Carbocyclic Skeleton Research Articles

Bisubstrate Inhibitors of Catechol O‐Methyltransferase (COMT): the Crucial Role of the Ribose Structural Unit for Inhibitor Binding Affinity

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.

Synthesis of the Carbocyclic Skeleton of Abyssomicins C and D.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of the Carbocyclic Skeleton of Abyssomicins C and D

[reaction: see text] Intramolecular Diels-Alder substrate trienyl methylenebutenolide 5 was prepared in six steps by coupling 3-methoxy-4-methylenebutenolide (6) with trienone keto aldehyde 7. Heating 5 in CHCl(3) for 2 d at 70 degrees C afforded 80% of a single Diels-Alder adduct 4 with the complete carbon skeleton of abyssomicin C. Addition of thiophenoxide to the enone double bond of 4 followed by an intramolecular Michael addition afforded 15 with the abyssomicin D carbon skeleton.

Nickel‐Catalyzed Intermolecular Alkyne Insertion into Cyclobutanones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Abietane Diterpenoids from the Roots of some MexicanSalvia Species (Labiatae): Chemical Diversity, Phytogeographical Significance, and Cytotoxic Activity

From the roots of some Mexican Salvia species, classified in subgenus Jungia, several diterpenoids belonging to abietane (i.e., 3-7), salvifolane (9-->20,10-->6)-diabeoabietane) (i.e., 2), and totarane (i.e., 10) carbocyclic skeletons were isolated together with two 20-nor- and one 6,7-secoabietane derivatives, 1 and 9, and 8, respectively. While compounds 2-10 were previously known from different sources, compound 1 is a new 20-norabietane derivative, whose structure was deduced by spectroscopic means and confirmed by X-ray-diffraction analysis. The phytogeographical significance of the distribution of 20-norabietanic diterpenoids in the genus suggested an evolutionary link between the Chinese and New-World Salvias. Compounds 2 and 8 were tested for cell-growth inhibition activity against several human cancer cell lines and human normal lymphocytes, while 2 showed a moderate cytotoxic activity, 8 exhibited a moderate yet selective activity against leukemia cell line.

Unsaturated Diterpenoids with a Novel Carbocyclic Skeleton from Salvia xalapensis

Two diterpenoids with an unprecedented carbocyclic skeleton, salvixalapadiene (3) and isosalvixalapadiene (4), have been obtained from the leaves of Salvia xalapensis. The rearranged skeleton of these products may be derived biogenetically from a salvigenane precursor. In addition, two new rearranged diterpenoids (1 and 2) belonging to already known skeletons were isolated. The structures of the new compounds (1-4) were elucidated on the basis of spectroscopic data interpretation.

Nickel-Catalyzed Intermolecular Alkyne Insertion into Cyclobutanones

Cyclobutanones reacted with alkynes in the presence of nickel(0) catalysts to produce cyclohexenones. Oxidative cyclization of the carbonyl group of the cyclobutanone and the alkyne with the nickel(0) was followed by beta-carbon elimination from the resulting oxanickelacyclopentene and subsequent reductive elimination. This reaction achieves a formal alkyne insertion between the carbonyl carbon and the alpha-carbon, providing a six-membered carbocyclic skeleton.

The development of a facile tandem Wolff/Cope rearrangement for the synthesis of fused carbocyclic skeletons.

A set of mild processes for the conversion of vinyl cyclopropyl diazo ketones to highly functionalized cycloheptadienones and vinyl cyclopentenones by use of a target-inspired tandem Wolff/Cope rearrangement sequence is described. A divergent reaction course of the vinyl cyclopropyl diazo ketone substrates under sono- or photochemical activation provides good to excellent yields (55-98%) of the product cycloheptadienones and vinyl cyclopentenones.

Synthesis of the Complete Carbocyclic Skeleton of Vinigrol

[reaction: see text] An efficient entry to the fully elaborated skeleton of vinigrol is described. The installation of the desired stereochemistry at C(12) and the construction of the eight-membered ring were achieved in one operation by a remarkably facile anionic oxy-Cope rearrangement of Z-isopropenyl isomer 24.

Importance of the Methyl Group at C(10) of Squalene for Hopene Biosynthesis and Novel Carbocyclic Skeletons with 6/5 + 5/5 + (6) Ring System(s)

[reaction: see text] Incubation of (6E,10E,14E,18E)-2,6,10,19,23-pentamethyl-tetracosa-2,6,10,14,18,22-hexaene with Alicyclobacillus acidocaldarius hopene cyclase afforded four products having two types of carbocyclic skeletons, i.e., two hopane products and two products having an unprecedented carbocyclic skeleton of 6/5 + 5/5 +6 pentacyclic and 6/5 + 5/5 tetracyclic ring systems. The former two hopane skeletons were formed from the bioconversion of C15-desmethylsqualene and the latter two skeletons from that of C10-desmethylsqualene.

A regioselective Wagner–Meerwein rearrangement directed towards the six-membered ring of the longipinane skeleton

A Wagner–Meerwein rearrangement was selectively promoted towards the six-membered ring of (1 R,3 S,4 S,5 S,7 R,9 R,10 R,11 R)-7,9-diacetyloxy-1-hydroxylongipinane ( 7 ) to generate a series of compounds which contain a new carbocyclic skeleton named uruapane. Their structures were elucidated by 1D and 2D NMR data in combination with the X-ray diffraction analysis of 9 . Molecular modeling was used to study the reaction mechanism and deuterium labeling was employed to confirm two consecutive hydride shifts which occurred during formation of 8 .

Progress toward the Total Synthesis of Ingenol: Construction of the Complete Carbocyclic Skeleton

[reaction: see text] The complete carbocyclic skeleton of ingenol is assembled via a route that employs ring-closing metathesis (RCM) to close the strained "inside-outside" BC ring system (i.e., 24 --> 25).

The cumbiasins, structurally novel diterpenes possessing intricate carbocyclic skeletons from the West Indian sea whip Pseudopterogorgia elisabethae (Bayer).

From the hexane extract of the West Indian gorgonian Pseudopterogorgia elisabethae, two diterpenes, cumbiasins A (1) and B (2), having a novel tetracyclic carbon skeleton named cumbiane, have been isolated. In addition, we have isolated cumbiasin C (3), a ring cleavage product of cumbiasin B that possesses an unusual carbocyclic framework named seco-cumbiane. The structures and relative configurations of metabolites 1-3 were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREI-MS and HRFAB-MS). The carbocyclic skeletons of the cumbiasins are unprecedented and represent new classes of C20 rearranged diterpenes. Cumbiasins A and B display mild in vitro anti-tuberculosis activity.

Novel terpenoids from the West Indian sea whip Pseudopterogorgia elisabethae (Bayer). Elisapterosins A and B: rearranged diterpenes possessing an unprecedented cagelike framework.

Four diterpenes and a nor-diterpenoid, all of which possess unusual carbocyclic skeletons, were isolated from the hexane solubles of the West Indian gorgonian Pseudopterogorgia elisabethae. The structures and relative configurations of novel metabolites elisabethin D (2), elisabethin D acetate (3), 3-epi-elisabanolide (5), elisapterosin A (6), and elisapterosin B (7) were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREI-MS and HRFAB-MS), chemical reactions, and X-ray diffraction analyses. The tetracyclic carbon skeleton of the elisapterosins is undescribed and constitutes a new class of C(20) rearranged diterpenes. Elisapterosin B displays strong in vitro anti-tuberculosis activity.

Unusual Terpenes with Novel Carbon Skeletons from the West Indian Sea Whip Pseudopterogorgia elisabethae (Octocorallia)(1).

From the hexane solubles of the West Indian gorgonian Pseudopterogorgia elisabethae collected near San Andrés Island, Colombia, were isolated a marine diterpenoid, two nor-diterpenoids, and a bisnor-diterpenoid, all of which possess most unusual carbocyclic skeletons. The structures and relative configurations of novel metabolites elisabethins A-C (1-3) and elisabanolide (4) were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods; IR, UV, and accurate mass measurements (HREIMS); chemical reactions; and X-ray diffraction analyses. One of these, elisabethin B (2), showed significant differential antitumor activity, and compounds 3 and 4 have weak in vitro antituberculosis activity.

Elaboration of S-(-)-α-Pinene into Functionalized Bicyclo[4.2.1]nonane Framework of Mediterraneols

A two-carbon ring expansion of (-)- α -pinene 1 to bicyclo[5.1.1]nonane system (+)-12 and 1,2-cationic rearrangement provides an entry into a functionalized bicyclo[4.2.1]nonane derivative, representing the carbocyclic skeleton, present in the novel marine diterpenes, mediterraneols.

New and Unusual Sesquiterpenes: Kelsoene, Prespatane, Epi-γ-gurjunene, and T-Cadinthiol, from the Tropical Marine Sponge Cymbastela hooperi

From the dichloromethane solubles of the tropical marine sponge Cymbastela hooperi were isolated four novel terpenoid metabolites. One of these, (1R*,2S*,5R*,6R*,7S*,8R*)-1,5-dimethyl-7-(1‘-methylethenyl)-tricyclo[6.2.0.32,6]decane (kelsoene, 1), possesses a most unusual carbocyclic skeleton and is the first member of a new class of sesquiterpenes, the kelsoanes. The remaining three compounds, (1R*,2S*,5R*,6R*,7R*,8S*)-1,5-dimethyl-8-(1‘-methylethenyl)tricyclo[5.3.0.22,6]decane (prespatane, 2), (1R*,4R*,7S*,10S*)-4,10-dimethyl-7-(1‘-methylethenyl)bicyclo[5.3.0]dec-5-ene (epi-γ-gurjunene, 3), and (1R*,6R*,7S*,10S*)-4,10-dimethyl-7-(1‘-methylethyl)-10-mercaptobicyclo[4.4.0]dec-4-ene (T-cadinthiol, 5), are unusual natural products, particularly as sponge metabolites. All structures and their relative configurations were established by spectroscopic methods, particularly 1H−1H and 1H−13C shift correlated 2D NMR spectroscopy and accurate mass measurement (HREIMS). Compound 5 has weak in vitro antimalarial acti...

Studies on cochleamycins, novel antitumor antibiotics. II. Physico-chemical properties and structure determination.

The structure of cochleamycins A, A2, B and B2 (Fig. 1), novel antitumor antibiotics, were elucidated by NMR spectral analysis. Cochleamycins were found to possess novel carbocyclic skeletons.

Ligulaverin A, a structurally novel sesquiterpenoid-derived metabolite possibly formed via a biological Diels–Alder reaction

The crystal structure of Ligulaverin A 1, isolated from Ligularia veitchiana(Hemsl.) Greenm., reveals a novel carbocyclic skeleton which is likely to be derived from a hydroxymethacrylate ester of an eremophilane sesquiterpenoid via an intramolecular Diels–Alder reaction.

Irregular cembranoids containing a 13-membered carbocyclic skeleton isolated from a soft coral, Sarcophyton species

The structures and absolute structures of three new 13-membered carbocyclic cembranoids, sarcotol ( 1), sarcotol acetate ( 2), and sarcotal acetate ( 3) from a soft coral, Sarcophyton sp. have been determined by spectroscopic and single crystal X-ray analyses, and chemical conversion. Ichthyotoxity tests were performed for 1, 2, 3, and their reduction products.