Enantioselective Synthesis of 15-Deoxy-Δ12,14-Prostaglandin J2.

An enantioselective synthesis of 15-deoxy-Δ12,14-prostaglandin J2 is reported. The synthesis begins with the preparation of enantiopure 3-oxodicyclopentadiene by a lipase-mediated kinetic resolution. A three-component coupling followed by a retro-Diels-Alder reaction provides the C8 stereochemistry of the prostaglandin skeleton with high enantioselectivity. Stereoretentive olefin metathesis followed by a Pinnick oxidation affords 15-deoxy-Δ12,14-prostaglandin J2 in high enantiopurity.

Synthesis of a Human Urinary Metabolite of Prostaglandin D2.

A chemical synthesis of the major human metabolite of prostaglandin D2, tricyclic-PGDM, is described. The synthetic route starts from iodocyclopentenone 1 (available from cyclopentadiene in 6 steps) and requires 13 synthetic transformations. The synthetic route takes advantage of a contrasteric allylation to establish the 1,2-cis relationship between the ring hydroxyl group and side chain. A second key sequence is the application of Fu's copper-catalyzed C-H insertion of a diazoacetate followed by an alkyne semihydrogenation to introduce the unsaturated side chain.

Short Total Synthesis of Δ12-Prostaglandin J2 and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic Δ12-Prostaglandin J2 Analogues.

Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are Δ12-prostaglandin J2 (Δ12-PGJ2) and Δ12-prostaglandin J3 (Δ12-PGJ3), whose unusual structural motifs and potent cytotoxicities present unique opportunities for chemical and biological investigations. Herein, we report a short olefin-metathesis-based total synthesis of Δ12-PGJ2 and its application to the construction of a series of designed analogues possessing monomeric, dimeric, trimeric, and tetrameric macrocyclic lactones consisting of units of this prostaglandin. Biological evaluation of these analogues led to interesting structure-activity relationships and trends and the discovery of a number of more potent antitumor agents than their parent naturally occurring molecules.

Design of PPAR-γ agonist based on algal metabolites and the endogenous ligand 15-deoxy-Δ12, 14-prostaglandin J2.

In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J2 (15 d-PGJ2). The exocyclic enone moiety of 15 d-PGJ2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)-6a1 was suggested as a potential PPAR-γ ligand.

Total Synthesis Confirms the Molecular Structure Proposed for Oxidized Levuglandin D2.

Levuglandins (LG)D2 and LGE2 are γ-ketoaldehyde levulinaldehyde derivatives with prostanoid side chains produced by spontaneous rearrangement of the endoperoxide intermediate PGH2 in the biosynthesis of prostaglandins. Covalent adduction of LGs with the amyloid peptide Aß1-42 promotes formation of the type of oligomers that have been associated with neurotoxicity and are a pathologic hallmark of Alzheimer's disease. Within 1 min of their generation during the production of PGH2 by cyclooxygenation of arachidonic acid, LGs are sequestered by covalent adduction to proteins. In view of this high proclivity for covalent adduction, it is understandable that free LGs have never been detected in vivo. Recently a catabolite, believed to be an oxidized derivative of LGD2 (ox-LGD2), a levulinic acid hydroxylactone with prostanoid side chains, was isolated from the red alga Gracilaria edulis and detected in mouse tissues and in the lysate of phorbol-12-myristate-13-acetate-treated THP-1 cells incubated with arachidonic acid. Such oxidative catabolism of LGD2 is remarkable because it must be outstandingly efficient to prevail over adduction with proteins and because it requires a unique dehydrogenation. We now report a concise total synthesis that confirms the molecular structure proposed for ox-LGD2. The synthesis also produces ox-LGE2, which readily undergoes allylic rearrangement to Δ6-ox-LGE2.

Identification and Structural Analysis of New Nrf2 Activators by Mechanism-Based Chemical Transformation of 15-Deoxy-Δ12, 14 -PGJ2.

Mechanism-based chemical transformation of 15-deoxy-Δ12, 14 -PGJ2 (15d-PGJ2 ) resulted in a series of new NF-E2-related factor-2 (Nrf2) activators and detailed elucidation of the function of each electrophilic binding site. In addition, HO-1 expression resulting from Nrf2 activation through enhanced dissociation of the Keap1-Nrf2 complex by the new activators was proved.

Synthesis and Biological Investigation of Δ(12)-Prostaglandin J3 (Δ(12)-PGJ3) Analogues and Related Compounds.

A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure-activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.

An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for their ability to reduce the secretion of proinflammatory cytokines. It was shown that the endocyclic enone is crucial for the bioactivity investigated and that the conjugated ω-side chain serves in a reinforcing manner.

Concise and enantioselective total synthesis of 15-deoxy-Δ-(12,14)-prostaglandin J(2).

The concise and enantioselective synthesis of 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been accomplished in 11 steps from a known alcohol. The key step of the synthesis involves an asymmetric Rh-catalyzed cycloisomerization of ene-ynone, followed by an olefin isomerization.

Enantio- and stereospecific syntheses of 15(R)-Me-PGD2, a potent and selective DP2-receptor agonist.

The first total synthesis of 15(R)-Me-PGD2 3 is reported. The synthesis is based on the enantioselective and stereospecific syntheses of synthon 17 and its attachment to the five-membered ring by a olefin cross metathesis reaction. This approach permits the introduction of a side chain with a predetermined stereogenic center into the prostanoid ring, resulting in the synthesis of 15R-methyl prostaglandin D2 and allows rapid access to other prostanoids.

Cross metathesis as a general strategy for the synthesis of prostacyclin and prostaglandin analogues.

[reaction: see text] A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized omega-side chain appendages of various prostacyclin and prostaglandin analogues, resulting in high (E)-selectivities for the C13-C14 double bond and leading to the total syntheses of isocarbacyclin, 15R-TIC, carbacyclin, and PGF(2)(alpha) and the formal syntheses of 15-deoxy-TIC and PGJ(2).

Polymer-assisted solution-phase synthesis and neurite-outgrowth-promoting activity of 15-deoxy-delta(12,14)-PGJ2 derivatives.

An efficient solution-phase synthesis of rac-15-deoxy-delta(12,14)-PGJ2 (15dPGJ2) derivatives that contain variable alpha and omega chains based on a polymer-assisted strategy and their neurite-outgrowth-promoting activity are described. The strategy for the synthesis of PGJ2 derivatives involves the use of a vinyl iodide bearing cyclopentenone as a key intermediate, which undergoes Suzuki-Miyaura coupling and subsequent Lewis acid catalyzed aldol condensation for incorporation of the omega and alpha chains, respectively. For easy access to the PGJ2 derivatives, a polymer-supported catalyst and scavengers were adapted for use in these four diverse steps, in which workup and purification can be performed by simple filtration of the solid-supported reagents. By using this methodology, we succeeded in the synthesis of 16 PGJ2 derivatives with four alkyl boranes and four aldehydes. The neurite-outgrowth-promoting activity of the 16 synthetic compounds in PC12 cells revealed that the side-chains play a major role in modulating their biological activity. The carboxylic acid on the alpha chain improved the biological activity, although it was not absolutely required. Furthermore, a PGJ2 derivative with a phenyl moiety on the omega chain was found to exhibit an activity comparable to that of natural 15dPGJ2.

Synthesis of 15R-PGD2: a potential DP2 receptor agonist.

The first total synthesis of 15R-PGD(2)3 was accomplished. The approach used in this report is also an efficient method to produce 15R-PGE(2). 15R-PGD(2), a potential DP(2) receptor agonist, could be an important novel tool for defining the role of this receptor in inflammatory diseases.

The first total synthesis of 15-deoxy-Delta12,14-prostaglandin J2 and the unambiguous assignment of the C14 stereochemistry.

[reaction: see text] The first total synthesis of 15-deoxy-Delta12,14-prostaglandin J2 is reported. The highly unsaturated cyclopentenone prostaglandin was obtained via a silicon-tethered allenic [2 + 2 + 1] cycloaddition reaction developed in our group. In addition, the stereochemistry at C14 has been assigned unambiguously.

First enantioselective total synthesis of (8S,12R,15S)-prostaglandin J(2).

Enantioselective synthesis of natural PGJ(2) has been accomplished for the first time starting from the commercially available enantiopure aldehyde 7 in 10% overall yield. The key reaction was a novel prostaglandin class interconversion, i.e., an allylic 1,3-transposition across alcohol 9 derived from compound 14 in 73% overall yield. In principle, the unnatural enantiomer of PGJ(2) could be obtained starting from the commercially available enantiopure monobenzoate 7a following our strategy.

First total synthesis of JS isoprostane.

A stereoselective Julia-Lythgoe olefination followed by an efficient 1,3-allylic transposition of the C-9 hydroxyl group of compound 13 has allowed the first total synthesis of J(2) isoprostane (1), a recently discovered member of the growing isoprostane family. This elusive compound opens up numerous new avenues for the molecular biology of cyclopentenone prostaglandins which are endowed of intriguing biological effects such as antitumor, antiinflammatory, and antiviral activities. In principle, our approach is flexible enough to allow an easy synthesis of other isoprostanes of the J family following the same methodology.