... and it is an inhibitor of cycloxygenase and lipoxygenase. the second act as leukotriene recettorial antagonists and are called Montelukast e Zafirlukast) ...
XVIII SSMC
Rio de Janeiro, Brasil Janeiro 23-27, 2012 “The Arachidonic Acid Cascade: Prostaglandins, Thromboxanes, Prostacyclins and Leukotrienes ”
Prof. Pier Giovanni Baraldi Dipartimento Scienze Farmaceutiche - Università di Ferrara – Italy
Prostaglandins of series 1-3
PGE 1
PGE 2
PGE 3
Wittig reaction
Wittig-Horner Reaction
1. Al/H g, M eOH /H 2O 2. H COOAc
OsO 4, Py Pb(OAc) 4, -40°C
DBN, 0°C Ac2O, Py
NaBH 4, EtOH , -20°C H 2SO 4, T H F/H 2O
E.J.Corey et al., JACS 1968, 90, 3245
DCC, CuCl2 Et 2O
1. K OH , 30°C 2. DH P, T sOH 3, K OH , 120°C M eOH /H 2O
E.J.Corey et al., JACS 1968, 90, 3245
Z n(BH 4) 2
Resolution of the hydroxy acid with (+)- Ephedrine and conversion to optically active PGF2a and PGE2 1. PhH ,heat
è
2. recr ystallization
(+)- Ephedrine
Synthetic equivalence between 3,5 disubstituted isoxazoles and bifunctional systems
Isoxazoles 3,5-disubstituted as latent functionalities of α,β-unsaturated ketones
P. G. Baraldi, G.P.Pollini et al. Synthesis, 1987, 851-869
Synthesis of PGF2α
DH P pT sOH
Synthesis of PGF2α PhNCO 1-Eptino
1. W ittig
6
5
2. DH P, pT sOH
1. Na, NH 3 (liq.) 2. SiO 2 3. NaBH 4 4. H +
P .G . Baraldi, G. P .Pollini et al, Tetrahedron 1987, 43 ,4669
Synthesis of PGF2α
DH P pT sOH
PhNCO 1-Eptino
1. W ittig 2. DH P, pT sOH
6
5
1. Na, NH 3 (liq.) 2. SiO 2 3. NaBH 4 4. H +
PGF2
Catalytic Enantioselective Synthesis of (-) PGE1 Methyl Ester via a tandem 1,4-addition-aldol reaction
B.L.Feringa,JOC.,2002, 67, 7244
Catalytic Enantioselective Synthesis of (-) Prostaglandin E1 Methyl Ester via a tandem 1,4-addition-aldol reaction
a. 3 mol % Cu(OTf)2, 6 mol % L1, toluene, -45°C, 18h; b. Zn(BH4)2, ether, -30°C,3h; c. (1) 3 eq.of Bu4NF(1 M in THF), methyl propionate, DMSO, 80°C, 20 min, (2) Ac2O, DMP; Pyr, 20 min;(3) 5 mol %Pd(CH3CN)2Cl2, THF, 3H; d. K2CO3, MeOH, 18h; e. (NH4)2Ce(NO3)6, MeCN, borate-HCl (ph=8),60°C, 2h.
B.L.Feringa,JOC.,2002, 67, 7244
Chiral Lewis Acids by protonation of the oxazaborolidines
Synthesis of chiral bicyclo [2.2.1]hepten-2-one Enantioselective Diels-Alder reaction
E. J. Corey, Angew. Chem. Int .Ed. 2002, 41, 1690
Synthesis of 8-Methyl Prostaglandin C2
Synthesis of 8-aza-11-desoxy-PGE1
P.G.Baraldi, G.P.Pollini, J.Org.Chem. 1979, 44, 1739
9,11-Etheno analog of PGH1 Exo specific in the Presence of BF3-Et2O PhM e, heat
Inhibitor of PGH isomerase
E.J.Corey et al., JACS, 1971, 93, 2815
Synthesis of 8-Aza-9,11-etheno PGH1 R= OOH PGG2 R= OH PGH2 benzene
DCC, T H F
Et 2O
DM SO
NaBH 4
NaH , T H F
M eOH
W ittig
Na, NH 3 (l)
L iAlH 4
K H CO 3, RX M eOH
L iOH
P.G.Baraldi, G.P.Pollini et al LIebig Ann.Chem.1982, 960-963
Synthesis of Vane's Prostacyclin, PGI2
1. NBS, T H F, CH Cl3
+
2. AcOH , H 2O/T H F
11, 15 bis THP ether of PGF2α Diastereoselectio 1:3 the mixture was separated by SGC
t - BuOK , t - BuOH
Isolated as the methyl ester or the pyrrolidinium salt
PGI2
Idrolysis of prostacyclin PGI2
Retrosynthesis and synthesis of Carbaprostacycline FGI
FGI
RET RO W ITTIG
RET RO WITTIG
FGI
FGI
P.G.Baraldi, G.P.Pollini et al.J.Org.Chem.,1980, 45, 4776
Retrosynthesis and Synthesis of Carbaprostacycline RET RO CL AI SEN
RET RO M I CH AEL
FGI
a d
Jones Reactive
K 2CO 3
RET RO BAY ER V I L L I GER
FGI NaOH
H 2O 2, OH -
P.G.Baraldi, G.P.Pollini et al.J.Org.Chem.,1980, 45, 4776 .
Synthesis of 11-thio-11-desoxy-carbaprostacyclin 1. O 3, -78°C, 2. H CO 2H -H 2O 2
H I 67%
Ba(OH ) 2, Fe
M ED, C 6H 6
r eflux
NaI O 4
Na2S, EtOH
Synthesis of 11-thio-11-desoxy-carbaprostacyclin B2H 6, T H F 0°C H 2SO 4 dil.
M ED
NaBH 4 H 2SO 4 dil
W ittig
weak antiaggregatory activity OH on C 11 is very important for the activity
P.G.Baraldi, G.P.Pollini et al. Gazzetta Chimica Italiana,114, 1984, 177-183
Main features of Prostanoids (PGs) Prostaglandins occur in nearly all mammalian tissues. Initially the PGs were isolated from sheep seminal plasma. Animal sources couldn’t supply sufficient amount for drug use. Then, a soft coral Plexaura homomalla from the Caribbean sea was identified to contain a large amount of PGs but still unsufficient to provide satisfactory and renewable natural source. Considerable effort has been exerted on the total synthesis of PGs and the high level of success achieved has opened the availability of PGs for pharmacological testing and subsequent drug use. Synthetic analogues have also been developed to modify and optimize biological activity. These studies have confirmed that biological activity is effectively confined to the natural enantiomers; the unnatural enantiomer of PGE1 had only 0.1% of the natural isomer.
Pharmacological effects of Prostanoids The prostaglandins PGs display a wide range of pharmacological activities: Contraction and relaxation of • • • •
the smooth muscle of the uterus, the cardiovascular system, the intestinal tract the bronchial tissue.
inhibit gastric acid secretion, control blood pressure and suppress blood platelet aggregation. Since the PGs control many important physiological processes in animal tissues, their drug potential is high, but the chances of stimulating unwanted side-effects are also high and this has so far limited their therapeutic use. There is, however, the possibility of controlling the production of natural PGs in body tissues by means of specific inhibitors.
Prostaglandins on the drug market
Prostanoids on the market A major area of application of prostaglandins as drugs is in obstetrics, where they are used to induce abortions during the early to middle stages of pregnancy or to induce labour at term. PGE2 (Dinoprostone) is used in both capacities. PGF2a Dinoprost
is less commonly prescribed and restricted to abortions.
PGF2a is rapidly metabolized in body tissues (t 1/2 less than 10 min) and the modified version the 15 methyl- PGF2a (Carboprost) has been developed to reduce deactivation by blocking oxidation at position 15. Gemeprost, the 16-dimethyl derivative, is another unnatural structure and is used to soften and dilate the cervis in early abortions. These agents are usually administered vaginally.
PGE1 (Alprostadil) differs from PGE1 by having unsaturation only in the b side chain. Having effects on uterine muscle, it also has vasodilator properties, and these are used for maintaining new-born infants with congenital heart defects., facilitating blood oxygenation prior to corrective surgery. The very rapid metabolism of PGE1 means that the drug must be delivered by continuous intravenous infusion. Alprostadil is also useful in male impotence, self-injectable preparations are used to obtain erection of the penis. Misoprostol is an interesting modification made on PGs, the hydroxyl and a methyl has been introduced in position 16.These modifications result in an orally active drugwhich inhibitsgastric secretion and can be usedto promote healing of gaxtric and duodenal ukcers . PGI2 (Prostacyclin) reduces blood pressure and also inhibits platelet aggregation by reducing calcium concentrations. It is employed to inhibit blood clotting during renal dialysis, but its very short half time (about three min) again necessitates continuous intravenous administration. Iloprost is a stable carbocyclic analogue of potential use in the treatment of thrombotic diseases.
MECHANISM OF ACTION OF NSAID AND GLICOCORTICOIDS It has been found that some established non-steroidal anti-inflammatory drugs (NSAIDs drugs), like aspirin, indomethacin, ibuprofen, inhibit early steps in the PGs biosynthesis that transform the unsaturated fatty acid into cyclic peroxides. Thus aspirin is known to inactivate the ciclooxygenase activity by selective acetylation of a serine residue of the enzyme. The anti-inflammatory activity of corticosteroids, like cortisone, cortisol, prednisone and prednisolone correlates well with their capacity to inhibit the enzyme phospholipase PLA2, and thus the release of arachidonic acid (AA) from the phospholipides, through the production of protein inhibitor Lipocortin .This a mechanism of indirect inhibition of enzyme PLA2. A steady supply of PGs precursors is required since PGs are continuosly synthesized and then deactivated. PGs are rapidly degraded by processes which include oxidation of the 15hydroxyl to ketone, reduction of the 13, 14-double bond and oxidative degradation of both side chains.
Radical Mechanism of Thromboxanes TXA2 and TXB2
Main features of Thromboxanes The thromboxanes were isolated from blood platelets and while TXA2 showed high biological activity, TXB2 was only weakly active. TXA2 causes blood platelets to aggregate to form a clot or thrombus, by increasing cytoplasmatic calcium concentrations, and thus deforming the platelets which then fuse together. It has the opposite effect to PGI2, and presumably the development of thrombosis reflects an imbalance in the two activities. Both compounds are produced from the same precursor, PGH2, which is converted in the blood platelet to TXA2, and in the blood vessel to PGI2. The highly unstable nature of the biologically active thromboxanes has made their synthesis difficult, and drug use of natural structures will probably be impracticable. It is likely that most efforts will be directed towards thromboxane antagonists to reduce blood platelet aggregation in patients with thrombosis.
Formation of Leukotrienes from Arachidonic acid
Stereospecific Synthesis of Leukotriene LTA4
Synthesis of hydroxy-epoxide B
Retrosynthetic analysis of LTB4
Synthesis of LTB4
Main features of Leukotrienes The leukotrienes are involved in allergic responses and inflammatory processes. An antigen-antibody reaction can result in the release of compounds such as histamine or materials termed slow reacting substance of anaphylaxis (SRSA). These substances are then mediators of hypersensitive reactions such as hay fever (allergic rhinitis) and asthma. Structural studies have identified SRSA as a mixture of LTC4, LTD4 and LTE4. These cysteine-containing leukotrienes are powerful bronchoconstrictors and vasoconstrictors. LTB4 appears to facilitate migration of leukocytes in inflammation and it is implicated in the pathology of psoriasis, inflammatory bowel disease, and arthritis. The biological effects of LTs are being actively studied to define the cellular processes involved. This may lead to control allergic and inflammatory reactions. Drugs inhibiting LTC4 and LTB4 are in clinical trials. Some drugs are entered in the market: the first called Zileuton and it is an inhibitor of cycloxygenase and lipoxygenase. the second act as leukotriene recettorial antagonists and are called Montelukast e Zafirlukast)
Acknowledgements ORGANIC CHEMISTRY GROUP (University of Ferrara) -Prof. G. P. Pollini -Prof. A. Barco -Prof.ssa S. Benetti
MEDICINAL CHEMISTRY GROUP -Prof. M. Guarneri -Prof. D. Simoni -Dr. R. Romagnoli
PEOPLE OF THE INDUSTRY -Prof. C. Gandolfi (Carlo Erba-Pharmitalia) -Dr. N. Mongelli -Dr. P. Cozzi
