Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs

[Structure: see text] The total synthesis and preliminary biological evaluation of the first bryostatin analogs (bryologs) to incorporate B-ring substitution are reported. Asymmetric syntheses of two new polyketide "spacer" domains are described, one exploiting the pseudosymmetry of the C1-C13 region. These fragments are convergently joined to the "recognition" domain through a remarkably versatile macrotransacetalization process. The resulting new analogs exhibit potent nanomolar or picomolar affinity to protein kinase C (PKC), comparable to or better than that found for bryostatin.     

The design, synthesis, and evaluation of C7 diversified bryostatin analogs reveals a hot spot for PKC affinity

The first series of systematically varied C7-functionalized bryostatin analogs (12 members in all) have been synthesized through an efficient and convergent route. A new hotspot for PKC affinity, not present in the natural products, has been discovered, allowing for affinity control and potentially for selective regulation of PKC isozymes. Several analogs exhibit single-digit nanomolar affinity to PKC and display superior activity compared to bryostatin against the leukemia cell line K562.     

Cyclopentadienes Annelated with Five-membered Heterocycles: Methods of Synthesis, Heteroorganic Derivatives, and Synthetic Precursors. (Review)

The review is devoted to cyclopentadienes annelated with five-membered heterocycles (furan, pyrrole, thiophene, and their benzo analogs) (hetarenocyclopentadienes), their heteroorganic derivatives, and the synthetic precursors (hetarenocyclopentanones).     

Dienone—phenol Rearrangement of C—9 Oxygenated Decalinic Dienone and Analogs through B—Ring Cleavage

Dehydrogenation of 9-hydroxy decalinic enones and analogs with DDQ resulted in a formal dienone-phenol type rearrangement via B-ring cleavage, while the corresponding dienone acetates underwent base-catalyzed formal dienone-phenol type rearrangement analogously.     

Synthesis and Biological Activity of Tonghaosu Analogs Containing Phenoxy-phenyl Moiety

A new series of phenoxy-phenyl moieties containing tonghaosu analogs with varied B-ring 9 were synthesized and characterized by spectral studies. Their insect antifeedant activity against Pieris brassicae and insecticidal activity against Culex quinquefasciatus were investigated. Compound 9e exhibited excellent antifeeding activity.     

Identification of a tunable site in bryostatin analogs: C20 Bryologs through late stage diversification

[structure: see text] The C20 region of our bryostatin analogs was identified as a nonpharmacophoric site that could be varied to tune analogs for function and physical properties without significantly affecting their binding affinity for PKC. The use of this site in a late-stage diversification strategy has enabled the facile synthesis of a variety of new C20 analogs, all of which retain nanomolar affinity for PKC, in agreement with our pharmacophore hypothesis.     

Chlorosulfenylated Carbonic Acid Derivatives

The present article deals first with the synthesis of chlorocarbonylsulfenyl chloride and its imino analogs. The chemical behavior of these bifunctional compounds is illustrated for selected examples. Special attention is given to the syntheses of five-membered heterocycles containing sulfur, oxygen, and/or nitrogen.     

Pathways of Intramolecular Cyclization of Phosphorylated Ureas and Thioureas: A Theoretical Study

The stability of phosphorylated ureas and thioureas containing various substituents at the P and N atoms and the stability of their cyclization products, the corresponding diazaphospholidines and/or oxaza(thiaza)phospholines, was evaluated by PM3, MNDO, and DFT calculations. The thermal effects of cyclizations involving phosphorylated ureas (or thioureas) and of separate steps of their synthesis were calculated. According to the calculations, diazaphospholidine structures are preferably formed from substituted ureas and thiazaphospholine structures, from their thio analogs; formation of five-membered heterorings with the P-N bond is thermodynamically preferable as compared to their six-membered analogs.     

Microwave-Assisted Synthesis of Five-Membered O,N,N-Heterocycles

The development of new strategies for synthesis of five-membered O,N,N-heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in oxygen and two nitrogen atoms containing five-membered heterocyclic compounds synthesis is presented, focusing on the developments in the past 5–10 years. This contribution covers the literature concerning the total synthesis of five-membered O,N,N-heterocycles.     

A new class of simplified phorbol ester analogues: synthesis and binding to PKC and eta PKC-C1B (eta PKC-CRD2)

[formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.     

B-norsteroids from Hymenoscyphus pseudoalbidus

Two viridin-related B-norsteroids, B-norviridiol lactone (1) and B-norviridin enol (2), both possessing distinct unprecedented carbon skeletons, were isolated from a liquid culture of the ash dieback-causing fungus Hymenoscyphus pseudoalbidus. Compound 2 was found to degrade to a third B-norsteroidal compound, 1β-hydroxy-2α-hydro-asterogynin A (3), which was later detected in the original culture. The proposed structure of 1 is, regarding connectivity, identical to the original erroneous structure for TAEMC161, which was later reassigned as viridiol. Compound 2 showed an unprecedented 1H-13C HMBC correlation through an intramolecular hydrogen bond. The five-membered B-ring of compounds 1-3 was proposed to be formed by a benzilic acid rearrangement. The known compound asterogynin A was found to be formed from 3 by a β-elimination of water. All compounds were characterized by NMR spectroscopy, LC-HRMS and polarimetry.     

Microwave-Assisted Synthesis of Five-Membered O,N-Heterocycles

The development of new strategies for the synthesis of five-membered O,N-heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in oxygen- and nitrogen-containing five-membered heterocyclic compounds synthesis is presented, focusing on the developments in the past 5–10 years. This contribution covers the literature concerning the total synthesis of five-membered O,N-heterocycles.     

Synethesis and Some Photo-Decomposition Studies of Arylphosphetane Chalcogenides

Abstract

To learn if the chemistry of four-membered phosphacycle chalcogenides will differ from that of three- and five-membered analogs, mesityl- and 2,6-dimethoxy phenyl- groups have been chosen to serve as bulky substituents for the synthesis 01 ring carbon unsubstituted arylphosphelanes. A one-pot reaction procedure was developed for the efficient synthesis of these two arylphospelanes in reasonable yields.     

Constraints of opsin structure on the ligand-binding site: studies with ring-fused retinals

Ring-fused retinal analogs were designed to examine the hula-twist mode of the photoisomerization of the 9-cis retinylidene chromophore. Two 9-cis retinal analogs, the C11-C13 five-membered ring-fused and the C12-C14 five-membered ring-fused retinal derivatives, formed the pigments with opsin. The C11-C13 ring-fused analog was isomerized to a relaxed all-trans chromophore (lambda(max) > 400 nm) at even -269 degrees C and the Schiff base was kept protonated at 0 degrees C. The C12-C14 ring-fused analog was converted photochemically to a bathorhodopsin-like chromophore (lambda(max) = 583 nm) at -196 degrees C, which was further converted to the deprotonated Schiff base at 0 degrees C. The model-building study suggested that the analogs do not form pigments in the retinal-binding site of rhodopsin but form pigments with opsin structures, which have larger binding space generated by the movement of transmembrane helices. The molecular dynamics simulation of the isomerization of the analog chromophores provided a twisted C11-C12 double bond for the C12-C14 ring-fused analog and all relaxed double bonds with a highly twisted C10-C11 bond for the C11-C13 ring-fused analog. The structural model of the C11-C13 ring-fused analog chromophore showed a characteristic flip of the cyclohexenyl moiety toward transmembrane segments 3 and 4. The structural models suggested that hula twist is a primary process for the photoisomerization of the analog chromophores.     

Comparison of the capacity of nitrogen, oxygen, sulfur, and selenium atoms to exist in onium states. quantum-chemical investigation of isomeric model systems with two heteroatoms

HF, B3LYP, and MP2 calculations with the 6-31+G(d) basis set with correction to the energy of zero-point vibrations were carried out to determine the energy characteristics of model molecules containing two heteroatoms in the sp ³- and sp ²-hybrid states; different combinations of N, O, S, and Se atoms were studied. The stability of the onium states of the nitrogen atom was found to be greater than for its chalcogen analogs and the relative stability of onium states of the chalcogen analogs was found to depend on the hybridization of these atoms. Analysis of these results permitted us to construct a stability series of onium derivatives and to interpret the positional selectivity in electrophilic substitution reactions of five-membered heterocyclic compounds with one heteroatom. To J. Stradins, an outstanding and tireless scientist, with our deep respect and sincere affection. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1801–1808, December, 2008.     

Conformationally Restricted Analogs of Platelet-Activating Factor (PAF)

The synthesis of the five-membered cyclic phosphorodiamidic-acid derivatives 10 and 11 as well as the preparation of the six-membered cyclic phosphates 18, 19, 22–25 , and phosphoramidates 27–32 is described. The effects of these conformationally restricted platelet-activating factor analogs on rabbit platelet aggregation are briefly discussed. The 2-oxo-1,3,2-dioxaphosphorinanes 19, 25 , and 30 were found to be equally potent platelet-activating factor antagonists as the known thiazolium salt 33 .     

Synthesis,antioxidant and antimicrobial properties of novel pyridyl-carbonyl thiazoles as dendrodoine analogs

Marine compound dendrodoine was first obtained from tunicate species ( Dendrodo grossularia ). It has a five-membered ring, namely, it is a heterocycle thiadiazole, which is found rarely in natural sources . Following its biological activities, novel analogs have been investigated recently. Synthesis of the analogs for this study is realized with uncommon thiazole closure, including methylene-carbonyl condensation. Structures are elucidated by NMR ( ¹ , ¹³ C) and HRMS spectrums. As an alkaloid derivative, antioxidant properties were evaluated with DPPH and FRAP assays and antimicrobial effect with microdilution method. Among the series, 3bc-3cf showed higher antioxidant activity than those having 3 or 4-pyridyl substituents. There is lesser activity for 2-pyridyl activity for 2-pyridyl containing group, which may be a result of intramolecular interactions. No activity was observed against gram-negative bacteria at 250 μg/mL. 3ae and 3ce showed activity at 64 μg/mL against S. aureus and 3ae showed activity at 16 μg/mL against S. epidermidis gram-positive bacteria. Chloramphenicol showed activity against all microorganisms at 8–16 μg/mL. Sixteen original dendrodoine analogs have been defined by close/higher activity compared to dendrodoine analogs and Trolox.     

Basicity and structure of α,β-unsaturated ketones of the heterocyclic series

The protolytic equilibrium constants of 1-(2-selenienyl)-3-phenyl-1-propenone, 1-(2-selenienyl)-3-phenyl-3-propenone, and 1, 3-di (2-selenienyl) propenone have been measured spectrophotometrically in solutions of sulfuric acid (monohydrate) in glacial acetic acid. The results obtained are compared with data on the basicity of chalcone and its thiophene and furan analogs. It is established that, in heterocyclic analogs of chalcone, five-membered heterocycles containing oxygen, sulfur, and selenium show an electron-donating effect which decreases in the order 2-furyl > 2-selenienyl > 2-thienyl.Forpart III, see [12].     

A DFT Study of the Structure and Relative Stability of 1,3-Thiasilacycloalkanes and Their S-Functional Derivatives

A series of 1,3-thiasilacycloalkanes and their S-oxides, S,S-dioxides, and sulfonium salts were studied by the DFT (B3LYP/6-31G*) method. In six-membered sulfoxides, the oxygen atom preferentially occupies the axial position, whereas in the corresponding sulfonium salts the S-alkyl group occupies the equatorial position. The calculation results explain the lower hydrolytic stability of the five-membered rings compared to the six-membered analogs and the lower stability of sulfoxides compared to sulfones.     

Facile Synthesis of (2R,3S)-2-Benzyloxy-3-hydroxybutyrolactone

The heterocyclic diols derived from L-dimethyl tartrate are important chiral synthons in organic synthesis. In particular, L-threosolactone and L-threosolactam structures are versatile precursors for the synthesis of biologically active molecules. Structurally, these functionalized five-membered rings contain two hydroxyl groups with R and S stereochemistry on C-2 and C-3 respectively. The preparation of (2R,3S)-2-benzyloxy-3-hydroxybutyrolactone (3) and of its derivatives, drawing upon L-dimethyl tartrate as an inexpensive chiral starting material, is described. The presented synthetic procedures are easy and effective for preparing L-threoso analogs. This protocol is also a better alternative in a large scale setup. All structures 3–6 and 8 are characterized using ¹H and ¹³C NMR spectroscopy.