ABSTRACT
Forty samples of optically active falcarindiol analogues are synthesized by using the easily available C2 symmetric (R)- and (S)-1,1'-binaphth-2-ol (BINOL) in combination with Ti(Oi Pr)4 , Zn powder and EtI. Their anticancer activities on Hccc-9810, HepG2, MDA-MB-231, Hela, MG-63 and H460 cells are assayed to elucidate their structure-activity relationships. These results showed that the falcarindiol analogue (3R,8S)-2 i with the terminal double bond has the most potent anti-proliferation effect on Hccc-9810 cells with IC50 value of 0.46â µM. The falcarindiol analogue (3R,8S)-2 i can induce obvious Hccc-9810â cell apoptosis in a concentration-dependent manner by Hoechst staining and flow cytometry analysis. The proposed mechanism suggests that the falcarindiol analogue (3R,8S)-2 i increases LDH release and MDA content, and reduces the levels of SOD activity, which lead to the accumulation of oxidative stress and induce apoptosis in Hccc-9810 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Diynes/pharmacology , Fatty Alcohols/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Diynes/chemical synthesis , Drug Screening Assays, Antitumor , Fatty Alcohols/chemical synthesis , Humans , L-Lactate Dehydrogenase/metabolism , Malondialdehyde/metabolism , Molecular Structure , Oxidative Stress/drug effects , Structure-Activity Relationship , Superoxide Dismutase/metabolismABSTRACT
A series of enantiomers of falcarinol analogues (2) were synthesized using a chiral 1,1'-binaphth-2-ol (BINOL)-based catalytic system. The neuroprotective effects of falcarinol (1a) and its analogues (2) on PC12 cells injured by sodium azide (NaN3) were investigated. The structure-function relationships and possible mechanism were studied. Pretreatment of PC12 cells with falcarinol analogues (R)-2d and (R)-2i for 1 h following addition of NaN3 and culture in a CO2 incubator for 24 h resulted in significant elevation of cell viability, as determined by a CCK-8 assay and Hoechst staining, with reduction of LDH release and MDA content, increase of SOD activity, and decrease of ROS stress, when compared with the activity of natural falcarinol (1a). These observations indicated that the falcarinol analogues (R)-2d and (R)-2i can protect PC12 cells against NaN3-induced apoptosis via increasing resistance to oxidative stress. For the first time, falcarinol (1a) and its analogue (R)-2i were found to have potential L-type calcium channel-blocking activity, as recorded using a manual patch clamp technique on HEK-293 cells stably expressing hCav1.2 (α1C/ß2a/α2δ1). These findings suggest that the mechanism of the L-type calcium channel-blocking activity of falcarinol (1a) and its analogue (R)-2i might be involved in neuroprotection by falcarinol-type analogues by inhibiting calcium overload in the upstream of the signaling pathway.
Subject(s)
Calcium Channel Blockers/pharmacology , Diynes/pharmacology , Fatty Alcohols/pharmacology , Neuroprotective Agents/pharmacology , Animals , Calcium Channel Blockers/chemical synthesis , Cell Survival/drug effects , Diynes/chemical synthesis , Fatty Alcohols/chemical synthesis , HEK293 Cells , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Oxidative Stress/drug effects , PC12 Cells , Rats , Signal Transduction/drug effectsABSTRACT
Alkenes are an important class of compounds common among biologically active molecules and often are used as intermediates in organic synthesis. Many alkenes exist in two stereoisomeric forms (E and Z), which have different structures and different properties. The selective formation of the two isomers is an important synthetic goal that has long inspired the development of new synthetic methods. However, the efficient synthesis of diastereopure, thermodynamically less stable, Z-alkenes is still challenging. Here, we demonstrate an efficient synthesis of diastereopure Z-alkenes (Z:E > 300:1) through a silver-catalyzed hydroalkylation of terminal alkynes, using alkylboranes as coupling partners. We also describe the exploration of the substrate scope, which reveals the broad functional group compatibility of the new method. Preliminary mechanistic studies suggest that a 1,2-metalate rearrangement of the silver borate intermediate is the key step responsible for the stereochemical outcome of the reaction.
Subject(s)
Alkenes/chemical synthesis , Alkynes/chemistry , Silver/chemistry , Alkenes/chemistry , Borates/chemistry , Capsaicin/analogs & derivatives , Capsaicin/chemical synthesis , Catalysis , Diynes/chemical synthesis , Fatty Alcohols/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30â mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Diynes/pharmacology , Enzyme Inhibitors/pharmacology , Heart/drug effects , Hydroxamic Acids/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/toxicity , Bacterial Proteins/antagonists & inhibitors , Cardiotoxicity , Diynes/chemical synthesis , Diynes/pharmacokinetics , Diynes/toxicity , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/toxicity , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/toxicity , Male , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/toxicity , Pseudomonas aeruginosa/drug effects , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Here we disclose a cascade strategy for naphthyne formation that capitalizes on the traditional benzyne generation (i.e., from an ortho-silyl aryl triflate) and the thermal hexadehydro-Diels-Alder (HDDA) reaction. In this transformation, three distinct aryne species work in tandem, two of which can be formally considered as a 1,2-benzidyne, and each undergoes a different type of trapping event. Many examples were explored by varying the naphthyne capture chemistry as well as the 1,2-benzdiyne equivalent. This strategy enables rapid construction of various naphthalene products and has potential for the synthesis of extended polycyclic arenes.
Subject(s)
Diynes/chemical synthesis , Naphthalenes/chemical synthesis , Cycloaddition Reaction , Density Functional Theory , Models, Chemical , Molecular StructureABSTRACT
A chiral amino alcohol based ligand was found to promote the highly enantioselective addition of terminal conjugated diynes to aromatic and aliphatic aldehydes. The combination of easily available C2 -symmetric (R)- and (S)-BINOL with Ti(OiPr)4 , Zn powder, and EtI was also found to catalyze the asymmetric addition of 1,3-diynes to aldehydes under mild reaction conditions, and thus, both enantiomers of the chiral conjugated diynols could be prepared with high enantioselectivities. The resulting optically active conjugated diynols were found to have potential anticancer activities with significant differences against HepG2 and HeLa cancer cells, and remarkable enantioselective cytotoxicity was observed for the first time.
Subject(s)
Aldehydes/chemistry , Amino Alcohols/chemistry , Antineoplastic Agents/chemistry , Diynes/chemistry , Aldehydes/chemical synthesis , Aldehydes/pharmacology , Amino Alcohols/chemical synthesis , Amino Alcohols/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Catalysis , Diynes/chemical synthesis , Diynes/pharmacology , HeLa Cells , Hep G2 Cells , Humans , Ligands , Naphthols/chemical synthesis , Naphthols/chemistry , Naphthols/pharmacology , Neoplasms/drug therapy , Stereoisomerism , Titanium/chemistry , Zinc/chemistryABSTRACT
Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives.
Subject(s)
Biological Products/pharmacology , Diynes/pharmacology , Fatty Alcohols/pharmacology , Polyynes/pharmacology , Receptors, GABA-A/metabolism , Biological Products/chemical synthesis , Biological Products/chemistry , Diynes/chemical synthesis , Diynes/chemistry , Fatty Alcohols/chemical synthesis , Fatty Alcohols/chemistry , Humans , Molecular Structure , Polyynes/chemistry , Protein Isoforms/drug effects , Protein Isoforms/metabolism , Receptors, GABA-A/chemistry , Water/chemistryABSTRACT
Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.
Subject(s)
Catalysis , Diynes/chemical synthesis , Pyrones/chemical synthesis , Cyclization , Diynes/chemistry , Molecular Structure , Pyrones/chemistry , Stereoisomerism , Water/chemistryABSTRACT
The first total synthesis of the polyacetylene natural product atractylodemayne A is reported. Stereoselective construction of the conjugated 8(Z),10(E)-diene moiety was achieved through a tethered ring-closing metathesis approach, comprising a Ru-catalyzed RCM followed by a base-induced elimination. A Pd-catalyzed Cadiot-Chodkiewicz coupling was used for the synthesis of the diyne. Overall, atractylodemayne A was synthesized in nine steps for the longest linear sequence.
Subject(s)
Biological Products/chemical synthesis , Diynes/chemical synthesis , Polyenes/chemical synthesis , Biological Products/chemistry , Catalysis , Cyclization , Diynes/chemistry , Fatty Alcohols , Molecular Structure , Polyenes/chemistry , StereoisomerismABSTRACT
An enantioselective total synthesis of chiral falcarindiol analogues from buta-1,3-diyn-1-yltriisopropylsilane is reported. The key step in this synthesis is BINOL-promoted asymmetric diacetylene addition to aldehydes. The two chiral centers of the falcarindiol analogues can be produced by using the same kind of catalyst with high selectivity, and the final product can be obtained in only six steps.
Subject(s)
Aldehydes/chemistry , Alkynes/chemistry , Diynes/chemistry , Fatty Alcohols/chemistry , Naphthols/chemistry , Catalysis , Diynes/chemical synthesis , Esters , Fatty Alcohols/chemical synthesis , Molecular StructureABSTRACT
The convergent total synthesis of the marine natural product phosphoiodyn A, a nanomolar agonist of human peroxisome proliferator-activated receptor delta (hPPARδ), was achieved in five steps total from commercially available and inexpensive starting materials. The synthesis relies on the unprecedented regioselective hydrozirconation of a terminal acetylene in the presence of a conjugated 1,3-diyne and on ammonolysis of a ß-chlorophosphonic acid monoester. The scheme also provides the newly isolated placotylene A, an inhibitor of bone marrow-derived macrophage (BMM) differentiation.
Subject(s)
Diynes/chemical synthesis , Fatty Alcohols/chemical synthesis , Hydrocarbons, Iodinated/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Polyynes/chemical synthesis , Acetylene/chemistry , Cell Differentiation , Diynes/chemistry , Diynes/pharmacology , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Humans , Hydrocarbons, Iodinated/chemistry , Hydrocarbons, Iodinated/pharmacology , Macrophages/drug effects , Molecular Structure , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , PPAR delta/agonists , Polyynes/chemistry , Polyynes/pharmacologyABSTRACT
Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders. Inhibition of ALDH2 impairs detoxification of reactive aldehydes and limits oxidative stress response, two crucial pathways for cellular viability.
Subject(s)
Aldehyde Dehydrogenase/antagonists & inhibitors , Alkynes/pharmacology , Antineoplastic Agents/pharmacology , Diynes/pharmacology , Enzyme Inhibitors/pharmacology , Fatty Alcohols/pharmacology , Aldehyde Dehydrogenase/chemistry , Aldehyde Dehydrogenase, Mitochondrial , Alkynes/chemical synthesis , Antineoplastic Agents/chemical synthesis , Catalytic Domain , Click Chemistry , Cysteine/chemistry , Diynes/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Fatty Alcohols/chemical synthesis , Hep G2 Cells , Humans , Kinetics , Recombinant Proteins/chemistryABSTRACT
Bidirectional syntheses of C2-symmetrical lipids embedding two terminal alkynylcarbinol pharmacophores are reported. Naturally occurring chiral alkenylalkynylcarbinol units were generated using Pu's procedure for enantioselective addition of terminal alkynes to aldehydes, allowing the first asymmetric synthesis of (3R,4E,16E,18R)-icosa-4,16-diene-1,19-diyne-3,18-diol, isolated from Callyspongia pseudoreticulata. Two synthetic analogues embedding the recently uncovered (S)-dialkynylcarbinol pharmacophore were secured using Carreira's procedure adapted to ynal substrates. The dramatic effect of the carbinol configuration on cytotoxicity was confirmed with submicromolar IC50 values against HCT116 cells.
Subject(s)
Alkynes/chemistry , Diynes/chemical synthesis , Lipids/chemical synthesis , Methanol/chemistry , Biological Phenomena , Catalysis , Diynes/chemistry , HCT116 Cells , Humans , Inhibitory Concentration 50 , Lipids/chemistry , Molecular Structure , StereoisomerismABSTRACT
The translation of organometallic reactions into a microwave reactor has numerous advantages. Herein, we describe the application of a previously developed solid-supported Glaser-Hay reaction to microwave conditions. Overall, an array of diynes has been prepared demonstrating the ability to conduct chemoselective reactions in the microwave within 20 min compared to the 16 h thermal conditions. Moreover, non-microwave transparent alkynes have been found to react more quickly, preventing catalyst quenching, and resulting in higher yields.
Subject(s)
Diynes/chemical synthesis , Catalysis , Diynes/chemistry , Microwaves , Molecular Structure , Time FactorsABSTRACT
We report a cholesterol imaging method using rationally synthesized phenyl-diyne cholesterol (PhDY-Chol) and stimulated Raman scattering (SRS) microscope. The phenyl-diyne group is biologically inert and provides a Raman scattering cross section that is 88 times larger than the endogenous C = O stretching mode. SRS microscopy offers an imaging speed that is faster than spontaneous Raman microscopy by three orders of magnitude, and a detection sensitivity of 31â µM PhDY-Chol (~1,800 molecules in the excitation volume). Inside living CHO cells, PhDY-Chol mimics the behavior of cholesterol, including membrane incorporation and esterification. In a cellular model of Niemann-Pick type C disease, PhDY-Chol reflects the lysosomal accumulation of cholesterol, and shows relocation to lipid droplets after HPßCD treatment. In live C. elegans, PhDY-Chol mimics cholesterol uptake by intestinal cells and reflects cholesterol storage. Together, our work demonstrates an enabling platform for study of cholesterol storage and trafficking in living cells and vital organisms.
Subject(s)
Cholesterol/metabolism , Lysosomes/metabolism , Molecular Imaging , Niemann-Pick Disease, Type C/metabolism , Animals , CHO Cells , Caenorhabditis elegans/chemistry , Caenorhabditis elegans/metabolism , Cholesterol/chemical synthesis , Cholesterol/isolation & purification , Cricetulus , Diynes/chemical synthesis , Diynes/chemistry , Lipid Droplets/chemistry , Lipid Droplets/metabolism , Lysosomes/pathology , Niemann-Pick Disease, Type C/pathology , Spectrum Analysis, RamanABSTRACT
Indole synthesis by a gold(I)-catalyzed intermolecular formal [4+2] reaction between 1,3-diynes and pyrroles has been developed. This reaction involves the hydroarylation of 1,3-diynes with pyrroles followed by an intramolecular hydroarylation to give the 4,7-disubstituted indoles. This reaction can also be applied to the synthesis of carbazoles when indoles are used as the nucleophiles instead of pyrroles.
Subject(s)
Diynes/chemistry , Gold/chemistry , Indoles/chemical synthesis , Pyrroles/chemistry , Catalysis , Diynes/chemical synthesis , Indoles/chemistry , Pyrroles/chemical synthesisABSTRACT
Nonafluorobutanesulfonyl azide is a highly efficient reagent for the copper-catalyzed coupling of terminal alkynes to give symmetrical and unsymmetrical 1,3-diynes in good to excellent yields and with good functional group compatibility. The reaction is extremely fast (<10 min), even at low temperature (−78 °C), and requires substoichiometric amounts of a simple copper(I) or copper(II) salt (25 mol %) and an organic base (0.6 mol %). A possible mechanistic pathway is briefly discussed on the basis of model DFT theoretical calculations. The quantitative assessment of the safety of use and shelf stability of nonafluorobutanesulfonyl azide has confirmed that this reagent is a superior and safe alternative to other electrophilic azide reagents in use today.
Subject(s)
Alkynes/chemistry , Alkynes/chemical synthesis , Azides/chemistry , Copper/chemistry , Diynes/chemistry , Diynes/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Oxidants/chemistry , Catalysis , Molecular StructureABSTRACT
A Ni/N-heterocyclic carbene catalyst couples diynes to the C(α)-C(ß) double bond of tropone, a type of reaction that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone. The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5-6-7] fused tricyclic product. This initial product undergoes two competing isomerizations, leading to the observed [5-6-7] and [5-7-6] fused tricyclic products.
Subject(s)
Diynes/chemistry , Diynes/chemical synthesis , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Tropolone/analogs & derivatives , Catalysis , Cyclization , Cycloaddition Reaction , Methane/chemistry , Models, Molecular , Molecular Conformation , Stereoisomerism , Substrate Specificity , Tropolone/chemical synthesis , Tropolone/chemistryABSTRACT
Site-selective sequential coupling reactions directed toward bis(diaryl)butadiynes are described. The reaction site could be controlled completely by the on/off application of electricity. The electro-oxidative homo-coupling of terminal alkynes (electricity ON) and the subsequent Suzuki-Miyaura coupling (electricity OFF) afforded bis(diaryl)butadiynes in high yields. The obtained 1,4-bis(diaryl)butadiynes could be converted to a 2,5-bis(diaryl)thiophene derivative, which exhibited blue fluorescence.
Subject(s)
Alkynes/chemistry , Chemistry Techniques, Synthetic/methods , Diynes/chemical synthesis , Electrochemical Techniques/methods , Catalysis , Diynes/chemistry , Molecular Structure , Oxidation-Reduction , Palladium/chemistryABSTRACT
An efficient Sonogashira coupling of terminal alkynes and styrenyl bromides has been achieved under the catalysis of hydroxyapatite-supported copper(I). The trans-styrenyl bromides produce the usual trans-enyne products, whereas the cis-styrenyl bromides lead to unsymmetric 1,3-diynes by the cross coupling of terminal alkyne and the alkyne generated from the cis-styrenyl bromide. A series of trans-enynes and unsymmetric 1,3-diynes have been synthesized by this protocol.