Scytophycins, including tolytoxin, represent a class of actin disrupting macrolides with strong antiproliferative effects on human cells. Despite intense research, little attention has been paid to scytophycin-induced cell death or the structural features affecting its potency. We show that tolytoxin and its natural analogue, 7-O-methylscytophycin B, lacking the hydroxyl substitution in its macrolactone ring, differ substantially in their cytotoxic effect. Both compounds increase the level of caspases 3/7, which are the main executioner proteases during apoptosis, in HeLa wild-type (WT) cells. However, no caspase activity was detected in HeLa cells lacking Bax/Bak proteins crucial for caspase activation via the mitochondrial pathway. Obtained data strongly suggests that scytophycins are capable of inducing mitochondria-dependent apoptosis. These findings encourage further research in structure-activity relationships in scytophycins and highlight the potential of these compounds in targeted drug delivery.

• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• hydroxidy chemie   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• makrolidy chemie   farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• pyrany chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The queens of social insects differ from sterile colony members in many aspects of their physiology. Besides adaptations linked with their specialization for reproduction and extended lifespan, the queens also invest in the maintenance of their reproductive dominance by producing exocrine chemicals signaling their presence to the nestmates. The knowledge of the chemistry of queen-specific cues in termites is scarce. In addition to the contact recognition based on cuticular hydrocarbons, long-range signals mediated by volatiles are expected to participate in queen signaling, especially in populous colonies of higher termites (Termitidae). In queens of the higher termite Silvestritermes minutus (Syntermitinae), we have detected a previously undescribed volatile. It is present in important quantities on the body surface and in the headspace, ovaries, and body cavity. MS and GC-FTIR data analyses led us to propose the structure of the compound to be a macrolide 10-pentyl-3,4,5,8,9,10-hexahydro-2 H-oxecin-2-one. We performed enantiodivergent syntheses of two possible enantiomers starting from enantiopure ( S)-glycidyl tosylate. The synthetic sequence involved macrolide-closing metathesis quenched with a ruthenium scavenging agent. The absolute and relative configuration of the compound was assigned to be (5 Z,9 S)-tetradec-5-en-9-olide. Identification and preparation of the compound allow for investigation of its biological significance.

• MeSH
• hmotnostní spektrometrie MeSH
• indikátory a reagencie MeSH
• Isoptera chemie   MeSH
• makrolidy chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• ovarium chemie   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• stereoizomerie MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

To examine reciprocal or unilateral implications between two cell destruction processes, autophagy and apoptosis, in 5-Fluorouracil (5-FU)-treated tumor cells, a combination of chemical inhibitors, RNAi and genetic approaches were used. In contrast to cancer cells harboring obstructed apoptosis, either at the DISC or the mitochondrial level, p53-deficiency generated signs of autophagy deregulation upon chemotherapy. On the other, hand disruption of lysosomal function by chloroquine, caused a profound decrease in apoptotic markers appearing in response to 5-FU. DR5, which is essential for 5-FU-induced apoptosis, accumulated in lysosomes and autophagosomes upon chloroquine treatment. Since neither 3-MA, RNAi of critical autophagy regulators or inhibition of cathepsins reversed apoptosis in a similar manner, it is likely that not autophagy per se but rather correct receptor transport is an important factor for 5-FU cytotoxicity. We found that apoptosis generated by TRAIL, the cognate ligand for DR5, remained unchanged upon chloroquine lysosomal interference, indicating that 5-FU activates the receptor by a discrete mechanism. In support, depletion of membrane cholesterol or hampering cholesterol transport drastically reduced 5-FU cytotoxicity. We conclude that targeting of lysosomes by chloroquine deregulates DR5 trafficking and abrogates 5-FU- but not TRAIL-stimulated cell elimination, hence suggesting a novel mechanism for receptor activation.

• MeSH
• antimetabolity antitumorózní farmakologie   MeSH
• apoptóza MeSH
• autofagie * MeSH
• buněčná membrána metabolismus   MeSH
• chlorochin chemie   MeSH
• cholesterol chemie   MeSH
• fagozomy MeSH
• fluorouracil chemie   MeSH
• HCT116 buňky MeSH
• lidé MeSH
• ligandy MeSH
• lyzozomy metabolismus   MeSH
• makrolidy chemie   MeSH
• mitochondrie metabolismus   MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein TRAIL farmakologie   MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• TRAIL receptory metabolismus   MeSH
• transport proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Didehydroroflamycoin (DDHR), a recently isolated member of the polyene macrolide family, was shown to have antibacterial and antifungal activity. However, its mechanism of action has not been investigated. Antibiotics from this family are amphiphilic; thus, they have membrane activity, their biological action is localized in the membrane, and the membrane composition and physical properties facilitate the recognition of a particular compound by the target organism. In this work, we use model lipid membranes comprised of giant unilamellar vesicles (GUVs) for a systematic study of the action of DDHR. In parallel, experiments are conducted using filipin III and amphotericin B, other members of the family, and the behavior observed for DDHR is described in the context of that of these two heavily studied compounds. The study shows that DDHR disrupts membranes via two different mechanisms and that the involvement of these mechanisms depends on the presence of cholesterol. The leakage assays performed in GUVs and the conductance measurements using black lipid membranes (BLM) reveal that the pores that develop in the absence of cholesterol are transient and their size is dependent on the DDHR concentration. In contrast, cholesterol promotes the formation of more defined structures that are temporally stable.

• MeSH
• amfotericin B chemie   MeSH
• antibakteriální látky chemie   MeSH
• antifungální látky chemie   MeSH
• cholesterol chemie   MeSH
• filipin analogy a deriváty   chemie   MeSH
• kinetika MeSH
• lipidové dvojvrstvy chemie   MeSH
• makrolidy chemie   MeSH
• unilamelární lipozómy chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A new polyene macrolide family, closely related to the pentaene macrolide antibiotic roflamycoin, was isolated from the both fermentation broth and biomass of Streptomyces durmitorensis wild-type strain MS405. The main compound was identified by NMR and Fourier transform ion cyclotron resonance mass spectrometry as 32,33-didehydroroflamycoin (1; DDHR). Additional four structurally related compounds were determined solely by MS analysis. DDHR induces cell death by apoptosis in various cancer cell lines as demonstrated by DNA fragmentation. Striking feature of DDHR is its internal fluorescence allowing visualization of labeled plasma membranes and internal membrane structures.

• MeSH
• antitumorózní látky chemie   metabolismus   MeSH
• barvení a značení MeSH
• buněčná membrána chemie   metabolismus   MeSH
• buněčná smrt účinky léků   MeSH
• fluorescence MeSH
• hmotnostní spektrometrie MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• makrolidy chemie   metabolismus   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• polyeny chemie   metabolismus   MeSH
• Streptomyces metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Precursor-directed biogenetic approach was used to produce a range of nonactin homologues in a 50 l fermentor cultivation of strain Streptomyces griseus 34/249 obtained by UV mutagenesis. The production medium contained sodium propionate, isobutyrate and isovalerate as individual precursors, and 10 g l(-1) Diaion HP20 styrene-divinylbenzene resin that maintains suitable precursor concentration by reversibly adsorbing and releasing it. The produced nonactin homologues were separated on two C18 reversed-phase liquid chromatography columns in series and analyzed by MS with ESI source in the positive ion mode. Formation of doubly charged ions was suppressed by an excess of Na(+) ions throughout the process. The production of the homologues increased up to day 5 and then it leveled off. Cultivations with individual precursors yielded a total of 18 nonactin homologues whose spectrum depended on the precursor used. The total production of the homologues was lowered but their spectrum was shifted to higher-molecular-weight compounds.

• MeSH
• butyráty analýza   MeSH
• chromatografie kapalinová metody   MeSH
• fermentace MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• isobutyráty MeSH
• kultivační média chemie   MeSH
• kyseliny pentanové analýza   MeSH
• makrolidy chemie   izolace a purifikace   metabolismus   MeSH
• propionáty analýza   MeSH
• Streptomyces griseus růst a vývoj   metabolismus   účinky záření   MeSH
• ultrafialové záření MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• antibakteriální látky farmakologie   chemie   metabolismus   MeSH
• antiprotozoální látky farmakologie   chemie   metabolismus   MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• léková rezistence MeSH
• lidé MeSH
• makrolidy farmakologie   chemie   metabolismus   MeSH
• regulace genové exprese MeSH
• Streptomyces metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

Prvním makrolidem použitým v klinické praxi byl erytromycin (EMY). Toto antibiotikum působí především na Gram-pozitivní koky a tzv. atypické patogeny (Mycoplasma pneumoniae, Legfonefla pneumophila a Chlamydia pneumoniae). Primárně je proto EMY používán v léčbě infekcí dýchacích cest, kůže a měkkých tkání, zejména v případech alergie na peniciliny. Omezením širšího využití EMY je nedostatečná aktivita vůči Haemophilus influenzae, nízká biologická dostupnost, krátký biologický poločas eliminace, vysoká incidence nedoucích účinků (NÚ) v oblasti GITu (gastrointestinální trakt) a široké spektrum možných lékových interakcí. Proto jsou zaváděny nové makrolidy, které mají výhodnější farmakokinetické vlastnosti, nižší výskyt NÚ a vysokou aktivitu proti Haemophilus influenzae. Tyto podmínky splňuje především klarítromycin, azitromycin a nová skupina makrolidů s 14ti členným kruhem označovaná jako ketolidy.

• MeSH
• antibakteriální látky aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• antibiotická rezistence MeSH
• azithromycin aplikace a dávkování   terapeutické užití   MeSH
• erythromycin aplikace a dávkování   terapeutické užití   MeSH
• makrolidy aplikace a dávkování   farmakologie   chemie   MeSH
• roxithromycin aplikace a dávkování   MeSH
• spiramycin aplikace a dávkování   MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• antibakteriální látky farmakologie   terapeutické užití   MeSH
• gastrointestinální trakt účinky léků   MeSH
• imunitní systém účinky léků   MeSH
• kardiovaskulární systém účinky léků   MeSH
• makrolidy farmakologie   chemie   imunologie   MeSH
• motilin agonisté   fyziologie   MeSH
• oportunní infekce farmakoterapie   MeSH
• Publikační typ
• kongresy MeSH
• přehledy MeSH