Cyclic Side Chains Research Articles

New Method for the Synthesis of Sulforaphane and Related Isothiocyanates

The biologically important isothiocyanate sulforaphane (4-isothiocyanatobutyl methyl sulfoxide) was synthesized in six simple steps from commercially available 4-aminobutan-1-ol with an overall yield of 64%. The new synthetic method is suitable for multigram-scale preparation of sulforaphane and does not require expensive or toxic reagents. A novel one-pot procedure was also developed for preparing isothiocyanates through reaction of amines with O-phenyl chlorothioformate under mild conditions. Additionally, methyl pyrrolidine-1-carbodithioate was obtained as an unexpected byproduct, and this protocol was shown to be useful for the synthesis of S-aryl or S-heterocyclic thiocarbamates with cyclic side chains.

Lathrophytoic acids A and B: two novel polyprenylated phloroglucinol derivatives from Kielmeyera lathrophyton

Two novel polyprenylated phloroglucinol derivatives were isolated from the trunk of Kielmeyera lathrophyton (Clusiaceae). Lathrophytoic acid A presented an unusual caged carbon skeleton with a 1,3-dione-4-cyclopentanol moiety. Lathrophytoic acid B exhibited a highly substituted bicycle[3.3.1]nonane skeleton and an isopropylfuran system which was formed by unusual cyclization of a prenyloxy side chain.

Abstract B66: Characterization of bis-phenazine compounds that inhibit estrogen signaling through direct interaction with estrogen response elements

Abstract Hormone therapies interfere with estrogen signaling by targeting Estrogen Receptors (ERs) and are routinely used for the prevention and treatment of ER-expressing breast cancers. However, current therapies have significant limitations related to inherent or acquired resistance. Thus, there is a need to develop therapeutic compounds that do not depend on competitive binding to the ER or on depleting cells of endogenous estrogen. Previous data suggested that certain bis-phenazines, such as our lead compound XR5944, possess potent antiestrogenic properties through a novel mechanism of action: they inhibit gene transcription via direct intercalation with DNA at estrogen response elements (EREs) which are located in estrogen-responsive gene promoters. While these studies have demonstrated the potent antiestrogenic activity of XR5944, they have also demonstrated its capacity to bind to alternative DNA motifs. In order to improve upon ERE target specificity, we have identified XR5944 derivatives that retain potent antiestrogenic properties but may have greater specificity for ERE sequences, to be developed as new therapies for the treatment of estrogen-driven cancers. Such compounds may also be effective in overcoming resistance to current antiestrogen therapies. Here, we characterize DNA sequence interactions and transcriptional effects of five XR5944 derivatives that differ from the parent compound in the composition of their linker chains (compounds 26357 and 26373), cyclic side rings (26576), or both (26536 and 27402). We utilized 1D 1H NMR titration experiments to monitor compound:DNA binding properties to a canonical ERE (AGGTCAcggTGACCT) containing a CGG trinucleotide spacer (ERECGG), electrophoretic mobility shift assays (EMSA) to assess the ability of the derivatives to disrupt ER:ERECGG interactions, and luciferase reporter assays to evaluate their potency in blocking estrogen-dependent transactivation through ERECGG. Our NMR results indicated that alteration of either linker chain or side ring structures of XR5944 reduced the affinity and specificity of compound:ERECGG interactions. These findings correlated with the ability of the compounds to inhibit ER:ERECGG binding in the order of XR5944>26576>26536>26373>26357>27402, as evaluated by EMSA. To further determine the effects of the compounds on ERECGG-driven transactivation, we performed luciferase reporter assays utilizing ERα-expressing MCF-7 breast cancer cells transfected with an ERECGG-luciferase reporter construct. Unlike the EMSA results, there was not a strict concordance between the compound-dependent potency in inhibiting estrogen-driven transcriptional responses and the specificity of interaction with DNA as determined by NMR. Specifically, inhibition of reporter activity was more potent with compounds that had the same cyclic side rings but altered linker chains as XR5944 (26373 and 26357) and was less effective with compounds possessing altered side rings (26576, 26536, and 27402). Together, our findings indicate that the cyclic side chain structures appear to be the most important components of bis-phenazines in disrupting the transcriptional potential of ER:ERE interactions. NMR can be useful for predicting the relative potency of XR5944 derivatives in blocking ER binding to EREs in vitro, but fails to predict their efficacy in inhibiting ERE-mediated transactivation. This information should prove valuable for the rational drug design of new antiestrogenic compounds with improved specificity for ERE sequences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B66.

Conformational behavior of stereo regular substituted polyglycolides is side chain dependent

Substituted polyglycolides having two asymmetric centers are attractive alternatives to materials derived from petroleum because of their biocompatibility and biodegradability. The conformational behavior of various substituted polyglycolides has been investigated by both quantum mechanical and molecular dynamics approaches. Polymethylglycolide (polylactide) and polyphenylmethylglycolide in RS or SR forms are predicted to adopt 27 ribbon type structures with φ, ψ values of ±30, ±50 or +30 or +50 respectively stabilised by carbonyl-carbonyl interactions. Isopropylglycolide and isobutyl-glycolide having branching at β & γ positions respectively in their side chains can be realized in all SS form with φ, ψ values lying in right handed helical region. In addition to carbonyl-carbonyl interactions, the hydrophobic interactions between the side chains in isopropylgly-colide the C-H-O interactions also contributes to the stability. With cyclic side chains directly attached to Cα of backbone, polyphenylglycolide (polymandelide) and polycyclohexylglycolide are found to adopt left handed helical structure without hydrogen bonds in RR form, stabilised by stacking interactions and hydrophobic interactions respectively. In all the forms of polyphenylglycolide & polycyclohexylglycolide, the cyclic side chains are found to be locked into unfavourable gauche plus conformation. The stability of substituted polyglycolides has been analyzed in terms of various interactions. The carbonyl-carbonyl interactions in all the conformations of all forms of substituted polyglycolides are found to be of highly shielded parallel motif with only one short carbon-oxygen interaction. Simulation studies of substituted polyglycolides in water give a good insight of the approach of water molecules to the backbone.

Building β-Peptide H10/12 Foldamer Helices with Six-Membered Cyclic Side-Chains: Fine-Tuning of Folding and Self-Assembly

The ability of the β-peptidic H10/12 helix to tolerate side-chains containing six-membered alicyclic rings was studied. cis-2-Aminocyclohex-3-ene carboxylic acid (cis-ACHEC) residues afforded H10/12 helix formation with alternating backbone configuration. Conformational polymorphism was observed for the alternating cis-ACHC hexamer, where chemical exchange takes place between the major left-handed H10/12 helix and a minor folded conformation. The hydrophobically driven self-assembly was achieved for the cis-ACHC-containing helix which was observed as vesicles ~100 nm in diameter.

Side Chain Cyclization Based on Serine Residues: Synthesis, Structure, and Activity of a Novel Cyclic Analogue of the Parathyroid Hormone Fragment 1−11

The N-terminal region of the parathyroid hormone (PTH) is sufficient to activate the G-protein-coupled PTH receptor 1 (PTHR1). The shortest PTH analogue displaying nanomolar potency is the undecapeptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH(2) that contains two helix-stabilizing residues (Aib(1,3)). To increase the helical character and proteolytic stability of this linear peptide, we replaced Gln(6,10) with (a) Lys(6) and Glu(10) to introduce a lactam bridge and (b) Ser(6,10) to form a diester bridge upon cross-linking with adipic acid. These cyclopeptides were, respectively, 468-fold less and 12-fold more potent agonists than the linear analogue. Despite their different potencies, all three analogues adopted similar α-helix structures, as shown by NMR and molecular dynamics studies. However, the diester bridge could better mimic the orientation and chemical properties of the side chains of Gln(6) and Gln(10) in the linear PTH analogue than the lactam moiety. This is apparently important for efficient receptor activation and provides further insights into the receptor-bound ligand conformation.

A Self-Threading Polythiophene: Defect-Free Insulated Molecular Wires Endowed with Long Effective Conjugation Length

Herein, we report on a self-threading polythiophene whose conjugated molecular wire is sheathed within its own cyclic side chains. The defect-free insulating layer prevents electronic cross-communication between the adjacent polythiophene backbone even in the solid film. Notably, the covalently linked cyclic side chains extend the effective conjugation length of the interior polythiophene backbone, which results in an excellent intrawire hole mobility of 0.9 cm(2) V(-1) s(-1).

ChemInform Abstract: Spontaneous Cyclization of the Aspartic Acid Side Chain to the Succinimide Derivative.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Conversion of Lapachol to Rhinacanthin-A and Other Cyclized Products.

A facile synthesis of rhinacanthin-A is achieved by the side chain cyclization of lapachol with meta-chloroperbenzoic acid along with stenocarpoquinone-A, stenocarpoquinone-B and its isomer.

Vibrational Analysis of Amino Acids and Short Peptides in Hydrated Media. VII. Energy Landscapes, Energetic and Geometrical Features of L-Histidine with Protonated and Neutral Side Chains

In manuscript VI of the same series (J. Phys. Chem. B 2010, 114, 1077-1088), we reported the geometrical and vibrational features of lysine and arginine, that is, two alpha-amino acids (alpha-AAs) with positively charged side chains, at physiological conditions. Here, we report our results on histidine, one of the most biologically important alpha-AAs, whose side chain can be neutral or positively charged through a protonation-deprotonation process of the nitrogens involved in its cyclic side chain at pH values in the physiological range. We have recorded at room temperature Raman scattering and Fourier-transform infrared (FT-IR) absorption spectra from the aqueous solutions of the AA at pH values 4, 6.8, and 8. It has been shown that a Raman spectrum recorded at the intermediate pH (6.8) can be perfectly reconstituted by a linear combination of those observed at two extreme pH values (4 and 8), allowing determination of the populations of histidine with protonated and neutral side chains in solution. The above-mentioned experimental data were completed by the vibrational spectra recorded in D(2)O. On the other hand, quantum mechanical calculations at the DFT/B3LYP/6-31++G* allowed us to analyze the energetic, geometrical, and vibrational features of histidine. Through a discussion on the basis of experimental and theoretical results, we comment on (i) the potential energy surfaces of histidine placed in a polarizable dielectric continuum, providing molecular energy landscapes as a function of its side chain orientations around C(alpha)-C(beta) and C(beta)-C(gamma) bonds; (ii) the full geometry optimization of the low energy conformers placed in a solvent continuum or in the presence of n explicit water molecules (n = 3, 7); (iii) the energy value separating the two histidine forms with neutral side chains; (iv) the determination of the side chain pK(a) by means of Raman spectra; and (v) the assignment of the observed vibrational modes by means of the lowest-energy conformers of hydrated histidine.

Estimating the activation barrier to each step of protein splicing for the non‐canonical P. abyssi PolII intein

Protein splicing is a post‐translational event by which an intervening polypeptide, called an intein, facilitates its own excision from the flanking polypeptides, called the exteins, and the ligation of the exteins. We are able to study the protein splicing of the Pyrococcus abyssi PolII intein in vitro, and can determine the rate of the overall splicing reaction as well as that of each step. The robust temperature‐dependence of this reaction allows us to estimate the activation barrier for individual steps of the reaction. This is especially interesting for the third step of the reaction, cyclization of Asn or Gln coupled to peptide bond cleavage. We will use these data to assess mechanistic models for the catalysis of side‐chain cyclization.This material is based upon work supported by the National Science Foundation under Grant No. 0320824 and CAREER grant No. 0447647.

Characteristic alkaline catalyzed degradation of kotalanol, a potent α-glucosidase inhibitor isolated from Ayurvedic traditional medicine Salacia reticulata, leading to anhydroheptitols: another structural proof

Stereochemical structure of kotalanol ( 2), a highly potent α-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, was proved by alkaline catalyzed degradation of natural kotalanol ( 2), in which characteristic stereospecific cyclization of the degradative side chain leading to anhydroheptitols ( 10 and 11) was involved.

Living/controlled cationic cyclopolymerization of divinyl ether with a cyclic acetal moiety: Synthesis of poly(vinyl ether)s with high glass transition temperature based on incorporation of cyclized main chain and cyclic side chains

AbstractCationic cyclopolymerization of 2‐methyl‐5,5‐bis(vinyloxymethyl)‐1,3‐dioxane (1), a divinyl ether with a cyclic acetal group, was investigated with the HCl/ZnCl2 initiating system in toluene and methylene chloride at −30 °C. The reaction proceeded quantitatively to give gel‐free, soluble polymers in organic solvents. The number‐average molecular weight (Mn) of the polymers increased in direct proportion to monomer conversion, and further increased on addition of a fresh monomer feed to the almost completely polymerized reaction mixture, indicating that the polymerization proceeded in living/controlled manner. The contents of the unreacted vinyl groups in the produced soluble polymers were less than ∼3 mol %, and therefore, the degree of cyclization was determined to be ∼97%. In contrast, the pendant cyclic acetal groups remained intact in the polymers under the present cationic polymerization conditions. These facts show that cyclopolymerization of 1 almost exclusively occurred and the poly(vinyl ether)s with the cyclized repeating units and cyclic pendant acetal rings were obtained. Glass transition temperature (Tg) and thermal decomposition temperature (Td) of poly(1) (Mn = 7870, Mw/Mn = 1.57) were found to be 166 and 338 °C, respectively, indicating that poly(1) had high Tg and high thermal stability. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 952–958, 2010

A Docking Study Using Atomistic Conformers Generated via Elastic Network Model for Cyclosporin A/Cyclophilin A Complex

Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest- frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet, surprisingly, the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking, the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also, the small backbone variations of a few Angstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 A and therefore have a strong influence on the efficiency of the conformational search during docking.

Side chain to side chain cyclization of an enkephalin analog results in loss of opioid receptor selectivity.

The cyclic enkephalin analog H-Tyr-D-Lys-Gly-Phe-Glu-NH2 (I) and the structurally related open chain analogs H-Tyr-D-Nle-Gly-Phe-Gln-NH2 (II) and H-Tyr-D-Lys(For)-Gly-Phe-Abu-NH2 (III) were tested in mu and delta opioid receptor-representative binding assays and bioassays. Whereas both linear analogs showed a pronounced preference for mu receptors over delta receptors, the conformationally restricted cyclic peptide I was found to be unselective. This finding represents the first reported example of a peptide cyclization resulting in a loss of receptor selectivity. From this and earlier studies, it was concluded that the receptor selectivity of cyclized peptide analogs relative to that of their linear correlates may depend on the size and relative rigidity of their ring structures.

Complexes of low energy beta emitters 47Sc and 177Lu with zoledronic acid for bone pain therapy

Targeted radiopharmaceuticals have been mostly developed to visualize and/or treat oncologic diseases. In targeted radiotherapy radionuclide selection is a key issue, because the radionuclide should provide the appropriate radiation absorbed dose, matching the desirable biologic effect, but at the same time it should preclude irradiation of surrounding healthy tissues. Among the last generation of bisphosphonates with cyclic side chains, zoledronic acid is the most potent bisphosphonate, described till now, which inhibits bone resorption. In this paper, we describe the synthesis, properties and hydroxyapatite binding of zoledronic acid labeled with two low energy beta emitters, 47Sc and 177Lu. Radiochemicals labeled with low energy electron emitters are preferred, because they deliver both a therapeutic dose to the bone and spare the bone marrow. Hydroxyapatite adsorption experiments have shown that the binding values obtained with complexes of zoledronic acid labeled with 46Sc and 177Lu are much higher than those of bisphosphonates labeled with 153Sm and 166Ho. Hence, complexes of zoledronic acid with either 46Sc or 177Lu seems to be a promising radiopharmaceutical for bone pain therapy.

Acid-catalyzed formation of 32,35-anhydrobacteriohopanetetrol from bacteriohopanetetrol

32,35-Anhydrobacteriohopanetetrol (anhydroBHT) is a functionalized hopanoid of unknown origin found recently in a wide range of sediments. Acidic treatment of cells of the bacterium Zymomonas mobilis and of bacteriohopanetetrol (BHT) led to the formation of anhydroBHTs in the form of an epimeric mixture. These laboratory experiments indicate that sedimentary anhydrobacteriohopanepolyols likely correspond to diagenetic transformation products of bacteriohopanepolyols formed by intramolecular acid catalyzed cyclization of the hopanoid side chain, rather than being biogenic products.

Study of 5-nitroindazoles' anti- Trypanosoma cruzi mode of action: Electrochemical behaviour and ESR spectroscopic studies

New indazole derivatives have been developed to know about structural requirements for adequate anti- Trypanosoma cruzi activity. In relation to position 1 of indazole ring, we have observed that a butylaminopentyl substituent ( 14) affords good activity, but N-oxidation of ω-tertiary amino moiety yields completely inactive compounds ( 17, 18); the substituent at position 3 of indazole ring affects drastically the in vitro activity, 3-OH derivative 13 being completely inactive. On the other hand, since compound 22, denitro-analogue of active compound 4, does not show activity, the 5-nitro substituent of indazole ring seems to be essential. Intramolecular cyclization of side chain at position 1 also affords inactive compounds ( 19, 20). The electrochemical studies showed that the trypanocidal 5-nitroindazole derivatives yielded nitro-anion radical via one-electron process at physiological pH. This electrochemical behaviour occurs in the parasite according to ESR experiment with the T. cruzi microsomal fraction showing that 5-nitroindazole derivatives suffer bio-reduction without reactive oxygen species generation.

A Prodigiosin from the Roseophilin Producer Streptomyces griseoviridis

Roseophilin is a unique metabolite containing two pyrrole and one furan ring and is structurally related to tripyrrole antibiotics, prodigiosins. Each homologous gene in the roseophilin producer Streptomyces griseoviridis was amplified by PCR using primers designed from the prodigiosin-biosynthesis genes redH, redM, and redW. A search for prodigiosins produced by S. griseoviridis resulted in the isolation of a new prodigiosin designated prodigiosin R1 (1). The molecular formula of 1 was established as C27H37N3O by high-resolution FABMS. The structure of 1 was elucidated by NMR spectroscopic analysis including COSY, HMQC, HMBC, and NOESY. Prodigiosin R1 (1) is a new member of the prodigiosin family possessing a cyclic alkyl side chain.

Synthesis and Conformational Analysis of a Cyclic Peptide Obtained via i to i+4 Intramolecular Side-Chain to Side-Chain Azide−Alkyne 1,3-Dipolar Cycloaddition

Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to side-chain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of Cu(I)-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including epsilon-azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(epsilon-N3) or the incorporation of Fmoc-Nle(epsilon-N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase Cu(I)-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(epsilon-N3)-Ser-Ile-Gln-Pra-Leu-Arg-NH2 (2) into the 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptide [Ac-Lys-Gly-Xaa(&(1))-Ser-Ile-Gln-Yaa(&(2))-Leu-Arg-NH2][(&(1)(CH2)4-1,4-[1,2,3]triazolyl-CH2&(2))] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys(13)(&(1)),Asp(17)(&(2))]hPTHrP(11-19)NH2 (II). CD and NMR studies of 3 and II in water/hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.