Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs.

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9ß-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9ß-PG analogs and future applications, are also discussed.

ß-Ketophosphonates with Pentalenofuran Scaffolds Linked to the Ketone Group for the Synthesis of Prostaglandin Analogs.

ß-Ketophosphonates with pentalenofurane fragments linked to the keto group were synthesized. The bulky pentalenofurane skeleton is expected to introduce more hindrance in the prostaglandin analogues of type III, greater than that obtained with the bicyclo[3.3.0]oct(a)ene fragments of prostaglandin analogues I and II, to slow down (retard) the inactivation of the prostaglandin analogues by oxidation of 15α-OH to the 15-keto group via the 15-PGDH pathway. Their synthesis was performed by a sequence of three high yield reactions, starting from the pentalenofurane alcohols 2, oxidation of alcohols to acids 3, esterification of acids 3 to methyl esters 4 and reaction of the esters 4 with lithium salt of dimethyl methanephosphonate at low temperature. The secondary compounds 6b and 6c were formed in small amounts in the oxidation reactions of 2b and 2c, and the NMR spectroscopy showed that their structure is that of an ester of the acid with the starting alcohol. Their molecular structures were confirmed by single crystal X-ray determination method for 6c and XRPD powder method for 6b.

Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.

To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.

New ß-ketophosphonates for the synthesis of prostaglandin analogues. 1. Phosphonates with a bicyclo[3.3.0]octene scaffold spaced by a methylene group from the ß-ketone.

The synthesis of ß-ketophosphonates, linked by a methylene group to a bicyclo[3.3.0]octene fragment, was performed by the reaction of dimethyl methanephosphonate with the ester group of two intermediates with this scaffold. Starting from a diol, protected with good leaving groups (mesyl and tosyl), we performed a sequence of reactions with good yields: the carbon chain lengthening by reaction with KCN, the hydrolysis of the nitrile groups to carboxyl, the esterification of carboxyl to ester and finally the phosphonate synthesis, which gave one bis-ß-ketophosphonate and two mono ß-ketophosphonates. The new ß-ketophosphonates are key intermediates for obtaining new prostaglandin analogues with a bicyclo[3.3.0]octene fragment in the ω-side chain. The bicyclo[3.3.0]octane scaffold, found in natural products and in anticancer compounds, are expected to keep their activity in PG analogs; the bulky scaffold, separated by a methylene group from the C-15 carbon atom, is expected to diminish the inactivation of the PG analog by enzyme oxidation of 15α-OH oxidation to 15-Keto via PGDH pathway.

Prostacyclin, atherothrombosis, and cardiovascular disease.

Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted.

Novel synthetic strategies for the preparation of prostacyclin and prostaglandin analogues--off the beaten track.

The recent increase in activity in the fields of neuroscience and life sciences has been mirrored by the design and synthesis of novel chemically and metabolically stable prostaglandin and prostacyclin analogues. Consequently, convenient and practical access to these important classes of compounds is greatly coveted. Various strategies for the preparation of prostacyclin, prostaglandin and isoprostane analogues are discussed, with particular focus on novel approaches developed in our own laboratories.

Chemical transformation of prostaglandin-A2: a novel series of C-10 halogenated, C-12 hydroxylated prostaglandin-A2 analogues.

[reaction: see text] Synthesis of a novel class of C-10 halogenated and C-12 oxygenated prostaglandin-A(2) derivatives (6a-6c) has been accomplished. (15S)-Prostaglandin-A(2) (1), from the gorgonian Plexaura homomalla, served as the starting material for the synthesis. The absolute configuration was determined using NMR.

Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate.

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase.

A novel bicyclic prostaglandin analogue, [1R-[l alpha,2 beta (5Z),3 beta,4 alpha]]-7-[3-[(hexyloxy)methyl]- 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1), and cogeners were found to be potent inhibitors of fatty acid cyclooxygenase. Compound 1 was the only stereoisomer out of eight possible structures that was active. Ether 1 was 20 times more potent than indomethacin (IND) in inhibiting arachidonic acid (AA) induced aggregation of human platelet-rich plasma. Compound 1 was also more potent than IND in several in vivo assays, AA-induced sudden death in the conscious mouse (2 times) and AA-induced bronchoconstriction in the anesthetized guinea pig (16-45 times).

Prostaglandins and congeners. 14. Synthesis and bronchodilator activity of dl-16,16-trimethyleneprostaglandins.

The interesting bronchodilator activity of novel dl-16,16-trimethyleneprostaglandin congeners and their preparation via the conjugate addition of the appropriate vinyl lithiocuprate reagent to several cyclopentenones are described. Also discussed is the preparation of the key intermediate vinyl iodine 7.

Synthesis of prostanoids with bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.2.2]octane ring systems. Activities of 15-hydroxy epimers on human platelets.

A number of prostanoids with bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.2.2]octane ring systems have been prepared by routes which allow the introduction of the omega chain after the alpha chain. The introduction of a 16-p-halophenoxy substituent confers platelet aggregation activity on both 15 alpha- and 15 beta-hydroxy epimers. In the case of the pinane thromboxane ring system, the natural omega-chain compound is an inhibitor of aggregation, whereas the 16-p-fluorophenoxy analogue is a potent aggregation agent.

Synthesis and gastrointestinal pharmacology of the 4-fluoro analogue of enisoprost.

A 4-fluoro analogue of enisoprost was prepared and evaluated for gastric antisecretory and mucosal protective activity in animals. The synthesis centered upon cuprate chemistry but also involved a Wittig reaction to produce a cis fluoro olefinic moiety, a furan rearrangement/isomerization reaction to provide the necessary hydroxycyclopentenone, and a two-carbon-homologation procedure. The fluoro analogue was much less potent as a gastric antisecretory and mucosal protective agent than enisoprost.

11,12-secoprostaglandins. 4. 7-(N-alkylmethanesulfonamido) heptanoic acids.

A series of 7-(N-alkylmethanesulfonamido) heptanoic acids has been prepared which represents an extension of our 8-aza-11,12-secoprostaglandin studies. The studies. The compounds mimic the natural prostaglandins in that they markedly stimulate cAMP formation in the mouse ovary assay.

N-(Methanesulfonyl)-16-phenoxyprostaglandincarboxamides: tissue-selective, uterine stimulants.

In an effort to develop tissue-selective prostaglandin analogues resistant to the metabolic inactivating pathways of the natural materials, hybrid compounds modified both at C-1 with a sulfonimide moiety and in the n-amylcarbinol side chain with substituted phenoxy groups were synthesized and evaluated in a variety of in vitro models. Several of these analogues exhibited potent, tissue-selective, uterine stimulant activity, a finding subsequently confirmed in clinical studies with one member of this series, N-(methanesulfonyl)-16-phenoxy-omega-tetranor-PGE2-carboxamide (CP-34089/ZK-57671, sulprostone).

Synthesis and biological activity of novel carbacyclins having bicyclic substituents on the omega-chain.

A number of carbacyclins having bicyclic substituents on the omega-chain have been synthesized and tested for antiplatelet aggregation activity in vitro (against collagen-induced aggregation of rat platelet), for reduction of systemic blood pressure in vivo (ability to reduce the blood pressure in anesthetized rat by iv injection), and for cytoprotective activity (protection against ethanol-induced rat gastric lesion). The most effective compound for each activity was [3aS-[2E,3a alpha,4 alpha (3R),5 beta,6a alpha]]-5-[hexahydro-5- hydroxy-4-[3-hydroxy-3-(2-indanyl)-1-propynyl]-2(1H)-pentalenylidene+ ++] pentanoic acid (compound 11a), while some 1,4-benzodioxan analogues had selectivity for organ-protective activity, and indan analogues showed selectivity in their antiaggregation activity.

Synthesis and biological activity of prostaglandin lactones.

Most of the primary prostaglandins and several biologically important prostaglandin analogues were converted to 1,9-, 1,11- or 1,15-lactones, in order to investigate the biological profiles of these internal esters and to assess their potential as prodrugs for the corresponding open-chain hydroxy acids. In each case, the key lactonization step was done using Corey's "double activation" procedure (cyclization of omega-hydroxy-2-pyridinethiol esters). In general, the 1,9-lactones exhibited less than 1% of the biological activity of the parent hydroxy acids in the standard prostaglandin test systems. The 1,11- and 1,15-lactones, on the other hand, were essentially equal to the parent hydroxy acids as antifertility agents (a 4-day assay which would allow time for in vivo enzymatic lactone hydrolysis). The 1,11- and 1,15-lactones exhibited very low activity in acute or in vitro screens (e.g., rat blood pressure and gerbil colon stimulation), assays which more closely reflect the intrinsic activity of the lactones themselves. These results are consistent with the observed relative ease of enzymatic hydrolysis of the prostaglandin lactones (1,15 greater than or equal to 1,11 much greater than 1,9). Several of the lactones whose parent hydroxy acids are resistant to metabolic inactivation (e.g., 15-methyl, 16-phenoxy, and 17-phenyl) exhibited potent abortifacient activity in the hamster. These lactones, with greatly diminished activity in the blood pressure and smooth muscle assays (indicators of potential side effects), represent a therapeutically useful class of antifertility agents.

11,12-Secoprostaglandins. 5. 8-Acetyl- or 8-(1-hydroxyethyl)-12-hydroxy-13-aryloxytridecanoic acids and sulfonamide isosteres as inhibitors of platelet aggregation.

The synthesis of a series of 8-acetyl- (or 1-hydroxyethyl-) 12-hydroxy-13-aryloxytridecanoic acids and their sulfonamide isosteres is described. These compounds are formally derived from members of earlier reported series of modified secoprostaglandins by replacing the omega-butyl chain termini by substituted aryloxy groups. A number of these compounds are potent inhibitors of collagen-induced blood platelet aggregation in guinea pigs on oral administration.

15,15-Ketals of natural prostaglandins and prostaglandin analogues. Synthesis and biological activities.

The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues. Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetranorprostaglandin F2alpha is a very active inducer of luteolysis in laboratory animals and cattle.

Azaprostaglandin analogues. Synthesis and biological properties of 11-azaprostaglandin derivatives.

New nitrogen analogues of prostaglandins (11, 11a, 12, and 12a) have been synthesized starting from a 4,5-disubstituted 2-pyrrolidinone nucleus (5 and 5a) containing one side chain and a suitable functionality for elaborating the second one. These analogues had no better activity than natural prostaglandins in vitro [guinea pig ileum and trachea, rat stomach fundus strip, uterus and portal vein, ADP-induced guinea pig platelet-rich plasma (PRP) aggregation]. They similarly lacked any interesting activity in vivo [anesthetized rat blood pressure, stress, and acetylsalycilic acid (ASA) induced gastric lesions in rat].

Synthesis and platelet aggregation inhibiting activity of prostaglandin D analogues.

Several prostaglandin D (PGD) analogues have been synthesized, incorporating the following variations: (a) varying degrees of side-chain unsaturation, (b) C-9 hydroxy removed or in the unnatural 9 beta configuration, (c) metabolically stabilized analogues (e.g., 15-methyl, 16,16-dimethyl, 17-phenyl, etc.), and (d) delta 12 isomers resulting from decomposition of PGD2. With regard to their ability to inhibit adenosine diphosphate (ADP) induced human platelet aggregation: (a) PGD3 greater than or equal to PGD2 greater than PGD1 greater than 13,14-dihydro-PGD1, (b) the 9 beta- and 9-deoxy-PGD2 analogues are more potent than PGD2, (c) metabolically stabilized analogues with bulky substituents at or near C-15 have substantially reduced antiaggregatory activity relative to PGD2 and (d) the delta 12 isomers of PGD2 are much less active than PGD2.