Functionalized Pyrrolidines Inhibit α-Mannosidase Activity and Growth of Human Glioblastoma and Melanoma Cells

Abstract

New substituted pyrrolidine-3,4-diol derivatives were prepared from D-(-)-and L-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean R-mannosidase (K i ) 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular, the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore, functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells when compared to normal cells.

Glycogen Debranching Enzyme 6 (AGL), Enolase 1 (ENOSF1), Ectonucleotide Pyrophosphatase 2 (ENPP2_1), Glutathione S-Transferase 3 (GSTM3_3) and Mannosidase (MAN2B2) Metabolism Computational Network Analysis Between Chimpanzee and Human Left Cerebrum

“…Inhibited OGG1 is involved in base excision repair; nucleoplasm, lyase activity, DNA repair, response to endogenous stimulus, carbohydrate metabolism, response to DNA damage stimulus, hydrolase activity and acting on glycosyl bonds (kegg, genmapp); colorectal cancer, cancer of prostate, spinocerebellar ataxia type 1, adenocarcinoma, parkinson disease, chromosome aberrations, carcinoma non-small-cell lung, colorectal carcinoma, skin cancer, glioma, loss of heterozygosity, microsatellite instability, adenocarcinoma of the lung, leukemia, xeroderma pigmentosum, genetic predisposition to disease, carcinoma squamous cell, neurodegenerative diseases, carcinoma of lung, somatic mutations, amyotrophic lateral sclerosis, stomach cancer, dysplasia, acute leukemia, Cockayne syndrome, Alzheimer's disease, ovarian cancer, neoplasms, nerve degeneration, hereditary diseases, malignant neoplasm of endometrium, inflammation, malignant neoplasms, cancer of bladder, malignant neoplasm of lung, cancer recurrence, type ii cockayne syndrome, non-small cell lung cancer, heart failure congestive, adenoma, polyposis, carcinoma, malignant tumor of colon, allelic imbalance, lung neoplasms, adenomatous polyposis coli, malignant neoplasm of breast, primary carcinoma of the liver cells, cholangiocarcinoma, colorectal cancer, lung cancer, Adenocarcinoma of the lung, lung cancer risk, alcohol abuse | smoking behavior, DNA damage, oxidative, stomach cancer, pneumoconiosis, coal workers', gastric cancer, pancreatic cancer, hepatocellular carcinoma, esophageal cancer, pterygium, cervical cancer, neural tube defects | cleft lip with cleft palate | cleft lip without cleft palate, cytogenetic studies, prostate cancer, bladder cancer (disease from CapitalBio MAS 3.0). We inferred lowexpression MAN2B2 metabolism network stronger glutathione metabolism but weaker base-excision repair as a result of inducing cell growth in chimpanzee left cerebrum.We also found evidences from literatures to support the inference[57][58][59][60][61].High-Expression MAN2B2 Metabolism Network Analysis in Human Left CerebrumTenth, we identified the different novel molecules of highexpression MAN2B2 metabolism network in human left cerebrum compared with chimpanzee left cerebrum. The different upstream ATP2B1, SGSH activated MAN2B2, and GSTM5, OGG1_2 inhibited MAN2B2; The different downstream MAN2B2 activated ATP2B1, CCNO, OGG1_1, OGG1_2, UNG and inhibited EPHX2, GSTM3_3, INSIG1 in human left cerebrum.…”

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

“…Kinetic evaluation of DNA and protein syntheses Thymidine incorporation and leucine incorporation were used to assess DNA and protein synthesis, respectively, as previously described [25]. Cells were grown in 48-well cell culture plates (Corning, NY, USA) until they were 20% confluent.…”

Cytotoxicity and enzymatic activity inhibition in cell lines treated with novel iminosugar derivatives

“…As an example, gem-diamine 1-N-iminosugars have been reported to suppress invasion of B16 melanoma and 3LL lung carcinoma cells [10]. Also, pyrrolidine-3,4-diol derivatives bearing aromatic and aliphatic amino side chains that are selective inhibitors of α-mannosidase, have been described to inhibit the growth of human glioblastoma and melanoma cells [11,12]. D-fagomine, a polyhydroxylated piperidine analogue ((2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol) is a naturally occurring iminosugar that has been reported to have inhibitory effects against α-, β-glucosidase and α-, β-galactosidase from mammals [13].…”