Concise asymmetric synthesis of configurationally stable 4-trifluoromethyl thalidomide.

BACKGROUND: Thalidomide is one of the promising multidimensional drugs that possess high activity against serious diseases such as rheumatoid arthritis, Crohn's disease, leprosy, AIDS and various cancers. However, its medicinal applications are plagued by its configurational instability, as it easily undergoes racemization under the physiological conditions (t(1/2) = 8 h at pH 7.1, 37°C in water). Consequently, the design and synthesis of configurationally stable analogs of thalidomide continue to be an important area of research in bioorganic and medicinal chemistry. DISCUSSION: 4-trifuoromethyl thalidomide-3c was identified as an important synthetic target, which was expected to be a configurationally stable analog of thalidomide. Synthetic challenges in preparation of compound 3c were truly multipronged, considering the unique steric, electronic as well as electrostatic characteristics of trifluoromethyl group, significantly affecting properties of parent amino acids. After numerous experiments and unsuccessful attempts, both (3S,4R) and (3R, 4S) enantiomers of 4-trifluoromethyl-substituted thalidomide were effectively synthesized in six steps starting from enantio- and diastereomerically pure 3-(trifluoromethyl)pyroglutamates, prepared by highly diastereoselective Michael addition reactions between achiral glycine equivalents and chiral 3-(trifluoromethyl)acrylate. CONCLUSION: We have developed a reliable asymmetric approach for preparation of hitherto unknown 4-trifluoromethyl-substituted thalidomide in (3S,4R) and (3R,4S) enantiomerically pure forms. These thalidomide derivatives were shown to be configurationally stable and therefore may serve as useful lead compounds for the development of a new generation of thalidomide-based pharmaceuticals.

Thalidomide analogs from diamines: Synthesis and evaluation as inhibitors of TNF-alpha production.

Fourteen thalidomide analogs bearing two phthalimido units were prepared in high yields (83-94%) by condensation of different diamines with phthalic or 3-nitrophthalic anhydride. An in vitro investigation of the compounds as inhibitors of the TNF-alpha production was performed. The inhibition was higher for compounds bearing amino and nitro groups and was modulated by increasing the size of the spacers between the phthalimide groups.

Talidomida: una visión nueva de un tóxico antiguo / Thalidomide: a new view of an old toxic

Desde que a principios de los años 60 la talidomida fuera retirada del mercadodebido a su acción teratogénica, este fármaco ha sido ampliamente estudiado,encontrándose en él propiedades terapéuticas que han despertado nuevamente elinterés por esta molécula. Recientemente, la FDA ha aprobado su empleo en eltratamiento de ENL (Erythema Nodosum Leprosum), una manifestación aguda dela lepra. Además, actualmente se encuentra en ensayos clínicos (fase II/III) enmieloma múltiple, cáncer de mama, próstata, riñón y pulmón, mostrando buenosresultados. En este artículo se ofrece una visión general de las propiedades de latalidomida, haciendo especial hincapié en su acción inhibitoria de la angiogénesis,que podría ser responsable, al menos en parte, de su actividad antineoplásica yteratogénica

Since the early 60s, when thalidomide was withdrawn from markets, this drug ;;has been widely studied due to its teratogenic activity. The finding of new therapeutic properties has raised a new interest in this molecule, and recently the FDA ;;has approved its use in the treatment of ENL (Erythema Nodosum Leprosum), an ;;acute manifestationof leprae. Besides, thalidomide is nowadays going through clinical ;;assays (PhaseII/III) in multiple myeloma, breast, prostate, kidney and lung ;;tumours, showing good results. This article offers an overview of thalidomide ;;properties focusing on its inhibition of angiogenesis, which would be responsible, ;;at least partially, of its antineoplastic and teratogenic activity

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity.

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and multiple myeloma and effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-alpha and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-alpha inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-alpha secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-alpha secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-alpha mRNA stability via its 3'-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-alpha inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-alpha inhibitory activity.

Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production.

In addition to its well known sedative and teratogenic effects, thalidomide also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of thalidomide has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of thalidomide remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of thalidomide as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be alpha1-acid glycoprotein (AGP). We show that the binding of thalidomide photoaffinity label to authentic human AGP is competed with both thalidomide and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of thalidomide.

Talidomida efeito sobre a ceruloplasmina serica / Thalidomide: effect on the serum ceruloplasmin

Ceruloplasmin enzymatic activity was determined in rat sera using p-phenylenediamine as substrate at pH 5.4. The levels of the oxidase in the animais treated with thalidomide by perenteral or gatro-intestinal routes were not statistically different from the values obtained in the control rats.

Lupus eritematoso discoide y talidomida

En base a los magnificos resultados que la talidomida ha dado en reaccion leprosa, los autores ensayan el medicamento en 21 pacientes de lupus eritematoso discoide y presentan sus observaciones de 20 casos: 17 mujeres en las cuales el medicamento se administra con anticonceptivos y en 3 hombres. La dosis de inicio fue de 300 mg. por dia y se realizo un cuidadoso estudio clinico, fotografico e histopatologico. Los resultados fueron muy buenos tanto clinica como histopatologicamente en todos los casos, en algunos hasta espectaculares. Solo una paciente tuvo manifestaciones de intolerancia que motivaron la suspension del medicamento. Los demas toleraron muy bien la droga: ligera somnolencia transitoria solamente. Juzgan los autores que el medicamento, sin saberse como actua, es de utilidad en lupus eritematyoso discoide y debe ensayarse en mayor numero de casos para comprobarse sus magnificos efectos