This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.
- MeSH
- antiinfekční látky chemická syntéza chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- biologické přípravky chemie farmakologie MeSH
- cholestanoly chemie MeSH
- cholestany chemie MeSH
- inhibitory angiogeneze chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- spermin analogy a deriváty chemie MeSH
- steroidy chemická syntéza chemie farmakologie MeSH
- triterpeny chemická syntéza chemie farmakologie MeSH
- vodní organismy chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.
- MeSH
- lidé MeSH
- nové syntetické drogy chemie terapeutické užití MeSH
- prekurzory léčiv chemie terapeutické užití MeSH
- rostliny chemie MeSH
- steroidy chemie terapeutické užití MeSH
- testosteron agonisté analogy a deriváty chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The first review article on steroid dimers by Li and Dias in 1997, followed by the second review and a book on steroid dimers by Nahar and Sarker in 2007 and 2012, respectively, covered steroid dimers reported until the end of 2010. Since then, there have been considerable amounts of research carried out on steroid dimers, prompting the need for another comprehensive review on this topic. Therefore, this present review appraises the literature published during the period 2011-2019 on various aspects of steroid dimers, including isolation from natural sources, synthesis and applications. A structured and systematic literature search was performed, using the key words: steroid dimer, steroidal dimer, dimeric steroid, bis-steroid, bis-steroidal conjugates, molecular umbrella, cephalostatins, ritterazines and crellastatins. Several databases like Web of Knowledge, Science Direct, PubMed and Google Scholar were consulted. During the period covered in this review, well over 200 new synthetic steroidal dimers, ring A-ring A connection being the major group, have been reported, only one natural steroid dimer has been isolated, and potential applications of steroid dimers in the treatment of cancers and tumors, and microbial infections have been indicated.
Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 μM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.
- MeSH
- alosterická regulace MeSH
- HEK293 buňky MeSH
- konformace proteinů MeSH
- lidé MeSH
- modulátory membránového transportu chemie farmakologie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- pregnenolon farmakologie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- steroidy chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Benzylidenespirostanols were prepared by two-step synthesis including BF3·Et2O-catalyzed aldol condensation of several acetylated steroid sapogenins with benzaldehyde followed by saponification. The obtained compounds showed moderate cytotoxicity against three cancer cell lines (T-lymphoblastic leukemia cell line CEM, breast carcinoma cell line MCF7 and cervical carcinoma cell line HeLa) and normal human fibroblasts (BJ). The most active of the five tested substances was 3c (lowest IC50 for MCF7 cells 19.9±0.1µM) without any selectivity towards human cancer and normal cells, respectively.
- MeSH
- antitumorózní látky fytogenní chemická syntéza chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- sapogeniny chemická syntéza chemie farmakologie MeSH
- spirostany chemická syntéza chemie farmakologie MeSH
- steroidy chemická syntéza chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sesquiterpene lactone trilobolide is a sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor, thus depleting the Ins(1,4,5)P3-sensitive intracellular calcium stores. Here, we describe a synthesis of a series of 6 trilobolide-steroids conjugates (estradiol, pregnene, dehydroepiandrosterone, and testosterone). We found that the newly synthesized Tb-based compounds possess different remarkable biological activities. Cancer cell cytotoxicity and preferential selectivity is represented in our study by a Tb-pregnene derivative. The most cytotoxic clickates of estradiol and pregnene were studied by FACS where impact on cell cycle and RNA synthesis was observed; live-cell microscopy revealed the impact on cell organelle morphology particularly endoplasmic reticulum, mitochondria and nucleus. Further, we have studied the estrogenic and androgenic properties of the clickate molecules using cell-based luciferase assays. Finally, antimycobacterial tests revealed that testosterone and estradiol derivatives potentiated the antimycobacterial activity up to IC50 of 10.6μM.
- MeSH
- androgenní receptory metabolismus MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- buňky A549 MeSH
- butyráty chemie MeSH
- Candida účinky léků MeSH
- furany chemie MeSH
- HCT116 buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- receptory pro estrogeny metabolismus MeSH
- steroidní receptory metabolismus MeSH
- steroidy chemie MeSH
- syntetická chemie okamžité shody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Within this study, a new method enabling monitoring of various estrogenic substances potentially occurring in milk and dairy products was proposed. Groups of compounds fairly differing in physico-chemical properties and biological activity were analyzed: four natural estrogens, four synthetic estrogens, five mycoestrogens, and nine phytoestrogens. Since they may pass into milk mainly in glucuronated and sulfated forms, an enzymatic hydrolysis was involved prior to the extraction based on the QuEChERS methodology. For the purification of the organic extract, a dispersive solid-phase extraction (d-SPE) with sorbent C18 was applied. The final analysis was performed by ultra-high-performance liquid chromatography (UHPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS). Method recovery ranged from 70 to 120% with a relative standard deviation (RSD) value lower than 20% and limits of quantification (LOQs) in the range of 0.02-0.60 μg/L (0.2-6.0 μg/kg dry weight) and 0.02-0.90 μg/kg (0.2-6.0 μg/kg dry weight) for milk and yogurt, respectively. The new procedure was applied for the investigation of estrogenic compounds in 11 milk samples and 13 yogurt samples from a Czech retail market. Mainly phytoestrogens were found in the studied samples. The most abundant compounds were equol and enterolactone representing 40-90% of all estrogens. The total content of phytoestrogens (free and bound) was in the range of 149-3870 μg/kg dry weight. This amount is approximately 20 times higher compared to non-bound estrogens.
- MeSH
- estrogeny chemie MeSH
- fytoestrogeny chemie MeSH
- houby MeSH
- jogurt analýza MeSH
- mléko chemie MeSH
- reprodukovatelnost výsledků MeSH
- steroidy chemie MeSH
- tandemová hmotnostní spektrometrie MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 μM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17-hydroxypregnenolone and 5β-androstane-3α,17β-diol were higher in ICP patients, 20α-dihydropregnenolone, 16α-hydroxy-steroids, sulfated 17-oxo-C19-steroids, and 5β-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3α/β-hydroxy-5α/β-androstane-17-ones to conjugated 5α/β-pregnane-3α/β, 20α-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP.
- MeSH
- 17-alfa-hydroxypregnenolon chemie krev MeSH
- 17-alfa-hydroxyprogesteron chemie krev MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- dospělí MeSH
- gestační stáří MeSH
- hydrokortison chemie krev MeSH
- intrahepatální cholestáza * diagnóza metabolismus patologie MeSH
- jaterní testy MeSH
- komplikace těhotenství * diagnóza metabolismus patologie MeSH
- lidé MeSH
- nuclei raphe dorsalis MeSH
- plocha pod křivkou MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- radioimunoanalýza MeSH
- ROC křivka MeSH
- steroidy * chemie krev metabolismus MeSH
- těhotenství MeSH
- žlučové kyseliny a soli analýza MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play a crucial role in excitatory synaptic transmission. However, the overactivation of NMDARs can lead to excitotoxic cell damage/death, and as such, they play a role in numerous neuropathological conditions. The activity of NMDARs is known to be influenced by a wide variety of allosteric modulators, including neurosteroids, which in turn makes them promising therapeutic targets. In this study, we describe a new class of neurosteroid analogues which possess structural modifications in the steroid D-ring region. These analogues were tested on recombinant GluN1/GluN2B receptors to evaluate the structure-activity relationship. Our results demonstrate that there is a strong correlation between this new structural feature and the in vitro activity, as all tested compounds were evaluated as more potent inhibitors of NMDA-induced currents (IC50 values varying from 90 nM to 5.4 μM) than the known endogeneous neurosteroid-pregnanolone sulfate (IC50 = 24.6 μM).
- MeSH
- HEK293 buňky MeSH
- lidé MeSH
- lipidy chemie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory MeSH
- sírany chemie MeSH
- steroidy chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Per(2,3,6-tri-O-benzyl)-γ-cyclodextrin was debenzylated by DIBAL-H to produce a mixture of C6(I),C6(IV) and C6(I),C6(V) isomeric diols, which were separated and isolated. The C2-symmetrical C6(I),C6(V) diol was transformed into dithiol and dimerized to produce a γ-cyclodextrin duplex structure. A crystal structure revealed tubular cavity whose peripheries are slightly elliptically distorted. The solvent accessible volume of the cavity of the γ-CD duplex is about 740 Å(3). Due to this large inner space the duplex forms very stable inclusion complexes with steroids; bile acids examined in this study show binding affinities to the γ-cyclodextrin duplex in the range of 5.3 × 10(7) M(-1)-1.9 × 10(8) M(-1).
- MeSH
- chemie farmaceutická metody MeSH
- dimerizace MeSH
- disulfidy chemie MeSH
- gama-cyklodextriny chemická syntéza chemie MeSH
- imatinib mesylát chemie MeSH
- kalorimetrie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- krystalografie rentgenová MeSH
- kyselina lithocholová chemie MeSH
- kyslík chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární konformace MeSH
- rozpouštědla chemie MeSH
- steroidy chemie MeSH
- sulfhydrylové sloučeniny chemie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
