Polyamine-based analogues as biochemical probes and potential therapeutics

2007 ◽  
Vol 35 (2) ◽  
pp. 356-363 ◽  
Author(s):  
T. Boncher ◽  
X. Bi ◽  
S. Varghese ◽  
R.A. Casero ◽  
P.M. Woster
Keyword(s):  
Histone Deacetylases ◽  
Biologically Active ◽  
Cellular Functions ◽  
Antiparasitic Activity ◽  
Polyamine Analogues ◽  
Naturally Occurring ◽  
Polyamine Derivatives ◽  
Structural Classes ◽  
Potential Therapeutics

The polyamines putrescine, spermidine and spermine are ubiquitous polycationic compounds that are found in nearly every cell type, and are required to support a wide variety of cellular functions. The existence of multiple cellular effector sites for naturally occurring polyamines implies that there are numerous targets for polyamine-based therapeutic agents. Through a programme aimed at the synthesis and evaluation of biologically active polyamine analogues, our laboratory has identified three distinct structural classes of polyamine derivatives that exhibit promising biological activity in vitro. We have synthesized more than 200 symmetrically and unsymmetrically substituted alkylpolyamines that possess potent antitumour or antiparasitic activity, depending on their backbone architecture and terminal alkyl substituents. Along similar lines, we have developed novel polyamino(bis)guanidines and polyaminobiguanides that are promising antitrypanosomal agents and that interfere with biofilm formation in the pathogenic bacterium Yersinia pestis. Finally, we recently reported a series of PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) that inhibit HDACs (histone deacetylases), and in some cases are selective for individual HDAC isoforms. These studies support the hypothesis that polyamine-based small molecules can be developed for use as biochemical probes and as potential therapies for multiple diseases.

scholarly journals Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 990 ◽  
Author(s):  
Giada Juli ◽  
Manuela Oliverio ◽  
Dina Bellizzi ◽  
Maria Eugenia Gallo Cantafio ◽  
Katia Grillone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylases ◽  
Mononuclear Cells ◽  
Single Agent ◽  
In Vitro Models ◽  
Biologically Active ◽  
Down Regulation ◽  
Peripheral Blood Mononuclear ◽  
Natural Agents

Olive oil contains different biologically active polyphenols, among which oleacein, the most abundant secoiridoid, has recently emerged for its beneficial properties in various disease contexts. By using in vitro models of human multiple myeloma (MM), we here investigated the anti-tumor potential of oleacein and the underlying bio-molecular sequelae. Within a low micromolar range, oleacein reduced the viability of MM primary samples and cell lines even in the presence of bone marrow stromal cells (BMSCs), while sparing healthy peripheral blood mononuclear cells. We also demonstrated that oleacein inhibited MM cell clonogenicity, prompted cell cycle blockade and triggered apoptosis. We evaluated the epigenetic impact of oleacein on MM cells, and observed dose-dependent accumulation of both acetylated histones and α-tubulin, along with down-regulation of several class I/II histone deacetylases (HDACs) both at the mRNA and protein level, providing evidence of the HDAC inhibitory activity of this compound; conversely, no effect on global DNA methylation was found. Mechanistically, HDACs inhibition by oleacein was associated with down-regulation of Sp1, the major transactivator of HDACs promoter, via Caspase 8 activation. Of potential translational significance, oleacein synergistically enhanced the in vitro anti-MM activity of the proteasome inhibitor carfilzomib. Altogether, these results indicate that oleacein is endowed with HDAC inhibitory properties, which associate with significant anti-MM activity both as single agent or in combination with carfilzomib. These findings may pave the way to novel potential anti-MM epi-therapeutic approaches based on natural agents.

scholarly journals Semisynthesis of Selenoauraptene

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2798
Author(s):  
Serena Fiorito ◽  
Francesco Epifano ◽  
Lorenzo Marchetti ◽  
Salvatore Genovese
Keyword(s):  
Short Communication ◽  
Biologically Active ◽  
Side Chain ◽  
Radical Scavenger ◽  
In Vitro Activity ◽  
Naturally Occurring ◽  
Antioxidant Agents ◽  
Approved Drugs ◽  
First Time

Selenium-containing compounds are gaining more and more interest due to their valuable and promising pharmacological properties, mainly as anticancer and antioxidant agents. Ebselen, the up to now only approved drugs, is well known to possess very good glutathione peroxidase mimicking effects. To date, the most of efforts have been directed to build pure synthetic Se containing molecules, while less attention have been devoted to Se-based semisynthetic products resembling natural compounds like terpenes, polyphenols, and alkaloids. The aim of this short communication is to report the synthesis of the first example of a Se-phenylpropanoids, namely selenoauraptene, containing a selenogeranyl side chain in position 7 of the umbelliferone core. The key step was the Newman-Kwart rearrangement to obtain a selenocarbamate in which the Se atom was directly attached to umbelliferone (replacing its 7-OH function) followed by hydrolysis to get diumbelliferyl diselenide, which was finally easily converted to the desired Se-geranyl derivative in quite a good overall yield (28.5%). The synthesized adduct displayed a greater antioxidant and a radical scavenger in vitro activity than parent auraptene. The procedure we describe herein, to the best of our knowledge for the first time in the literature, represents an easy-to-handle method for the synthesis of a wide array of seleno analogues of naturally occurring biologically active oxyprenylated secondary metabolites.

Characterization of the acidic forms of ovine pituitary luteinizing hormone

1990 ◽  
Vol 123 (5) ◽  
pp. 563-570 ◽  
Author(s):  
B. A. Keel ◽  
R. L. Harms ◽  
H. E. Grotjan
Keyword(s):  
Luteinizing Hormone ◽  
Biologically Active ◽  
In Vitro Bioassay ◽  
Naturally Occurring

Abstract. The naturally occurring acidic forms of ovine pituitary LH were examined by chromatofocusing. Immunoreactive oLH eluted as six variants (elutions pHs of >7.4, 6.83, 6.59, 6.23, 5.5-4.0, and <4.0, designated as "basic forms" and variants II-VI, respectively). In rams, the percentage in each variant averaged 46, 9, 28, 10, 5 and 2, respectively, of the total LH recovered. oLH from non-implanted wethers or wethers implanted with dihydrotestosterone, E2 or dihydrotestosterone +E2 eluted as six similar variants but differences were noted in the distribution of oLH among the variants. Compared to rams, pituitary extracts from non-implanted and dihydrotestosterone-implanted wethers contained significantly higher percentages of oLH eluting as basic forms. In contrast, E2- or dihydrotestosterone-implanted wethers exhibited significantly higher percentages of oLH in the acidic variants. Each of these variants was demonstrated to contain biologically active oLH using an in vitro bioassay. Furthermore, the basic forms of oLH were the most abundant biologically active forms present in pituitary extracts. These results suggest that in addition to the seven basic forms of oLH previously described, there are at least five naturally occurring acidic forms of oLH in pituitary extracts which are biologically active, and the distribution of pituitary oLH among its isohormones, including the acidic forms, appears to be modified by steroids.

scholarly journals Effect of the Chloro-Substitution on Electrochemical and Optical Properties of New Carbazole Dyes

Materials ◽  
2021 ◽  
Vol 14 (11) ◽  
pp. 3091
Author(s):  
Przemysław Krawczyk ◽  
Beata Jędrzejewska ◽  
Klaudia Seklecka ◽  
Joanna Cytarska ◽  
Krzysztof Z. Łączkowski
Keyword(s):  
Optical Properties ◽  
Fluorescent Probes ◽  
Quantum Chemical ◽  
Biological Properties ◽  
Biologically Active ◽  
In Vitro Tests ◽  
Naturally Occurring ◽  
Active Substances

Carbazole derivatives are the structural key of many biologically active substances, including naturally occurring and synthetic ones. Three novel (E)-2-(2-(4-9H-carbazol-9-yl)benzylidene)hydrazinyl)triazole dyes were synthesized with different numbers of chlorine substituents attached at different locations. The presented research has shown the influence of the number and position of attachment of chlorine substituents on electrochemical, optical, nonlinear, and biological properties. The study also included the analysis of the use of the presented derivatives as potential fluorescent probes for in vivo and in vitro tests. Quantum-chemical calculations complement the conducted experiments.

scholarly journals Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility

2011 ◽  
Vol 22 (2) ◽  
pp. 278-289 ◽  
Author(s):  
Nadia Cernotta ◽  
Andrea Clocchiatti ◽  
Cristina Florean ◽  
Claudio Brancolini
Keyword(s):  
Growth Factors ◽  
Cell Motility ◽  
Histone Deacetylases ◽  
Glycogen Synthase ◽  
Consensus Sequence ◽  
Ubiquitin Proteasome System ◽  
Serum Starvation ◽  
Cellular Functions ◽  
Histone Deacetylase 4

HDAC4 (histone deacetylase 4) belongs to class IIa of histone deacetylases, which groups important regulators of gene expression, controlling pleiotropic cellular functions. Here we show that, in addition to the well-defined nuclear/cytoplasmic shuttling, HDAC4 activity is modulated by the ubiquitin–proteasome system. Serum starvation elicits the poly-ubiquitination and degradation of HDAC4 in nontransformed cells. Phosphorylation of serine 298 within the PEST1 sequence plays an important role in the control of HDAC4 stability. Serine 298 lies within a glycogen synthase kinase 3β consensus sequence, and removal of growth factors fails to trigger HDAC4 degradation in cells deficient in this kinase. GSK3β can phosphorylate HDAC4 in vitro, and phosphorylation of serine 302 seems to play the role of priming phosphate. We have also found that HDAC4 modulates random cell motility possibly through the regulation of KLF2 transcription. Apoptosis, autophagy, cell proliferation, and growth arrest were unaffected by HDAC4. Our data suggest a link between regulation of HDAC4 degradation and the control of cell motility as operated by growth factors.

scholarly journals Bioactivity and Biotechnological Overview of Naturally Occurring Compounds from the Dinoflagellate Family Symbiodiniaceae: A Systematic Review

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jeysson Sánchez-Suárez ◽  
Mariana Garnica-Agudelo ◽  
Luisa Villamil ◽  
Luis Díaz ◽  
Ericsson Coy-Barrera
Keyword(s):  
Marine Invertebrates ◽  
Biological Properties ◽  
Biologically Active ◽  
Bioactive Substances ◽  
The Past ◽  
Naturally Occurring ◽  
Vital Functions ◽  
Ecological Implications

Marine invertebrates are a significant source of biologically active compounds. Recent studies have highlighted the role of microbiota associated with marine invertebrates in the production of bioactive compounds. Corals and sponges are the main marine invertebrates producing bioactive substances, and Symbiodiniaceae dinoflagellates are well-recognized endosymbionts with corals and sponges playing vital functions. The biological properties of Symbiodiniaceae-derived compounds have garnered attention in the past decades owing to their ecological implications and potentiality for bioprospecting initiatives. This study aims to systematically review studies on bioactivities and potential biotechnological applications of Symbiodiniaceae-derived compounds. The PRISMA guidelines were followed. Our study showed that anti-inflammatory and vasoconstrictive activities of Symbiodiniaceae-derived compounds have been the most investigated. However, very few studies have been published, with in vitro culturing of Symbiodiniaceae being the most significant challenge. Therefore, we surveyed for the metabolites reported so far, analyzed their chemodiversity, and discussed approaches to overcome culturing-related limitations.

scholarly journals Progestin Receptor Subtypes in the Brain: The Known and the Unknown

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2750-2756 ◽  
Author(s):  
Shaila Mani
Keyword(s):  
Classical Model ◽  
Membrane Receptors ◽  
Biologically Active ◽  
Receptor Subtypes ◽  
Cellular Functions ◽  
Progestin Receptor ◽  
Peptide Growth Factors ◽  
Steroid Sensitive

Progesterone (P), the most biologically active progestin of ovarian origin, modulates numerous cellular functions in the central nervous system to coordinate physiology and reproduction. The neurobiological activity of P is mediated not by a single form of the progestin receptor (PR), but by two neural isoforms of PRs, PR-A and PR-B. Classical model of P action assumes that these neural effects are primarily mediated via their intracellular PRs, acting as transcriptional regulators, in steroid-sensitive neurons, modulating genes and genomic networks. Evidence has emerged, however, that activation of neural PRs is much more diverse; four distinct classes of molecules, neurotransmitters, peptide growth factors, cyclic nucleotides, and neurosteroids have been shown to activate the PRs via cross-talk and pathway convergence. In addition, rapid signaling events associated with membrane receptors and/or subpopulations of cytoplasmic PRs, via activation of protein kinase cascades, regulate PR gene expression in the cytoplasm independent of PR nuclear action. The increasing in vitro and in vivo evidence of differential transcriptional activities and coregulator interactions between PR-A and PR-B predict that these isoforms could have distinct roles in mediating additional and/or alternate signaling pathways within steroid-sensitive neurons. In this minireview, we evaluate the available data and discuss the possible roles of the isoforms in the regulation of neurobiological processes.

scholarly journals Polyamine analogues: potent inducers of nucleosomal array oligomerization and inhibitors of yeast cell growth

2007 ◽  
Vol 405 (3) ◽  
pp. 541-545 ◽  
Author(s):  
Lenny M. Carruthers ◽  
Laurence J. Marton ◽  
Craig L. Peterson
Keyword(s):  
Cell Growth ◽  
Yeast Cell ◽  
Higher Order ◽  
Polyamine Metabolism ◽  
Polyamine Analogues ◽  
Naturally Occurring ◽  
Nucleosomal Array ◽  
Carcinogenic Process

Polyamines are naturally occurring intracellular polycations that are essential for viability and growth of eukaryotes. Dysregulation of polyamine metabolism is a hallmark of cancer and the carcinogenic process, and consequently development of polyamine analogues has emerged as a viable strategy for therapeutic intervention. Previously, we showed that the naturally occurring polyamines spermidine and spermine were quite effective at inducing the oligomerization of nucleosomal arrays in vitro, suggesting that polyamines may play a key role in regulating higher order chromatin structures in vivo. Here, we analyse the ability of a number of synthetic polyamine analogues to potentiate formation of higher order chromatin structures in vitro. We find that a class of long-chain polyamines called oligoamines are potent inducers of nucleosomal array oligomerization in vitro and that these same polyamine analogues rapidly block yeast cell growth.

Correlation Between Cellular Functions and Morphological Changes of Human Trophoblast in Vitro

1975 ◽  
Vol 33 ◽  
pp. 600-601
Author(s):  
John C. Garancis ◽  
Robert O. Hussa ◽  
Michael T. Story ◽  
Donald Yorde ◽  
Roland A. Pattillo
Keyword(s):  
Electron Microscopy ◽  
Cellular Proliferation ◽  
Morphological Changes ◽  
Culture Fluid ◽  
Cellular Functions ◽  
Human Trophoblast ◽  
Transmission Electron ◽  
Marked Activity ◽  
Malignant Trophoblast

Human malignant trophoblast cells in continuous culture were incubated for 3 days in medium containing 1 mM N6-O2'-dibutyryl cyclic adenosine 3':5'-monophosphate (dibutyryl cyclic AMP) and 1 mM theophylline. The culture fluid was replenished daily. Stimulated cultures secreted many times more chorionic gonadotropin and estrogens than did control cultures in the absence of increased cellular proliferation. Scanning electron microscopy revealed remarkable surface changes of stimulated cells. Control cells (not stimulated) were smooth or provided with varying numbers of microvilli (Fig. 1). The latter, usually, were short and thin. The surface features of stimulated cells were considerably different. There was marked increase of microvilli which appeared elongated and thick. Many cells were covered with confluent polypoid projections (Fig. 2). Transmission electron microscopy demonstrated marked activity of cytoplasmic organelles. Mitochondria were increased in number and size; some giant forms with numerous cristae were observed.

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

2020 ◽  
Author(s):  
Daniel Herp ◽  
Johannes Ridinger ◽  
Dina Robaa ◽  
Stephen A. Shinsky ◽  
Karin Schmidtkunz ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Neuroblastoma Cell ◽  
Hdac Inhibitors ◽  
Anticancer Therapy ◽  
Colony Growth ◽  
Autophagic Flux ◽  
Enzymatic Conversion ◽  
Lysine Deacetylase

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

Sign in / Sign up

Export Citation Format

Share Document