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PubMed2006

Synthesis and properties of cyclopropane-derived peptidomimetics.

Small peptides exhibit a wide range of biological activities, but although there are some notable exceptions, they are not generally useful as drugs. This has spurred widespread interest in designing peptidomimetics and introducing them as replacements of portions of native peptides to enhance their biological properties. Special attention has been focused upon rigid replacements because of their potential to preorganize the resulting pseudopeptide in a conformation corresponding to its bound structure. Toward this goal, we invented trisubstituted cyclopropanes as novel peptidomimetics, anticipating that the cyclopropane ring would locally orient the backbone and the corresponding amino acid side chain in the biologically active conformation. Selected aspects of the syntheses and applications of these cyclopropane-derived peptidomimetics are presented in this Account.

Cyclopropanes↗

PubMed1985

Effects of replacement of a double bond by a cyclopropane ring in phosphatidylethanolamines: a 2H NMR study of phase transitions and molecular organization.

The thermotropic behavior and molecular properties of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-dihydrosterculoyl-sn-glycero-3-phosphoethanolamine (PDSPE) have been investigated by 2H NMR spectroscopy using samples selectively labeled at the 5'-, 9'-, 10'-, and 16'-positions of the sn-2 chains. Comparison with the corresponding phosphocholine analogues (POPC and PDSPC), obtained as intermediate synthetic products, was used to monitor the role of the polar head group. Replacement of the choline moiety by ethanolamine increased the gel to liquid-crystal transition temperature by 10-32 degrees C and led to a significantly higher ordering of the fatty acyl chains in the liquid-crystalline bilayer state. The lateral compression effect, due to the smaller area per polar head group in PE, results in a bilayer to hexagonal phase transition at elevated temperatures. The effects on both PC and PE due to replacement of the olefinic group by a cyclopropane unit are similar. A decrease in the temperature of the gel to liquid-crystal phase transition, Tc, is observed upon introduction of a cyclopropane ring; it goes from 26 degrees C in POPE to approximately 10 degrees C in PDSPE. In addition, a very significant broadening of the transition profile is observed. These observations are consistent with the poor packing ability of mixed saturated and cyclopropane-containing chains due to the bulky substituent effect. The temperature of the bilayer-hexagonal phase transition of PE samples was decreased by 15-20 degrees C on replacement of oleoyl chains by dihydrosterculoyl chains at the sn-2 position.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry, Differential Scanning↗

PubMed2004

Isotope and elemental effects indicate a rate-limiting methyl transfer as the initial step in the reaction catalyzed by Escherichia coli cyclopropane fatty acid synthase.

Cyclopropane fatty acid (CFA) synthases catalyze the formation of cyclopropane rings on unsaturated fatty acids (UFAs) that are natural components of membrane phospholipids. The methylene carbon of the cyclopropane ring derives from the activated methyl group of S-adenosyl-L-methionine (AdoMet), affording S-adenosyl-L-homocysteine (AdoHcys) and a proton as the remaining products. This reaction is unique among AdoMet-dependent enzymes, because the olefin of the UFA substrate is isolated and unactivated toward nucleophilic or electrophilic addition, raising the question as to the timing and mechanism of proton loss from the activated methyl group of AdoMet. Two distinct reaction schemes have been proposed for this transformation; however, neither was based on detailed in vitro mechanistic analysis of the enzyme. In the preceding paper [Iwig, D. F. and Booker, S. J. (2004) Biochemistry 43, http://dx.doi.org/10.1021/bi048693+], we described the synthesis of two analogues of AdoMet, Se-adenosyl-L-selenomethionine (SeAdoMet) and Te-adenosyl-L-telluromethionine (TeAdoMet), and their intrinsic reactivity toward polar chemistry in which AdoMet is known to be involved. We found that the electrophilicity of AdoMet and its onium congeners followed the series SeAdoMet > AdoMet > TeAdoMet, while the acidity of the carbons adjacent to the relevant heteroatom followed the series AdoMet > SeAdoMet > TeAdoMet. When each of these compounds was used as the methylene donor in the CFA synthase reaction, the kinetic parameters of the reaction, k(cat) and k(cat) K(M)(-1), followed the series SeAdoMet > AdoMet > TeAdoMet, suggesting that the reaction takes place via methyl transfer followed by proton loss, rather than by processes that are initiated by proton abstraction from AdoMet. Use of S-adenosyl-L-[methyl-d(3)]methionine as the methylene donor resulted in an inverse isotope effect of 0.87 +/- 0.083, supporting this conclusion and also indicating that the methyl transfer takes place via a tight s(N)2 transition state.

Catalysis↗

PubMed2002

Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding.

Isothermal titration calorimetry and X-ray crystallography have been used to determine the structural and thermodynamic consequences associated with constraining the pTyr residue of the pYEEI ligand for the Src Homology 2 domain of the Src kinase (Src SH2 domain). The conformationally constrained peptide mimics that were used are cyclopropane-derived isosteres whereby a cyclopropane ring substitutes to the N-Calpha-Cbeta atoms of the phosphotyrosine. Comparison of the thermodynamic data for the binding of the conformationally constrained peptide mimics relative to their equivalent flexible analogues as well as a native tetrapeptide revealed an entropic advantage of 5-9 cal mol(-1) K(-1) for the binding of the conformationally constrained ligands. However, an unexpected drop in enthalpy for the binding of the conformationally constrained ligands relative to their flexible analogues was also observed. To evaluate whether these differences reflected conformational variations in peptide binding modes, we have determined the crystal structure of a complex of the Src SH2 domain bound to one of the conformationally constrained peptide mimics. Comparison of this new structure with that of the Src SH2 domain bound to a natural 11-mer peptide (Waksman et al. Cell 1993, 72, 779-790) revealed only very small differences. Hence, cyclopropane-derived peptides are excellent mimics of the bound state of their flexible analogues. However, a rigorous analysis of the structures and of the surface areas at the binding interface, and subsequent computational derivation of the energetic binding parameters, failed to predict the observed differences between the binding thermodynamics of the rigidified and flexible ligands, suggesting that the drop in enthalpy observed with the conformationally constrained peptide mimic arises from sources other than changes in buried surface areas, though the exact origin of the differences remains unclear.

Binding Sites↗

PubMed2005

Enantioselective organocatalytic cyclopropanations. The identification of a new class of iminium catalyst based upon directed electrostatic activation.

A new method for enantioselective organocatalytic cyclopropanation is described. This study outlines the identification of a new class of iminium catalyst based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide and enal substrates through a proposed electrostatic activation and stereodirected protocol. Formation of trisubstituted cyclopropanes with high levels of enantio- and diastereoinduction is accomplished for a variety of alpha,beta-unsaturated aldehydes and sulfonium ylides. In addition, mechanistic studies have found that this cyclopropanation reaction exhibits enantioselectivity and reactivity profiles that are in accord with the proposed DEA step.

Aldehydes↗

PubMed2005

Spiro-cyclopropanation from oxoallylsilanes.

A novel highly stereoselective spiro-cyclopropanation reaction from oxoallylsilanes is described. Oxoallylsilanes are readily obtained by silylcupration of allene followed by conjugate addition to enones. The former oxoallylsilanes undergo a tandem cyclization-cyclopropanation reaction when treated with CH2I2/Me3Al, leading to hydroxylated polycyclic systems bearing the spiro-cyclopropane moiety. The scope of the process is studied, and a feasible pathway is discussed.

Biological Factors↗

PubMed2003

Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents.

(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.

Cyclopropanes↗

PubMed2003

Diastereoselective synthesis of cyclopropane amino acids using diazo compounds generated in situ.

A simple and high-yielding method for the preparation of cyclopropane amino acids is described. The novel method involves the one-pot cyclopropanation of readily available dehydroamino acids using aryl and unsaturated diazo compounds generated in situ from the corresponding tosylhydrazone salts. It was found that thermal 1,3-dipolar cycloaddition followed by nitrogen extrusion gave the cyclopropane amino acid derivatives with good E selectivity, while reactions in the presence of meso-tetraphenylporphyrin iron chloride gave predominantly the corresponding Z isomers. The synthetic utility of this process was demonstrated in the synthesis of (+/-)-(Z)-2,3-methanophenylalanine [(+/-)-(Z)-1], the anti-Parkinson (+/-)-(E)-2,3-methano-m-tyrosine [(+/-)-(E)-2], and the natural product (+/-)-coronamic acid [(+/-)-3].

Amino Acids↗

PubMed2004

An expedient and practical method for the synthesis of a diverse series of cyclopropane alpha-amino acids and amines.

A practical synthesis for the preparation of a diverse series of cyclopropane alpha-amino acids is described. Nitrocyclopropane carboxylates can be readily prepared through treatment of alpha-nitroesters and iodobenzene diacetate or alpha-nitro-alpha-diazoesters with a Rh(II) catalyst and an olefin. Reduction of the nitro group using zinc/HCl in i-PrOH affords substituted cyclopropane alpha-amino esters in modest to high yields (54-99%). A "one-pot" procedure involving sequential cyclopropanation and reduction is described. The method can also be applied to the preparation of arylcyclopropyl amines (three examples).

Amines↗

PubMed2005

Nitrile anion cyclization with epoxysilanes followed by Brook rearrangement/ring-opening of cyclopropane nitriles/alkylation.

[reactions: see text] The reaction of delta-silyl-gamma,delta-epoxypentanenitrile derivatives 9-12 with a base and an alkylating agent affords (Z)-delta-siloxy-gamma,delta-unsaturated pentanenitrile derivatives via a tandem process that involves the formation of a cyclopropane derivative by epoxy nitrile cyclization followed by Brook rearrangement and an anion-induced cleavage of the cyclopropane ring. Exclusive formation of a (Z)-derivative from trans-epoxides is explained by the reaction pathway that involves a backside displacement of the epoxide by the alpha-nitrile carbanion and the O-Si bond formation followed by concerted processes involving Brook rearrangement and the anti-mode of eliminative ring fission of the cyclopropane from the rotamer 19. The fact that (E)-isomers are exclusively obtained from cis-epoxides and alpha-cyclopropyl-alpha-silylcarbinol derivative 26 provides experimental support for the proposed pathway.

Alkylation↗

PubMed2007

Density functional theory investigations on sulfur ylide promoted cyclopropanation reactions: insights on mechanism and diastereoselection issues.

The mechanism and diastereoselectivity of synthetically useful sulfur ylide promoted cyclopropanation reactions have been studied using the density functional theory method. Addition of different substituted ylides (Me2S+CH-R) to enone ((E)-pent-3-en-2-one, MeHC=CH-COMe) has been investigated. The nature of the substituent on the ylidic carbon brings about subtle changes in the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode, leading to 1,2-trans and 1,2-cis cyclopropanes, respectively, via syn and anti betaine intermediates. The simplest and highly reactive model ylide (R=H) prefers a transoid addition mode. Diastereoselectivity is controlled by the barrier for cisoid-transoid rotation in the case of stabilized ylides, whereas the initial electrophilic addition is found to be the diastereoselectivity-determining step for semistabilized ylides. High selectivity toward trans cyclopropanes with stabilized ylides are predicted on the basis of the relative activation energies of diastereomeric torsional transition states. The energy differences between these transition states could be rationalized with the help of weak intramolecular as well as other stereoelectronic interactions.

Computer Simulation↗

PubMed2006

Asymmetric synthesis of orthogonally protected trans-cyclopropane gamma-amino acids via intramolecular ring closure.

The synthesis of enantiomerically-enriched trans-cyclopropane amino- and hydroxy-acids can be achieved by intramolecular ring closure in moderate to good yields. The optically active cyclopropane precursors are easily prepared in a short sequence from inexpensive, commercially available olefins and tert-butyl acetate. Several leaving groups and bases were compared for the cyclopropanation step, showing that the diphenylphosphinate and tosyl leaving groups give the best results when used in combination with either LDA or NaHMDS.

Amino Acids↗

PubMed1965

Some factors affecting cyclopropane acid formation in Escherichia coli.

1. The fatty acid composition of the extractable lipids of Escherichia coli varied with growth conditions. 2. The principal fatty acids were palmitic acid, hexadecenoic acid, octadecenoic acid and the cyclopropane acids, methylenehexadecanoic acid and methyleneoctadecanoic acid. 3. Cyclopropane acid formation from monoenoic acids was increased by acid media, poor oxygen supply, or high growth temperature. 4. Cyclopropane acid formation was decreased by alkaline media, well oxygenated conditions, the presence of citrate, or lack of Mg(2+).

Chromatography, Gas↗

PubMed1995

Identification of a gene involved in the biosynthesis of cyclopropanated mycolic acids in Mycobacterium tuberculosis.

Mycolic acids represent a major constituent of the mycobacterial cell wall complex, which provides the first line of defense against potentially lethal environmental conditions. Slow-growing pathogenic mycobacteria such as Mycobacterium tuberculosis modify their mycolic acids by cyclopropanation, whereas fast-growing saprophytic species such as Mycobacterium smegmatis do not, suggesting that this modification may be associated with an increase in oxidative stress experienced by the slow-growing species. We have demonstrated the transformation of the distal cis double bond in the major mycolic acid of M. smegmatis to a cis-cyclopropane ring upon introduction of cosmid DNA from M. tuberculosis. This activity was localized to a single gene (cma1) encoding a protein that was 34% identical to the cyclopropane fatty acid synthase from Escherichia coli. Adjacent regions of the DNA sequence encode open reading frames that display homology to other fatty acid biosynthetic enzymes, indicating that some of the genes required for mycolic acid biosynthesis may be clustered in this region. M. smegmatis overexpressing the cma1 gene product significantly resist killing by hydrogen peroxide, suggesting that this modification may be an important adaptation of slow-growing mycobacteria to oxidative stress.

Amino Acid Sequence↗

PubMed1977

Gas chromatographic determination of Ostwald solubility coefficients for cyclopropane, halothane and trichloroethene (trichloroethylene).

Gas chromatographic methods using solvent extraction for the analysis of cyclopropane and and trichloroethene (trichloroethylene) are described and evaluated; cyclopropane was extracted into carbon tetrachloride and trichloroethene into carbon disulphide, using chloroform and toluene respectively as the internal standards. Ostwald solubility coefficients were measured for cyclopropane, halothane and trichloroethene in Krebs solution: at 310 K the respective values +/- SEM of the Ostwald coefficients are 0.181 +/- 0.009, 0.78 +/- 0.02 and 1.54 +/- 0.02; over the temperature range 295-310 K the respective temperature coefficients of solubility are -2.27, -4.18 and -3.81 in units of per cent/K at 310 K.

Chromatography, Gas↗

PubMed1982

The effect of acute phencyclidine administration on cyclopropane requirement (MAC) in rats.

The effect of acute administration of phencyclidine (PCP) on the anesthetic requirement (MAC) was studied in rats. Rats were anesthetized with cyclopropane and MAC determinations were made by the tail-clamp technique. PCP, 2 or 4 mg/kg, subcutaneously, produced a 32 and 42 per cent decrease, respectively, in cyclopropane MAC. The PCP-induced decrease in MAC was not altered by naloxone treatment indicating that an interaction of PCP with opiate mechanisms is unlikely. Central monoamine depletion with reserpine decreased cyclopropane MAC by 20 per cent. In these monoamine-depleted rats, 4 mg/kg PCP produced a further reduction in MAC of 22 per cent. In rats almost totally depleted of catecholamines by pretreatment with reserpine and alpha-methyl-p-tyrosine, a marked (43 per cent) decrease in MAC was observed. The administration of 2 mg/kg PCP, in these catecholamine-depleted rats produced an additional 10 per cent decrease in MAC for a total reduction in MAC of 53 per cent. The effect of PCP in the monoamine- and catecholamine-depleted rats indicates that while an effect on central monoamines may play a part in the mechanism of action of PCP, it is not the sole mode of action of the drug. In patients intoxicated with PCP there is a significant potential for anesthetic overdose as their anesthetic requirement may be much less than would be expected in the nonintoxicated state.

Anesthesia↗

PubMed1975

Effects of general anaesthetics on the pH of gastric contents in man during surgery: a survey of halothane, fluoroxene and cyclopropane anesthesia.

The effect of premedication and three general anaesthetics on gastric content pH was investigated. Neither premedication with pentobarbital-atropine nor morphine-scopolamine given 1-2 h prior to anaesthesia appeared to affect the acidity of the gastric contents. Halothane invaribly increased the pH of the gastric contents; none of the seven patients studied had a gastric pH of less than 2.5 (mean 5.1) after 1 h of anesthesia. Cyclopropane uniformly maintained the acidity of the gastric contents; only one out of seven patients had a gastric content pH above 2.5 (mean 1.7) after 1 h of anaesthesia. This effect of cyclopropane in maintaining the pH of gastric contents was unaffected by the use of premedication and induction with thiopental. Fluorexene affected the pH of the gastric contents much less uniformly. Although the pH for the group as a whole gradually increased (after one hour from 1.7 plus or minus 0.2 (s.e. mean) to 3.1 plus or minus 0.7), some of the seven patients studied reacted to fluroxene with a constant low gastric content pH. The findings are discussed, and it is concluded that the risk of pulmonary complications in case of vomiting and aspiration upon emergence from anaesthesia is greater if the anaesthetic agent is cyclopropane or fluoroxene, than if it is halothane.

Anesthesia, General↗

PubMed1980

The cardiovascular effects of pancuronium during halothane and cyclopropane anaesthesia.

The effect of pancuronium 0.1 mg/kg i.v. on heart rate (HR) and mean arterial blood pressure were investigated in two groups of eight patients, each receiving inhalational anaesthesia with either halothane or cyclopropane. A more pronounced effect on HR in the cyclopropane group with a mean increase of 104% occurred. The mean increase in the halothane group was 54%. There was a statistically significant difference (P less than 0.05) between the HR increases The vagolytic effect of pancuronium and the influence of halothane and cyclopropane on the autonomic nervous system are discussed.

Adult↗