

Targeted Isolation of Indole Alkaloids from Streptomyces sp. CT37

Four compounds (1–4) were isolated from the extracts of Streptomyces sp. CT37 using bioassay in conjunction with mass spectrometric molecular networking (MN) driven isolation. Their complete structures were established by high-resolution electrospray ionization mass spectrometry (HR-ESIMS), and 1D and 2D nuclear magnetic resonance (NMR) data. Legonimide 1 was identified as a new alkaloid containing a rare linear imide motif in its structure, while compounds 2–4 were already known and their structures were elucidated as 1H-indole-3-carbaldehyde, actinopolymorphol B, (2R,3R)-1-phenylbutane-2,3-diol, respectively. The biosynthetic pathways of 1–4 were proposed based on the reported biogenesis of indole alkaloids in literature. Bioactivity tests for 1 and 2 revealed moderate growth inhibition activity against Candida albicans ATCC 10231 with MIC95 values of 21.54 µg/mL and 11.47 µg/mL, respectively.