ChemMedChem

Elongated and shortened peptidomimetic inhibitors of the proprotein convertase furin ()
Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacteyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, e.g., Nα(carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki = 6.2 pM), contain additional basic residues at the N-terminus and inhibit furin in the low picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds lacking the P5-moiety were prepared. The best inhibitors of this series, 5-(guanidino)-valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert.leucine analogue, displayed Ki values of 2.50 nM and 1.26 nM, respectively. Selected inhibitors, together with our previously described 4-amidinobenzylamide derivatives as references, were tested in cell culture for their activity against furin-dependent infectious pathogens. The propagation of the alphaviruses Semliki Forest virus and chikungunya was strongly inhibited in the presence of selected derivatives. Moreover, a significant protective effect of the inhibitors against diphtheria toxin was observed. These results confirm that the inhibition of furin should represent a promising approach for a short-term treatment of acute infectious diseases.
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Molecular features of the YAP inhibitor, Verteporfin - synthesis of hexasubstituted dipyrrins as potential inhibitors of YAP/TAZ, the downstream effectors of the Hippo pathway ()
Porphyrin derivatives, and in particular Verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of YAP-TEAD interaction and transcriptional activity. We herein report the efficient convergent synthesis of the dipyrrin western half-part of protoporphyrin IX dimethyl ester (PPIX-DME) where the sensitive vinyl group was created at the final stage by a dehydroiodation reaction. Two other dipyrrin derivatives were synthesized including dipyrrin 19 containing two vinyl groups. We found that VP and dipyrrin 19 showed a significant inhibitory effect on TEAD transcriptional activity in MDA-MB-231 cells whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment whereas dipyrrin 19 treatment primarily reduced the level of YAP and the receptor kinase Axl, a downstream target of YAP. Altogether, our data suggests that in function of their chemical structure, porphyrin- and dipyrrin-related derivatives can directly target YAP and/or TAZ proteins and inhibits TEAD transcriptional activity.
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An improved model of the Trypanosoma brucei CTP synthetase glutaminase domain:acivicin complex. ()
The natural product acivicin inhibits the glutaminase activity of CTP synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1 Å resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the Protein Data Bank and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model. We now report an improved and corrected inhibitor structure with changes to the chirality at one position, the orientation and covalent structure of the isoxazoline moiety and the location of a chloride in an oxyanion binding site that is exploited during catalysis. The model is now in agreement with established chemical principles and allows an accurate description of molecular recognition of the ligand and the mode of binding in a potentially valuable drug target.
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Synthesis of the T-705-Ribonucleoside and -Ribonucleotide and Studies on the Chemical Stability ()
T-705 (favipiravir) is a fluorinated hydroxypyrazine carboxamide that exhibits antiviral activities against a variety of RNA viruses. Due to the lack of potent agents to combat these infections caused by a large number of these high-impacting pathogens, huge emphasis has been put on the studies of T-705's antiviral properties and its mechanism of action. T-705 acts as a nucleobase analogue; hence, it is metabolized to the corresponding ribonucleoside triphosphate intracellularly. We herein report a reliable synthesis of T-705-ribonucleoside and its 5'-monophosphate. Moreover, we disclose detailed studies on the remarkable lability of the heterocycle when attached to ribose under very mild conditions, as they're typically applied for biochemical studies.
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Site of metabolism prediction based on ab initio derived atom representations ()
Machine learning models for site of metabolism (SoM) prediction offer the ability to identify metabolic soft spots in low molecular weight drug molecules at low computational cost and enable data-based reactivity prediction. SoM prediction is an atom classification problem. Successful construction of machine learning models requires atom representations that capture the reactivity-determining features of a potential reaction site. We have developed a descriptor scheme that characterizes an atom's steric and electronic environment and its relative location in the molecular structure. The partial charge distributions were obtained from fast quantum mechanical calculations. We successfully trained machine learning classifiers on curated cytochrome p450 metabolism data. The models based on the new atom descriptors showed sustained accuracy for retrospective analyses of metabolism optimization campaigns and lead optimization projects from Bayer Pharmaceuticals. The results obtained demonstrate the practicality of quantum-chemistry-supported machine learning models for hit-to-lead optimization.
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Improving non-specific binding and solubility: bicycloalkyls and cubanes as p-phenyl bioisosteres ()
Bicycloalkyl groups have previously been described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction in complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl group improves solubility by at least 50-fold, and markedly decreases non-specific binding (NSB) as measured using CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits with regard to non-specific binding or solubility, whereas substitutions with cubane-1,4-diyl also showed an improvement in both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl substituted molecules.
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Synthesis and Opioid Activity of Tyr1-[(Z)CF=CH]-Gly2 and Tyr1-[(S)/(R)-CF3CH-NH]-Gly2 Leu-enkephalin Fluorinated Pep-tidomimetics ()
We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH−NH]-Gly2) analogs of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exihibited low nanomolar functional activity (5.0 ± 2 nM and 60 ± 15 nM for δ- and μ−opioid receptors, respectively) with a μ/δ-selectivity ratio that mimicked the natural peptide. However, the trifluoroethyl-amine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substitu-ents are not tolerated at this position.
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Pyrrole-Based, Macrocyclic, Small-Molecule Inhibitors Targeting Oocyte Maturation ()
Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic AB103-8 that targets polo box domain (PBD) of PLK1 affected oocyte meiotic maturation and meiosis resumption. However, to overcome the peptidic drawbacks, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and screened against porcine oocyte maturation rates. Among them, compound 4 showed the highest inhibitory activity with enhanced inhibition against the embryos blastocyst formation. Furthermore, the addition of this compound to culture medium efficiently blocked the maturation of porcine and mouse oocytes, indicating that the lead compound could penetrate zona pellucida and cell membrane. To prove the PLK1 inhibition, we investigated the compound 4 treated mouse oocytes which confirmed the PLK1 inhibition by showing impaired spindle formation. Finally, molecular modeling studies with PLK1 PBD also confirmed the presence of significant interactions between compound 4 and Plk1 PBD binding pockets, including phosphate, tyrosine-rich and pyrrolidine binding pockets. Collectively, these results suggest that the macrocyclic compound 4 may serve as a promising template for the development of novel contraceptive agents.
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Design, Synthesis, in vitro and in vivo Evaluation of (Z)-3,4,5-Trimethoxystyryl Benzenesulfonamides/Sulfonates as Highly Potent Tubulin Polymerization Inhibitors ()
Abstract: Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug discovery process. Structure based docking studies illustrates the basic underlying concepts, which have been carried out, reveal interactions of sulfonamide group and hydrophobic interactions are crucial. Based on this strategy over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of sixty human cancer cell lines, majority of these compounds exhibited promising cytotoxicity with GI50 values ranging between 18-50 nM, and among them compounds 7a and 9a were found to be potent. Similar results were obtained against three human cancer cell lines with IC50values ranging between 0.04-3.0 µM. Further studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro tubulin polymerization and disorganized the microtubule assembly in MCF-7 and HeLa cancer cells. The lead compounds 7a and 9a displayed notable in vivo antitumor activity in HeLa tumor xenograft model. Our studies resulted in the identification of a scaffold that can target tubulin polymerization having significant potential towards the development of new antitumor drugs.
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Anticancer Activity of Stilbene-based Derivatives ()
Anticancer Activity of Stilbene-based Derivatives Barbara De Filippis,* Alessandra Ammazzalorso, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina Maccallini, Rosa Amoroso Dipartimento di Farmacia, Università "G. d'Annunzio", via dei Vestini 31, 66100 Chieti, Italy; * E-mail: barbara.defilippis@unich.it Stilbene is a very present structural scaffold in nature and stilbene-based compounds are largely described for their biological activity such as cardioprotective, potent antioxidant, anti-inflammatory, and anticancer agents. Starting from their potent chemotherapeutic activity against a wide variety of cancers, stilbene scaffold of resveratrol has been subjected to synthetic manipulations with the aim to obtaining new resveratrol analogues with improved anticancer activity and better bioavailability. In the last decade, majority of new synthetic stilbenoids demonstrated significant anticancer activity against a large number of cancer cell lines employed, depending on the type and position of substituents on stilbene skeleton. Given the importance of this topic and the vast therapeutic potential, especially in the field of cancer research, in the last years, some reviews have been published focusing on general pharmacological activity or, more recently, on the usefulness of hybrid molecule containing stilbene scaffold. The present review article focuses on the pharmacological profile of the key compounds containing stilbene scaffold and classify them on the type of structural modifications in stilbene skeleton.
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Structure-based design and synthesis of Harmine derivatives with different selectivity profiles in kinase vs monoamine oxidase inhibition ()
DYRK1A is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design we have synthesized a collection of harmine analogs with tunable selectivity towards these two enzymes. Modifications in position 7 typically decreased affinity for DYRK1A while substitution in position 9 had a similar effect on MAO-A inhibition while maintaining DYRK1A inhibition. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.
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1,3,5-Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu2/3 Receptors ()
The metabotropic glutamate subtype 2 (mGlu2) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2 receptor function with a negative allosteric modulator (NAM) enhances activity dependent glutamate release which may be of therapeutic benefit for treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) study on specific parts of the molecule. From close to micromolar potency we could obtain compounds of single digit nanomolar activity in the mGlu2 NAM GTPγS assay. Besides SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration and ex vivo mGlu2 receptor occupancy. Finally, in order to obtain improved drug-like compounds, plans for future research are suggested towards increasing free brain concentration while maintaining high in vitro potency.
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Identifying protein allosteric transitions for drug discovery using 1D NMR ()
Allosteric drugs present many advantages over orthosteric drugs and represent therefore an attractive approach in drug discovery, yet highly challenging. First, the binding of ligands in protein allosteric pockets do not ensure allosteric effect and second, allosteric ligands can possess diverse modes of pharmacology even within a compound family. Here we report a new method (1) to detect allosteric communication between protein binding sites and (2) to compare the effect of allosteric ligands on the allosteric transitions of the protein target. The method, illustrated with the Glycogen Phosphorylase protein, consists in comparing 1D NMR STD spectra of a molecule spy (here fragments) in the absence and presence of allosteric ligands. The modification of the STD spectrum of the fragment indicates whether the protein dynamics/conformations have been changed in the presence of the allosteric modulator, therefore highlighting allosteric coupling between the binding pocket of the reference compound (here the fragment) and the allosteric pocket.
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Physiochemical tuning of potent E. coli antiadhesives by microencapsulation and methylene homologation ()
Thiazolylaminomannosides (TazMan) are FimH antagonists with anti-adhesive potential against adherent-invasive Escherichia coli (AIEC) promoting gut inflammation in patients with Crohn's disease (CD). The lead TazMan is highly potent in vitro but shows limited in vivo efficiency probably due to low pH stability and water solubility. We recently developed a second generation of stable TazMan but the anti-adhesive effect was decreased compared to the first. Here, we report the co-crystal structure of the lead TazMan in FimH, revealing that the anomeric NH and the second thiazole moiety provide a positive H-bonding interaction with a trapped water molecule, and π-stacking with Tyrosine 48 of FimH, respectively. Consequently, we have developed NeoTazMan homologated with a methylene group for low pH and mannosidase stability with a conserved NH group and bearing various heterocyclic aglycons. Microencapsulation of the lead NeoTazMan in a γ-cyclodextrin dramatically improved the water solubility without disrupting the FimH affinity or the anti-adhesive effect against AIEC isolated from patients with CD.
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Synthesis and antiproliferative effect of ethyl 4-(4-substitutedpiperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives on human leukemic cells ()
Acute leukemia is a hematological malignancy with high incidence and recurrence rates, and is characterized by an accumulation of blasts in bone marrow due to proliferation of immature lymphoid or myeloid cells associated with a blockade of differentiation. The heterogeneity of leukemia led to look for new specific molecules for leukemia subtypes or even for therapy-resistant cases. Among heterocyclic derivatives that attracted attention due to their large spread biological activities, we have focused our interest towards the pyrrolo[1,2-a]quinoxaline heterocyclic framework that has been previously identified as an interesting scaffold for antiproliferative activities against various human cancer cell lines. In this work, new ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives 1a-o have been designed, synthesized and evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines), and K562, U937, HL60 (myeloid cell lines), and also on normal human peripheral blood mononuclear cells (PBMNCs). These new pyrrolo[1,2-a]quinoxaline series showed interesting cytotoxic potential against all tested leukemia cell lines. In particular, pyrroloquinoxalines 1a and 1m-n seem to be interesting due to their high activity against leukemia and their low activity against normal hematopoietic cells leading to high index of selectivity.
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Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A1 Adenosine Receptor Antagonist Cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX) ()
The A1 adenosine receptor (A1AR) antagonist [18F]cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX), used in imaging human brain A1ARs by PET, is stable in the brain but rapidly undergoes transformation into one major (M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with n.c.a.[18F]CPFPX contained the major metabolite, M1, as well as radioactive metabolites corresponding to derivatives functionalized at the cyclopentyl moiety, but no N1-despropyl species or metabolites resulting from functionalizations of the N3-fluoropropyl chain. The putative metabolites displaced the binding of [3H]CPFPX to the A1AR in pig brain cortex at Kis between 1.9 and 380 nM and the binding of [3H]ZM 241385 to the A2AAR in pig striatum at Kis greater than 180 nM. One metabolite, a derivative functionalized at the omega-position of the N1-propyl chain, showed high affinity (Ki 2 nM) to and very good selectivity (> 9000) for the A1AR.
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N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase ()
A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver. No inhibition of human recombinant β-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA). Sweet GBA inhibitors! A series of 1-N-iminosugars were synthesized to supply the need for glycosidase inhibitors that are both highly potent and selective for β-glycosidases. These iminosugar inhibitors differ from the currently available inhibitors in that they possess a guanidine or urea group at the endocyclic position of the 1,5-dideoxy-1,5-imino-d-xylitol ring. The guanidine series was found to be extremely potent and highly specific against the β-glycosidases, with IC50 values in the nanomolar range.
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The 13th Winter Conference on Medicinal and Bioorganic Chemistry ()
The Medicinal and Bioorganic Chemistry Foundation (MBCF) hosted its 13th biannual Winter Conference on Medicinal and Bioorganic Chemistry (WCMBC) this past January 22nd–26th in Steamboat Springs, Colorado (USA). The gathering this year kept true to the tradition of this conference series, with an impressive lineup of presenters from both academia and industry. With about 125 delegates, the conference took all the advantages of a mid-sized gathering: a sufficiently wide spectrum of scientists in attendance, yet an intimate atmosphere conducive to solid networking and frank, open discussions. This conference report summarizes the presentations that were given this year. Synthesis, SAR studies, and snow: The Medicinal and Bioorganic Chemistry Foundation (MBCF) hosted its biannual Winter Conference on Medicinal and Bioorganic Chemistry (WCMBC) this past January in Steamboat Springs, Colorado (USA). It was another highly invigorating exposure to cutting-edge medicinal chemistry, peppered with a healthy dose of winter activities that kept the blood flowing and thus the brain keen and ready to absorb and discuss some of the latest results in drug discovery research.
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Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists ()
N-Methyl-d-aspartate (NMDA) receptors are fundamental for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over-activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism, and the most promising compound showed an IC50 value on the same order of magnitude as that of memantine, an NMDA receptor antagonist in clinical use for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is brain permeable (determined by an in vitro assay) and non-hepatotoxic. All these results indicate that (3S,7aS)-7a-(4-chlorophenyl)-3-(4-hydroxybenzyl)tetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (compound 5 b) is a potential candidate for the treatment of pathologies associated with the over-activation of NMDA receptors. Catch 22: Twenty two novel enantiopure bicyclic lactams were synthesized and evaluated as NMDA receptor antagonists. The most promising compound displayed an IC50 value on the same order of magnitude as that of memantine. In vitro assays indicated that this compound is brain permeable and non-hepatotoxic; it is a potential candidate for the treatment of pathologies associated with the over-activation of NMDA receptors.
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Synthesis and Cytotoxicity Evaluation of C4- and C5-Modified Analogues of the α,β-Unsaturated Lactone of Pironetin ()
Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α-tubulin via conjugate addition into the natural product's α,β-unsaturated lactone. Although pironetin's α,β-unsaturated lactone is involved in its binding to tubulin, the structure–activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure–activity relationships at the C4 and C5 positions of the α,β-unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β-unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not. Lactone substitution matters: Twelve analogues of the α-tubulin-binding natural product pironetin were prepared by total synthesis to evaluate structure–activity relationships at the C4 and C5 positions of the α,β-unsaturated lactone. Modifications of the stereochemistry at the C4 and/or C5 positions resulted in loss of antiproliferative activity. The propyl and cyclopropyl groups were tolerated well at the C4 position.
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Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates ()
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery. The long-neglected sulfoximine group has recently enjoyed a rapidly increasing interest in the life sciences. The synthetic methodology for sulfoximines has progressed over the last decade; however, the general understanding of this functional group regarding is medicinal-chemistry-relevant properties is limited. We report the synthesis and in vitro characterization of six sulfoximine analogues of marketed drugs and clinical candidates.
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Synthesis of 4,4-Disubstituted 3-Methylidenechroman-2-ones as Potent Anticancer Agents ()
The synthesis of a new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones applying Horner–Wadsworth–Emmons methodology for the construction of an exo-methylidene moiety is reported. Corresponding 3-diethoxyphosphorylchroman-2-ones were synthesized in a three-step reaction sequence consisting of O-methylation of ethyl 2-diethoxyphosphoryl-3-oxoalkanoates, followed by reaction of the obtained 2-diethoxyphosphoryl-3-methoxy-2-alkenoates with phenols or 1-naphthol. The resulting 3-diethoxyphosphorylochromen-2-ones proved to be effective Michael acceptors in reactions with various Grignard reagents. Preliminary biological evaluations showed that many of the synthesized 3-methylidenechroman-2-ones possess very high cytotoxic activity against NALM-6 and HL-60 cancer cell lines (IC50<1.0 μm) as well as high activity against the MCF-7 cancer cell line (IC50<10 μm). Furthermore, two of the highly active 3-methylidenechroman-2-ones with geminal methyl and ethyl substituents at position 4 showed promising therapeutic indexes of 10 and 13 in tests against human umbilical vein endothelial cells (HUVECs). First place, position 4: The efficient synthesis of a new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones using Horner–Wadsworth–Emmons methodology is described. These compounds can be regarded as molecular hybrids containing two pharmacophore units: an α-methylidene-δ-lactone moiety and a chroman-2-one skeleton. Cytotoxicity tests revealed that many of these chroman-2-ones are highly cytotoxic against NALM-6 and HL-60 cancer cell lines (IC50<1.0 μm) and have high activity against the MCF-7 cancer cell line (IC50<10 μm).
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Enrichment and Viability Inhibition of Circulating Tumor Cells on a Dual Acid-Responsive Composite Nanofiber Film ()
The formation and metastatic colonization of circulating tumor cells (CTCs) are responsible for the vast majority of cancer-related deaths. Over the last decade, drug-delivery systems (DDSs) have rapidly developed with the emergence of nanotechnology; however, most reported tumor-targeting DDSs are able to deliver drugs only to solid tumor cells and not CTCs. Herein, a novel DDS comprising a composite nanofiber film was constructed to inhibit the viability of CTCs. In this system, gold nanoparticles (Au NPs) were functionalized with doxorubicin (DOX) through an acid-responsive cleavable linker to obtain Au-DOX NPs. Then, the Au-DOX NPs were mixed in a solution of an acid-responsive polymer {i.e., poly[2-(dimethylamino)ethyl methacrylate]} to synthesize the nanofiber film through electrospinning technology. After that, the nanofiber film was modified with a specific antibody (i.e., anti-EpCAM) to enrich the concentration of CTCs on the film. Finally, the Au-DOX NPs were released from the nanofiber film, and they consequently inhibited the viability of CTCs by delivering DOX to the enriched CTCs. This composite nanofiber film was able to decrease the viability of CTCs significantly in the suspended and fluid states, and it is expected to limit the migration and proliferation of tumor cells. On target: A novel drug-delivery system that targets circulating tumor cells (CTCs) and that comprises a composite nanofiber film that can enrich fluid CTCs and deliver a drug to these enriched CTCs under stimulation of the extra/intercellular environment at different pH values was developed. This drug-delivery system can be used to decrease the activity of CTCs and limit the migration and proliferation of tumor cells.
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Probing the Interactions of Cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and Its PtIV Derivatives with Human Serum ()
The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its PtIV derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The PtII complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a Kd value of ∼1.5×10−6 m. All PtIV complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2](TFA)2 (Pt56MeSS(OAc)2) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato)2](TFA)2 (Pt56MeSS(PhB)2), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the PtIV complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS. Spontaneous reduction: The stability and protein interactions of Pt56MeSS and its PtIV derivatives were assessed in phosphate buffer, human serum, and lipoproteins. The carboxylate derivatives of Pt56MeSS were found to be stable in human serum; however, in phosphate buffer (pH≥7) they undergo “spontaneous” reduction. The hydroxido derivative was stable in both solutions. The addition of axial ligands to Pt56MeSS prevents interaction of its phenanthroline moiety with proteins. Pt56MeSS(PhB)2 interacts strongly with proteins via the phenylbutyrate group.
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Theranostic Nanoparticles Loaded with Imaging Probes and Rubrocurcumin for Combined Cancer Therapy by Folate Receptor Targeting ()
The combination of different therapeutic modalities is a promising option to combat the recurrence of tumors. In this study, polylactic and polyglycolic acid nanoparticles were used for the simultaneous delivery of a boron–curcumin complex (RbCur) and an amphiphilic gadolinium complex into tumor cells with the aim of performing boron and gadolinium neutron capture therapy (NCT) in conjunction with the additional antiproliferative effects of curcumin. Furthermore, the use of Gd complexes allows magnetic resonance imaging (MRI) assessment of the amount of B and Gd internalized by tumor cells. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were targeted to ovarian cancer (IGROV-1) cells through folate receptors, by including in the formulation a PEGylated phospholipid functionalized with the folate moiety. NCT was performed on IGROV-1 cells internalizing 6.4 and 78.6 μg g−1 of 10B and 157Gd, respectively. The synergic action of neutron treatment and curcumin cytotoxicity was shown to result in a significant therapeutic improvement. Seek and destroy: Herein we present an innovative theranostic agent based on folate-targeted poly(lactic-co-glycolic acid) nanoparticles loaded with a boron–curcumin complex (rubrocurcumin) and the MRI contrast agent Gd-DOTAMA. This approach combines boron neutron capture therapy with the anticancer activity of curcumin for the imaging-guided treatment of human ovarian cancer (IGROV-1) cells.
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Analogues of Dehydroacetic Acid as Selective and Potent Agonists of an Ectopic Odorant Receptor through a Combination of Hydrophilic and Hydrophobic Interactions ()
Identification of potent agonists of odorant receptors (ORs), a major class of G protein-coupled receptors, remains challenging due to complex receptor–ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological functions in non-olfactory tissues. Selective and potent agonists specific for particular ORs can be used to investigate physiological functions of ORs in non-chemosensory tissues. In this study, we designed and synthesized novel synthetic dehydroacetic acid analogues as agonists of odorant receptor 895 (Olfr895) expressed in bladder. Among the synthesized analogues, (E)-3-((E)-1-hydroxy-3-(piperidin-1-yl)allylidene)-6-methyl-2H-pyran-2,4(3H)-dione (10) exhibited extremely high agonistic activity for Olfr895 in Dual-Glo luciferase reporter (EC50=9 nm), Ca2+ imaging, and chemotactic migration assays. Molecular docking and site-directed mutagenesis studies suggested that a combination of hydrophilic and hydrophobic interactions is central to the selective and specific binding of 10 to Olfr895. The design of agonists armed with both hydrophilic and hydrophobic portions could therefore lead to highly potent and selective ligands for ectopic ORs. Beyond sensory: Dehydroacetic acid analogues were synthesized and evaluated as agonists of the ectopic odorant receptor 895 (Olfr895), which is expressed in the bladder. The most promising compound exhibited strong activation of Olfr895, with an EC50 value of 9 nm in luciferase reporter assays. In vitro Ca2+ imaging, chemotactic migration, and site-directed mutagenesis experiments indicate that this compound is a highly potent and selective agonist for Olfr895 and can be used to investigate its physiological functions.
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A Molecular Dynamics–Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Receptor α ()
Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein′s active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand–protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptor α (PPARα). Findings derived from the dynamic analysis of interactions were then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach. The MYSHAPE approach is a new way of studying ligand–receptor interactions. In this method, a pharmacophore model is created that exploits information derived from multiple short MD simulations, using different molecules within the binding pocket of the target. Conformational information is retrieved from the full trajectory and not only from clustered frames. This approach can help improve virtual screening performance, especially for the early enrichment of active ligands in the virtual screening process.
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Cover Picture: Aqueous Instability of δ-Fluorobutylpiperidines (ChemMedChem 6/2017) ()
The front cover picture shows the fate of a δ-fluorobutylpiperidine in a mixture of organic solvent and water. Fluorinated alkyl groups are chemically quite robust in general. However, when carrying a single fluorine atom (green sphere) four carbon atoms away from an amine nitrogen center (large blue sphere), a fluoroalkyl group may become labile under very mild assay conditions, such as for the determination of lipophilicity. Such δ-fluoroalkyl amines suffer fluorine expulsion through intramolecular attack by the amine nitrogen to form cyclic products, represented here by the karate kick. The reactivity is extraordinary as such fluorinated N-alkylamine derivatives are otherwise fully stable in various organic solvents during synthesis, isolation, and purification. These findings constitute an important caveat to molecular design in drug discovery. More information can be found in the Full Paper by Klaus Müller et al. on page 431 in Issue 6, 2017 (DOI: 10.1002/cmdc.201700027).
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Back Cover: Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR (ChemMedChem 6/2017) ()
The back cover picture shows BmrR (shown bound to the Bmr promoter, pBMR), a bacterial multidrug resistance (MDR) regulator of Bmr efflux pump (membrane-embedded proteins) expression, is activated by structurally diverse ligands, including rhodamine 6G (RH6G, pink spheres) and benzyl triethyl ammonium (BTEA, green spheres). RH6G displays a much higher affinity to BmrR than BTEA; however, the latter elicits higher activation, suggesting unconventional coupling between signal recognition and signal control in the BmrR. We propose that the observed coupling may be important for offering broad, robust responses to multiple, unrelated cytotoxic chemicals. The background image (transparent) highlights the scope of ligand recognition by MDR systems. More information can be found in the Communication by Herschel Wade et al. on page 426 in Issue 6, 2017 (DOI:10.1002/cmdc.201700017).
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The Isoxazole Ring and Its N-Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics ()
Mental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor-related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N-oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood–brain barrier (BBB) permeability. Various drug-like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions. A key core structure: This review briefly outlines the main features of neuropsychiatric conditions and critically covers the isoxazole ring, which is present in a diverse array of derivatives, as a potent therapeutic targeting these debilitating diseases. A summary of key aspects and prospects in this active field are also briefly laid out.
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Recent Advances in the Discovery of PqsD Inhibitors as Antimicrobial Agents ()
The treatment of the infections caused by Pseudomonas aeruginosa, an opportunistic Gram-negative bacterium, is very difficult. High intrinsic tolerance toward common antibiotics and the development of new resistant strains challenge us to find a new treatment as soon as possible. PqsD is an enzyme essential for the P. aeruginosa quorum-sensing apparatus, which catalyzes the final and key step in the biosynthesis of 4-hydroxy-2-heptylquinolone (HHQ), which is a signal molecule of the P. aeruginosa quorum-sensing system. In this review, following an outline on their structures, we present a brief introduction of the PqsD inhibitors including their mechanisms of action, inhibitory activity, and structure–activity relationships. Scrambling their signals: Antibiotic resistance is a growing threat to public health. Recently, anti-quorum sensing (QS) has been recognized as an attractive strategy in the fight against bacteria based on antivirulence and antibiofilm action, and not on bacterial killing. The target protein PqsD is a key player in the quorum-sensing system of Pseudomonas aeruginosa. This review highlights recent advances in the search for new synthetic PqsD inhibitors, focusing on their biological activity, selectivity, and structure–activity relationship information.
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Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR ()
BmrR is a multidrug resistance (MDR) regulator that responds to diverse ligands. To obtain insight into signal recognition, allosteric control, and cooperativity, we used a quantitative in vitro transcription assay to determine the ligand-dependent activation profiles for a diverse set of cations, zwitterions, and uncharged ligands. As for many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively. Our results suggest unconventional coupling between ligand binding and allosteric control, with weakly interacting ligands exhibiting the highest levels of activation. Such properties are in stark contrast to those often exhibited by biological switch proteins, whereby ligand binding and allostery are tightly coupled, yielding both high selectivity and ultrasensitivity. We propose that weakened coupling, as observed for BmrR, may be important for providing robust activation responses to unrelated ligands. We also propose that other MDR proteins and other polyspecific switch systems will show similar features. To gain insight into signal recognition, allosteric control, and cooperativity in the multidrug-sensing regulator BmrR, we used a quantitative in vitro transcription assay to determine the activation profiles for a diverse set of ligands. Comparisons with signal-specific systems suggest weakened coupling between signal recognition and allostery in BmrR. This type of coupling may be important for providing robust responses to unrelated ligands. We propose that other MDR proteins and other polyspecific systems will show similar features.
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Aqueous Instability of δ-Fluorobutylpiperidines ()
In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines. Don't go alone at δ. Among many N-fluoroalkylpiperidines, those with a single fluorine substituent at the δ-position proved to be unstable under very mild biophysical assay conditions. This is a caveat to molecular design in drug discovery.
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Discovery of Cdc25A Lead Inhibitors with a Novel Chemotype by Virtual Screening: Application of Pharmacophore Modeling Based on a Training Set with a Limited Number of Unique Components ()
Cdc25 phosphatase was studied as an attractive target for cancer therapy. Multiple pharmacophore models with the unique core features of classic quinone inhibitors and those of novel inhibitors were used to discover a novel lead inhibitor. A total of 21 compounds with qualified physical properties were screened from the Maybridge HitFinder database containing 14 400 compounds by pharmacophore models. Four compounds were found to inhibit Cdc25A activity by more than 50 % at a concentration of 100 μm. Among these compounds, KM10389 (N-{2-[(furan-2-ylmethyl)thio]ethyl}-2-[(4-hydroxy-6-propylpyrimidin-2-yl)thio]acetamide) showed high inhibitory activity with an IC50 value of 7.9 μm. Selective cytotoxicity toward HeLa cells was observed with an IC50 value of 66.3 μm, whereas the IC50 value for HEK293 cells was higher than 100 μm. Blocking of the G1/S transition was also observed for HeLa cells in the presence of the compound by increasing the G1 phase by 16.15 %. Together with compounds HTS02435 and HTS01205, a novel lead inhibitor structure was identified and analyzed by a molecular docking study. The implication of virtual screening by using different pharmacophore models representing the different features is fully discussed. Training set to win: New inhibitors of Cdc25A were identified by using a combination of pharmacophore models and molecular docking. The biological activities were evaluated by enzyme activity assays, cytotoxicity tests, and cell-cycle analyses. Structure–activity relationship studies of the lead structure were analyzed by molecular docking studies.
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Trachycladines and Analogues: Synthesis and Evaluation of Anticancer Activity ()
The synthesis of four new analogues of marine nucleoside trachycladine A was accomplished by direct regio- and stereoselective Vorbrüggen glycosylations of 2,6-dichloropurine and 2-chloropurine with a d-ribose-derived chiron. Naturally occurring trachycladines A and B and a series of analogues were examined for their cytotoxic activity against a number of cancer cell lines (glioblastoma, lung, and cervical cancer). Parent trachycladine A and two analogues (the diacetate of the 2,6-dichloropurine derivative and N-cyclopropyl trachycladine A) resulted in a significant decrease in cell viability, with the latter exhibiting a stronger effect. The same compounds enhanced the cytotoxic effect of docetaxel in lung cancer cell lines, whereas additional experiments revealed that their mode of action relies on mitotic catastrophe rather than DNA damage. Moreover, their activity as autophagic flux blockers was postulated. Killer nucleosides: Natural trachycladines and their analogues were synthesized. Trachycladine A and two of its analogues showed potent cytotoxic activity against glioblastoma, lung, and cervical cancer cell lines by mitotic catastrophe and enhanced the cytotoxic effect of docetaxel in lung cancer cell lines. They also led to a decrease in autolysosomal fusion.
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Synthesis, Biological Evaluation, and Molecular Docking Studies on the DNA Binding Interactions of Platinum(II) Rollover Complexes Containing Phosphorus Donor Ligands ()
Cyclometalated rollover complexes of the type [PtMe(κ2N,C-bipyO-H)(L)] [bipyO-H=cyclometalated 2,2′-bipyridine N-oxide; L=tricyclohexylphosphine (PCy3, 2 a), 2-(diphenylphosphino)pyridine (PPh2py, 2 b), P(OPh)3 (2 c)] were synthesized by treating [PtMe(κ2N,C-bipyO-H)(SMe2)] (1) with various monodentate phosphine and phosphite ligands. These complexes were characterized by NMR spectroscopy, and the structure of 2 a was confirmed by single-crystal X-ray diffraction. Complex 1 was treated with bis(diphenylphosphino)methane (dppm) at a 1:1 ratio to give the corresponding [PtMe(κ2N,C-bipyO-H)(κ1P-dppm)] (3 b) complex, in which the dppm ligand acts as a monodentate pendant ligand. The biological activities of these complexes were evaluated against a panel of four standard cancer cell lines: lung carcinoma (A549), ovarian carcinoma (OV-90 and SKOV3), and breast carcinoma (MCF-7). Complexes 2 c and especially 3 b indicated effective potent cytotoxic activity regarding the cell lines. Electrophoresis mobility shift assays and molecular-modeling investigations were performed to determine the specific binding mode and the binding orientation of these alkylating agents to DNA. Detection of cellular reactive oxygen species was also determined. P ligands make a difference: Platinum (II) complexes of the type [PtMe(κ2N,C-bipyO-H)(L)], in which bipyO-H is a cyclometalated 2,2′-bipyridine N-oxide, and L is a different monodentate phosphine, phosphite, or diphosphine, were prepared from [PtMe(κ2N,C-bipyO-H)(SMe2)]. In vitro cytotoxic activities against a panel of four human cancer cell lines show high inhibition of cellular growth, with IC50 values similar to that of cisplatin.
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Synthesis of 5α,8α-Ergosterol Peroxide 3-Carbamate Derivatives and a Fluorescent Mitochondria-Targeting Conjugate for Enhanced Anticancer Activities ()
Inspired by the significant anticancer activity of our previously screened natural ergosterol peroxide (1), we synthesized and characterized a series of novel ergosterol peroxide 3-carbamate derivatives. The antiproliferative activities of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, SK-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. 5α,8α-Epidioxyergosta-3-yl-(piperazine-1)carbamate (3 d) and 5α,8α-epidioxyergosta-3-yl-(piperidin-4-methylamine)carbamate (3 f) and their hydrochloride salts exhibited significant in vitro antiproliferative activities against the tested tumor cell lines, with IC50 values ranging from 0.85 to 4.62 μm. Furthermore, fluorescent imaging showed that the designed coumarin–3 d conjugate (5) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure 1. As a whole, it appeared that substituent changes at the C3 position could serve as a promising launch point for further design of this type of steroidal anticancer agent. Small changes, big difference! Through structural changes, we synthesized a series of 5α,8α-ergosterol peroxide 3-carbamate derivatives 3 a–3 j. Compounds 3 d and 3 f and their hydrochlorides exhibited significant in vitro antiproliferative activity against tumor cell lines. A fluorescent conjugate, obtained by linking coumarin-3-carboximide with 3 d, localized in mitochondria and exhibited enhanced anticancer activity over the parent structure.
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