Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps.

Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.

Therapeutic uses of prostaglandin F(2α) analogues in ocular disease and novel synthetic strategies.

The pharmacological management of glaucoma and ocular hypertension has significantly changed over the last 18 years with the introduction of PGF2α analogues, more specifically latanoprost (6), travoprost (8), bimatoprost (10) and tafluprost (12). Prostanoids are currently the first-line medicines among ocular antihypertensive drugs in terms of efficacy, safety, patient compliance and medical economy. Their ability to effectively reduce intraocular pressure with once-per-day dosing, ocular tolerability comparable to timolol and general lack of systemic adverse effects have made them the mainstay of pharmacological therapy for glaucoma and ocular hypertension all over the world. The present review reports a novel, convergent and highly diastereoselective method for the synthesis of PGF2α analogues from the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 and new ω-chain synthons. The biochemistry, clinical efficacy and side effects of four commercially available PGF2α analogues, currently used as first-line agents for reducing intraocular pressure in patients with glaucoma or ocular hypertension, are also discussed.

New prostaglandin derivative for glaucoma treatment.

A hydrogen sulphide-releasing derivative of latanoprost acid (ACS 67) was synthesized and tested in vivo to evaluate its activity on reduction of intraocular pressure and tolerability. Glutathione (GSH) and cGMP content were also measured in the aqueous humour. The increased reduction of intraocular pressure, with a marked increase of GSH and cGMP and the related potential neuroprotective properties, make this compound interesting for the treatment of glaucoma. This is the first time that an application of a hydrogen sulphide-releasing molecule is reported for the treatment of ocular diseases.

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.

Prostaglandin photoaffinity probes: synthesis and biological activity of azide-substituted 16-phenoxy- and 17-phenyl-PGF2 alpha prostaglandins.

The development of a prostaglandin PGF2 alpha photoaffinity probe led to the synthesis and biological evaluation of azide-substituted 17-phenyl-18,19,20-trinorprostaglandin F2 alpha and 16-phenoxy-17,18,19,20-tetranorprostaglandin F2 alpha derivatives. Two approaches for the preparation of iodinated versions of these prostaglandins were evaluated: (1) iodination of a phenyl azide bearing an activating hydroxyl group and (2) iodination of an aniline precursor to the phenyl azide group and subsequent conversion of the aniline to the phenyl azide. In the first approach, 17-(4-azido-2-hydroxyphenyl)-18,19,20-trinorprostaglandin F2 alpha, 16-(5-azido-3-hydroxyphenoxy)-17,18,19,20-tetranorprostaglandin F2 alpha, and 16-(4-azido-2-hydroxyphenoxy)-17,18,19,20-tetranorprostaglandin F2 alpha were prepared by using the Corey synthesis, but were biologically inactive presumably as a result of the hydrophilic phenolic hydroxyl group. In the second approach, the iodination of a 17-(4-aminophenyl)-18,19,20-trinorprostaglandin F2 alpha derivative delivered 17-(4-azido-3-iodophenyl)-18,19,20-trinorprostaglandin F2 alpha, which exhibited competitive binding with natural [3H]PGF2 alpha to ovine luteal cells and to plasma membranes of bovine corpora lutea. [125I]-17-(4-Azido-3-iodophenyl)-18,19,20-trinorprostaglandin F2 alpha was utilized in a preliminary photoaffinity cross-linking experiment.

Structure-activity studies of 16-methoxy-16-methyl prostaglandins.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

Synthesis and biological evaluation of the methyl esters of (+)-12-fluoro-13,14-dihydroprostaglandin F2alpha and (+)-15-epi-12-fluoro-13,14-dihydroprostaglandin F2alpha.

(+)-12-Fluoro-13,14-dihydroprostaglandin F2alpha methyl ester (2a) and (+)-15-epi-12-fluoro-13,14-dihydroprostaglandin F2alpha methyl ester (2b) were prepared from the readily available (-)-7-fluorospiro[bicyclo[2.2.1]hept-5-ene-2,2'-[1,3]dioxolane]-7-methanol (3). Fluoroprostaglandins 2a and 2b possess truly significant separations of antifertility activity from smooth-muscle stimulating properties. In addition, our studies showed that 2a and 2b were totally inert toward the placental 15-hydroxyprostaglandin dehydrogenase.

Prostaglandin analogues possessing antinidatory effects. 1. Modification of the omega chain.

Novel prostaglandin analogues modified in the omega chain were prepared by the reaction of the vinyl aldehydes 1a--e with a variety of organometallic reagents as a key step of the syntheses. Compared with the natural prostaglandin F2 alpha in antinidatory effect, the analogues 4, 7, and 10 were 40 times more potent and the analogue 11 was 50--100 times more potent in the rat.

Prostaglandin analogues possessing antinidatory effects. 2. Modification of the alpha chain.

Additional double bonds were introduced into the alpha chain in 16-phenoxy-, 16-(3-chlorophenoxy)-, 16-[3-(tri-fluoromethyl)phenoxy]-, and 16-(4-chlorophenoxy)-17,18,19,20-tetranorprostaglandins which have antinidatory effects. Of these analogues, the delta 3-cis-delta 5 analogues 23b is 1200 times more potent than prostaglandin F2 alpha in antinidatory effect in the rat and more potent than any other known prostaglandin analogues.

Synthesis and biological evaluation of 10-oxa-11-deoxyprostaglandin E1 and 10-nor-9,11-secoprostaglandin F1 and their derivatives.

Three 10-oxa-11-deoxyprostaglandin E1 and two 10-nor-9,11-secoprostaglandin F1 analogues were prepared. The compounds were evaluated for pregnancy interruptions, oxytocin-like activity (uterine strip), and antiprostaglandin activity. One of the 10-nor-9,11-secoprostaglandin F1 analogues displayed activity as a PGE2 antagonist in the gerbil colon smooth muscle preparation.

Synthesis and biological activity of carboxyl-terminus modified prostaglandin analogues.

A series of PGE2, 16,16-dimethyl-PGE2, and PGF2 alpha analogues modified at the carboxyl terminus with tetrazole, amide, acylurea, imide, and sulfonimide functionalities was evaluated for uterine stimulant, bronchodilator, hypotensive, gastric antisecretory, and diarrheal activity. These compounds were prepared by modification of the Corey prostaglandin synthesis utilizing as a key step condensation of known hemiacetals with the ylide derived from the requisite substituted phosphonium salts. Structure--activity relationships suggest that a proton at the C-1 position appears necessary for agonist activity and the acidity of this proton has a relatively greater influence on activity than pendant steric bulk. Noteworthy are the tissue-selective bronchodilator activity of N-acetyl-PGE2-carboxamide and the selectivity for uterine tissue of N-methanesulfonyl-PGE2-carboxamide, 2-decarboxy-2-(tetrazol-5-yl)-16,16-dimethyl-PGE2, N-acetyl-16,16-dimethyl-PGE2-carboxamide, and N-methanesulfonyl-16,16-dimethyl-PGE2-carboxamide.

Fluoroprostaglandins: synthesis and biological evaluation of the methyl esters of (+)-12-fluoro-, (-)-ent-12-fluoro-, (+)-15-epi-fluoro-, and (-)-ent-15 epi-12-fluoroprostaglandin F2 alpha.

The synthesis and biological activity of the methyl esters of (+)-12-fluoroPGF2 alpha, (+)-15-epi-12-fluoroPGF2 alpha, (-)-ent-12-flurorPGF2 alpha, and (-)-ent-15-epi-12-fluoroPGF2 alpha are described. Each fluoroprostaglandin has been evaluated from pregnancy interruption in the hamster and smooth-muscle stimulating effects on gerbil colon and hamster uterine strips. All fluoroprostaglandins synthesized were shown to be neither substrates for the 15-hydroxyprostaglandin dehydrogenase nor inhibitors of the enzyme.

C(14)-fluorinated prostaglandins: synthesis and biological evaluation of the methyl esters of (+)-14-fluoro-, (+)-15-epi-14-fluoro-, (+)-13(E)-14-fluror-, and (+)-13(E)-15-epi-14-fluoroprostaglandin F2 alpha.

The synthesis and biological evaluation of the methyl esters of (+)-14-fluoroPGF2 alpha, (+)-15-epi-14-fluoroPGF2 alpha, (+)-13(E)-14-fluoroPGF2 alpha, and (+)-13(E)-15-epi-14-fluoroPGF2 alpha are described. Each fluoroprostaglandin has been evaluated for pregnancy interruption in the hamster and smooth-muscle stimulating effects on gerbil colon and hamster uterine strips.

Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

An efficient synthesis of 3-hetero-13,14-dihydro prostaglandin F1alpha analogues.

[structure: see text]. A new class of 3-hetero-13,14-dihydro prostaglandin F(1)(alpha) analogues was synthesized from a common intermediate. The latter was constructed via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl) group, was synthesized in enantiopure form using Jacobsen's (salen)Co-catalyzed kinetic resolution of a terminal epoxide with phenol.

Mass spectra of tert-butyldimethylsilyl ether derivatives of the major metabolite of prostaglandin F.

The EI mass spectra of four tert-butyldimethylsilyl ether derivatives of the major metabolite of prostaglandins F1 alpha and F2 alpha (PGF-M) are presented and discussed. Proposed ion assignments and fragmentation pathways are based on substituent shifts, on data from a deuterium-labeled methoxime analog, and on the analysis of collision-induced dissociation spectra of selected ions. Fragment ions suitable for identification and quantification work are proposed.

A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma.

PURPOSE: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. METHODS: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. RESULTS: NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. CONCLUSIONS: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.