Cyclopropane Group Research Articles

Design, Synthesis, and Biological Evaluation of New Type of Gemini Analogues with a Cyclopropane Moiety in Their Side Chain.

We synthesized two new gemini analogues, UG-480 and UG-481, that incorporate a modified longer side chain containing a cyclopropane group. The evaluation of the bioactivities of the two gemini analogues indicated that the 17,20 threo (20S) compound, UG-480, is the most active one and is as active as 1,25(OH)2D3. Docking and molecular dynamics (MD) data showed that the compounds bind efficiently to vitamin D receptor (VDR) with UG-480 to form an energetically more favorable interaction with His397. Structural analysis indicated that whereas the UG-480 compound efficiently stabilizes the active VDR conformation, it induces conformational changes in the H6-H7 VDR region that are greater than those induced by the parental Gemini and that this is due to the occupancy of the secondary channel by its modified side chain.

Anti-enzymatic and DNA docking studies of montelukast: A multifaceted molecular scaffold with in vitro investigations, molecular expression analysis and molecular dynamics simulations

Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the present studies, montelukast was subjected to in vitro inhibitory assays followed by kinetic and in silico investigations. Montelukast demonstrated inhibitory activity against yeast α-glucosidase (IC50 44.31 ± 1.21 μM), jack bean urease (JB urease, IC50 8.72 ± 0.23 μM), human placental alkaline phosphatase (hPAP, IC50 17.53 ± 0.19 μM), bovine intestinal alkaline phosphatase (bIAP, IC50 15.18 ± 0.23 μM) and soybean 15-lipoxygenase (15-LOX, IC50 2.41 ± 0.13 μM). Kinetic studies against α-glucosidase and urease enzymes revealed its competitive mode of inhibition. Molecular expression analysis of montelukast in breast cancer cell line MCF-7 down-regulated AP by a factor of 0.27 (5 μM) compared with the 0.26 value for standard inhibitor levamisole (10 μM). Molecular docking estimated a binding affinity ranging −8.82 to −15.65 kcal/mol for the enzymes. Docking against the DNA dodecamer (ID: 1BNA) observed −9.13 kcal/mol via minor groove binding. MD simulations suggested stable binding between montelukast and the target proteins predicting strong inhibitory potential of the ligand. Montelukast features a chloroquinoline, phenyl ring, a cyclopropane group, a carboxylic group and a sulfur atom all of which collectively enhance its inhibitory potential against the said enzymes. These in vitro and computational investigations demonstrate that it is possible and suggested that the interactions of montelukast with more than one targets presented herein may be linked with the side effects presented by this drug and necessitate additional work. The results altogether suggest montelukast as an important structural scaffold possessing multitargeted features and warrant further investigations in repurposing beyond its traditional pharmacological use.

Synthesis and characterization of high-density biosynthetic fuels from myrtenal

Apopinene was synthesized from myrtenal by catalytic decarbonylation followed by either hydrogenation to generate dihydroapopinene or Simmons-Smith cyclopropanation to generate exo-(1R,2R)-7,7-dimethyltricyclo[4.1.1.02,4]octane (cyclopropanated apopinene, CPA). Key fuel properties of apopinene and the two derivative fuels were evaluated including density, heat of combustion, and low temperature viscosity. CPA exhibited a density of 0.918 g mL−1 and a volumetric net heat of combustion (NHOC) 20 % higher than the lower limit for conventional jet fuel. This exceptional NHOC is a result of the high density of the tricyclic compound and the ring strain of the bridging cyclobutane and fused cyclopropane groups. Dihydroapopinene exhibited a high freezing point that will limit its applications as a jet fuel blendstock. In contrast, no freezing point down to −80 °C was observed for CPA via differential scanning calorimetry (DSC). In addition, CPA exhibited a moderate kinematic viscosity of 10.11 mm2 s−1 at −20 °C and 22.76 mm2 s−1 at −40 °C. This work demonstrates that fuels with both high energy densities and excellent low temperature properties can be generated from bio-based substrates through cyclopropanation reactions.

Palladium-Catalyzed Cross-Coupling of Tertiary Cyclopropyl Carbagermatranes with Acyl Chlorides.

A simple method for the synthesis of cyclopropane compounds via cross-coupling reaction between tertiary cyclopropyl carbagermatranes and acyl chlorides was reported. Derivatives of acryloyl chloride and aliphatic acyl chloride also performed to be suitable substrates. This process can be used to introduce a wide range of functionalized cyclopropane groups and acyl groups directly.

Palladium‐Catalyzed Cyclopropanation of Aryl/Heteroaryl Fluoro‐sulfonates

AbstractThe cyclopropane group is widely present as an important motif in pharmaceuticals and natural products. Herein, we report a cyclopropanation strategy by inexpensive and readily available aryl/heteroaryl fluorosulfonates. The strategy displays wide functional group compatibility and furnishes the corresponding cyclopropane products in excellent yields. The power of this new platform is showcased through one‐pot and gram‐scale experiments. This is reinforced by its application in late‐stage functionalization.

The Norsesquiterpene Glycoside Ptaquiloside as a Poisonous, Carcinogenic Component of Certain Ferns

Previous studies related to the ptaquiloside molecule, a carcinogenic secondary metabolite known from the world of ferns, are summarised. Ptaquiloside (PTA) belongs to the group of norsesquiterpenes of the illudane type. The name illudane refers to the fungal taxa from which the first representatives of the molecular group were identified. Ptaquiloside occurs mainly in Pteridium fern species, although it is also known in other fern taxa. The species of the genus Pteridium are common, frequent invasive species on all continents, and PTA is formed in smaller or larger amounts in all organs of the affected species. The effects of PTA and of their derivatives on animals and humans are of great toxicological significance. Its basic chemical property is that the molecule can be transformed. First, with the loss of sugar moiety, ptaquilosine is formed, and then, under certain conditions, a dienone derivative (pteridienone) may arise. The latter can alkylate (through its cyclopropane groups) certain molecules, including DNA, in animal or human organisms. In this case, DNA adducts are formed, which can later have a carcinogenic effect through point mutations. The scope of the PTA is interdisciplinary in nature since, for example, molecules from plant biomass can enter the body of animals or humans in several ways (directly and indirectly). Due to its physico-chemical properties (excellent water solubility), PTA can get from the plant into the soil and then into different water layers. PTA molecules that enter the soil, but mainly water, undergo degradation (hydrolytic) processes, so it is very important to clarify the toxicological conditions of a given ecosystem and to estimate the possible risks caused by PTA. The toxicoses and diseases of the animal world (mainly for ruminant farm animals) caused by PTA are briefly described. The intake of PTA-containing plants as a feed source causes not only various syndromes but can also enter the milk (and meat) of animals. In connection with the toxicological safety of the food chain, it is important to investigate the transport of carcinogenic PTA metabolites between organisms in a reassuring manner and in detail. This is a global, interdisciplinary task. The present review aims to contribute to this.

COPOLYMERS ON THE BASIS OF (p-CHLOROPHENOXYCARBONYL)-CYCLOPROPYL STYRENE WITH STYRENE AND METHYL METHACRYLATE

The radical copolymerization of (p-chlorophenoxycarbonyl)cyclopropyl styrene with styrene and methyl methacrylate has been carried out. New cyclopropane-containing copolymers have been obtained. It has been established that the synthesized copolymers due to peculiarities of their structure and polyfucntionality, namely with content of carbonyl and cyclopropane groups sensitive to UV irradiation in the macromolecule have photosensitivity. The constant values of relative activity of monomers have been determined and Q-e parameters on Alfrey and Price have been calculated. The copolymerization constants of this compound (r1) with styrene and methyl methacylate (r2), calculated on Fineman-Ross method are: r1 = 1.1 and1.05, but r2 = 0.56 and 0.48, respectively; Q and e parameters values: Q1 = 3.1 and 2.4, e1 = –1.4 and –0.8, respectively. The photochemical structuring has been investigated and it has been shown that the structuring process proceeds due to of cyclopropane ring opening and carbonyl group. The composition and structure of these copolymers have been established and their some characteristics (heat resistance, hardness, adhesive strength, water absorption) have been investigated. The structuring process has been also studied and it has been established that the synthesized copolymer has relatively high photosensitivity (50–55 cm2J-1)

Antitumor Profile of Carbon-Bridged Steroids (CBS) and Triterpenoids.

This review focuses on the rare group of carbon-bridged steroids (CBS) and triterpenoids found in various natural sources such as green, yellow-green, and red algae, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in amoebas, fungi, fungal endophytes, and plants. For convenience, the presented CBS and triterpenoids are divided into four groups, which include: (a) CBS and triterpenoids containing a cyclopropane group; (b) CBS and triterpenoids with cyclopropane ring in the side chain; (c) CBS and triterpenoids containing a cyclobutane group; (d) CBS and triterpenoids containing cyclopentane, cyclohexane or cycloheptane moieties. For the comparative characterization of the antitumor profile, we have added several semi- and synthetic CBS and triterpenoids, with various additional rings, to identify possible promising sources for pharmacologists and the pharmaceutical industry. About 300 CBS and triterpenoids are presented in this review, which demonstrate a wide range of biological activities, but the most pronounced antitumor profile. The review summarizes biological activities both determined experimentally and estimated using the well-known PASS software. According to the data obtained, two-thirds of CBS and triterpenoids show moderate activity levels with a confidence level of 70 to 90%; however, one third of these lipids demonstrate strong antitumor activity with a confidence level exceeding 90%. Several CBS and triterpenoids, from different lipid groups, demonstrate selective action on different types of tumor cells such as renal cancer, sarcoma, pancreatic cancer, prostate cancer, lymphocytic leukemia, myeloid leukemia, liver cancer, and genitourinary cancer with varying degrees of confidence. In addition, the review presents graphical images of the antitumor profile of both individual CBS and triterpenoids groups and individual compounds.

Synthesis and characterization of new polymers containing cyclopropane groups

New polymeric products containing cyclopropane groups in the macromolecules have been obtained by catalytic cyclopropanation of syndiotactic 1,2-PB with diazomethane. A comparative estimate of the activity and regioselectivity of the catalysts used in the 1,2-PB cyclopropanation is given. It has been shown that varying the catalyst nature allows one to control the cyclopropanation process and to obtain modified polymers with predefined structure and degree of functionalization. The effect of the degree of modification on the molecular characteristics and properties of cyclopropanated polymers, such as viscosity of solutions and melts, glass transition point, crystallinity and thermal stability, has been studied. It has been shown that the incorporation of cyclopropane groups into macromolecules of syndiotactic 1,2-PB gives amorphous thermoplastic polymeric products that are rather energy rich and are of practical interest.

Grafting of Ring-Opened Cyclopropylamine Thin Films on Silicon (100) Hydride via UV Photoionization.

The grafting of cyclopropylamine onto a silicon (100) hydride (Si-H) surface via a ring-opening mechanism using UV photoionization is described here. In brief, radicals generated from the Si-H surface upon UV irradiation were found to behave in classical hydrogen abstraction theory manner by which the distal amine group was first hydrogen abstracted and the radical propagated down to the cyclopropane moiety. This subsequently liberated the strained bonds of the cyclopropane group and initiated the surface grafting process, producing a thin film approximately 10-15 nm in height. Contact angle measurements also showed that such photoionization irradiation had yielded an extremely hydrophilic surface (∼21.3°) and X-ray photoelectron spectroscopy also confirmed the coupling was through the Si-C linkage. However, when the surface underwent high-temperature hydrosilylation (>160 °C), the reaction proceeded predominantly through the nucleophilic NH2 group to form a Si-N linkage to the surface. This rendered the surface hydrophobic and hence suggested that the Si-H homolysis model may not be the main process. To the best of our knowledge, this was the first attempt reported in the literature to use photoionization to directly graft cyclopropylamine onto a silicon surface and in due course generate a highly rich NH-terminated surface that was found to be highly bioactive in promoting cell viability on the basis of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide studies.

New way to make chiral fluorinated arenes

A trifluoromethyl-substituted cyclopropane group can play a key role in a drug candidate. The group’s rigid cyclopropyl ring can increase the compound’s lipophilicity and metabolic stability while its fluorines can boost the candidate’s stability and ability to permeate membranes. But installing trifluoromethylcyclopropyl groups in a highly enantioselective manner is hard. A team led by Rudi Fasan at the University of Rochester now reports a combined chemical and biocatalytic approach that could make it easier to add trifluoromethylcyclopropyl groups to compounds enantioselectively for drug design (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b00768). Erick M. Carreira of the Swiss Federal Institute of Technology (ETH), Zurich, and coworkers developed the only previous method for adding the fluorinated groups in a fairly stereoselective manner. In that technique, cobalt catalysts generate trans-trifluoromethylcyclopropyl derivatives of arene substrates with enantiomeric excesses between 84 and 94% (Angew. Chem. Int. Ed. 2011, DOI: 10.1002/anie.201004269). Fasan notes that medicinal chemists

DNA Interstrand Crosslinks by H-pin Polyamide (S)-seco-CBI Conjugates.

Although DNA interstrand crosslinking (ICL) agents are widely used as antitumor drugs, DNA sequence-specific ICL agents are quite rare. In this study, H-pin imidazole-pyrrole polyamide 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-CBI) conjugates that produce sequence-specific DNA ICLs were designed and synthesized. Conjugates with H-pin polyamide and seco-CBI moieties were constructed to recognize a 7 bp DNA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high-resolution denaturing gel electrophoresis and sequence-specific plasmid cleavage. One conjugate (6), which contained a chiral (S)-seco-CBI, exhibited greater sequence-specific ICL activity toward the target DNA sequence and was cytotoxic to a cancer cell line. Molecular modeling studies indicated that the greater activity of 6 resulted from the relative orientation of the cyclopropane group in the (S)-CBI unit.

Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase

The natural product curacin A, a potent anticancer agent, contains a rare cyclopropane group. The five enzymes for cyclopropane biosynthesis are highly similar to enzymes that generate a vinyl chloride moiety in the jamaicamide natural product. The structural biology of this remarkable catalytic adaptability is probed with high-resolution crystal structures of the curacin cyclopropanase (CurF ER), an in vitro enoyl reductase (JamJ ER), and a canonical curacin enoyl reductase (CurK ER). The JamJ and CurK ERs catalyze NADPH-dependent double bond reductions typical of enoyl reductases (ERs) of the medium-chain dehydrogenase reductase (MDR) superfamily. Cyclopropane formation by CurF ER is specified by a short loop which, when transplanted to JamJ ER, confers cyclopropanase activity on the chimeric enzyme. Detection of an adduct of NADPH with the model substrate crotonyl-CoA provides indirect support for a recent proposal of a C2-ene intermediate on the reaction pathway of MDR enoyl-thioester reductases.

Dispersive interactions in solution complexes.

Dispersive interactions are known to play a major role in molecular associations in the gas phase and in the solid state. In solution, however, their significance has been disputed in recent years on the basis of several arguments. A major problem until now has been the separation of dispersive and hydrophobic effects, which are both maximized in water due the low polarizability of this most important medium. Analyses of complexes between porphyrins and systematically varied substrates in water have allowed us to discriminate dispersive from hydrophobic effects, as the latter turned out to be negligible for complexations with flat surfaces such as porphyrins. Also, for the first time, it has become possible to obtain binding free energy increments ΔΔG for a multitude of organic residues including halogen, amide, amino, ether, carbonyl, ester, nitro, sulfur, unsatured, and cyclopropane groups, which turned out to be additive. Binding contributions for saturated residues are unmeasurably small, with ΔΔG > 1 kJ/mol, but they increase to, e.g., ΔΔG = 5 kJ/mol for a nitro group, a value not far from, e.g., that of a stacking pyridine ring. Stacking interactions of heteroarenes with porphyrins depend essentially on the size of the arenes, in line with polarizabilities, and seem to be rather independent of the position of nitrogen within the rings. Measurements of halogen derivatives indicate that complexes with porphyrins, cyclodextrins, and pillarenes as hosts in different media consistently show increasing stability from fluorine to iodine as the substituent. This, and the observed sequence with other substrates, is in line with the expected increase in dispersive forces with increasing polarizability. Induced dipoles, which also would increase with polarizability, can be ruled out as providing the driving source in view of the data with halides: the observed stability sequence is opposite the change of electronegativity from fluorine to iodine. The same holds for the solvent effect observed in ethanol-water mixtures. Dispersive contributions vary not only with the polarizability of the used media but also with the interacting receptor sites; it has been shown that for cucurbiturils the polarizability inside the cavity is extremely low, which also explains why hydrophobic effects are maximized with these hosts. Complexations with other known host compounds, however, such as those between cryptands or cavitands with, e.g., noble gases, bear the signature of dominating dispersive forces. Some recent examples illustrate that such van der Waals forces can also play an important role in complexations with proteins. Again, a clue for this is the increase in ΔG for inhibitor binding by 7 kJ/mol for, e.g., a bromine in comparison to a fluorine derivative.

Molecular dynamics of the Diels-Alder reactions of tetrazines with alkenes and N2 extrusions from adducts.

The cycloadditions of tetrazines with cyclopropenes and other strained alkenes have become among the most valuable bioorthogonal reactions. These reactions lead to bicyclic Diels-Alder adducts that spontaneously lose N2. We report quantum mechanical (QM) and quasiclassical trajectory simulations on a number of these reactions, with special attention to stereoelectronic and dynamic effects on spontaneous N2 loss from these adducts. QM calculations show that the barrier to N2 loss is low, and molecular dynamics calculations show that the intermediate is frequently bypassed dynamically. There is a large preference for N2 loss anti to the cyclopropane moiety rather than syn from adducts formed from reactions with cyclopropenes. This is explained by the interactions of the Walsh orbitals of the cyclopropane group with the breaking C-N bonds in N2 loss. Dynamical effects opposing the QM preferences have also been discovered involving the coupling of vibrations associated with the formation of the new C-C bonds in the cycloaddition step, and those of the breaking C-N bonds during subsequent N2 loss. This dynamic matching leads to pronounced nonstatistical effects on the lifetimes of Diels-Alder intermediates. An unusual oscillatory behavior of the intermediate decay rate has been identified and attributed to specific vibrational coupling.

ChemInform Abstract: Rhodium‐Catalyzed Carbonylative Skeleton Rearrangement of 1,4‐Enynes Tethered by a Cyclopropane Group.

The carbonylative skeleton rearrangement of 1,4 enynes tethered by a cyclopropane group proceeded smoothly in the presence of [Rh(CO)(2)Cl](2) under CO atmosphere to give the corresponding 1,2,4,5,6,7-hexahydrocyclopenta[a]inden-3(3bH)-one derivatives in moderate yields.

Derivatives of syndiotactic cyclopropane-containing 1,2-polybutadiene

The results of syndiotactic 1,2-polybutadiene cyclopropanation with diazomethane are demonstrated in an organic solvent in the presence of an organometallic catalyst to produce new polymers containing an unsubstituted cyclopropane group in the macrochain. A comparative evaluation of the levels of activity and regioselectivity of catalysts in 1,2-polybutadiene cyclopropanation is performed. This modification of syndiotactic 1,2-polybutadiene is shown to make it possible to obtain thermoplastic products with a relatively high energy saturation.

Rhodium-Catalyzed Carbonylative Skeleton Rearrangement of 1,4-Enynes Tethered by a Cyclopropane Group

The carbonylative skeleton rearrangement of 1,4 enynes tethered by a cyclopropane group proceeded smoothly in the presence of [Rh(CO)(2)Cl](2) under CO atmosphere to give the corresponding 1,2,4,5,6,7-hexahydrocyclopenta[a]inden-3(3bH)-one derivatives in moderate yields.

Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors.

The enantioselective synthesis of two novel cyclopropane-fused diazabicyclooctanones is reported here. Starting from butadiene monoxide, the key enone intermediate 7 was prepared in six steps. Subsequent stereoselective introduction of the cyclopropane group and further transformation led to compounds 1a and 1b as their corresponding sodium salt. The great disparity regarding their hydrolytic stability was rationalized by the steric interaction between the cyclopropyl methylene and urea carbonyl. These two novel β-lactamase inhibitors were active against class A, C, and D enzymes.

Synthesis of steryl ferulates with various sterol structures and comparison of their antioxidant activity

Steryl ferulates synthesised from commercial sterols as well as commercial oryzanol were used to better understand how structural features affect antioxidant activity in vitro by the ABTS+ radical decolorization assay, by oxidative stability index (OSI) of soybean oil, and by analysis of antioxidant activity during frying. Steryl ferulates inhibited the ABTS+ radical by 6.5–56.6%, depending on their concentration, but were less effective, especially at lower concentrations, than ferulic acid. Ferulic acid and steryl ferulates had either no effect, or lowered the OSI of soybean oil by up to 25%, depending on the concentration. In their evaluation as frying oil antioxidants, steryl ferulates with a saturated sterol group had the best antioxidant activity, followed by sterols with one double bond in the C5 position. The results indicate that a dimethyl group at C4 as well as a C9,C19 cyclopropane group, as found in oryzanol, negatively affects antioxidant activity in frying oils.