Immunosuppressive activities

Miller an d Rich assumed th at cyclosporin A an d its MeHrn t an alogs share a common hioactive con formation. fheir molecular mech an ics calculation s found such a conformation, fh e Boltzmann population of th e proposed hioactive conformation correlates with the immunosuppressive activities of the compounds. 

The researchers investigated three MeBmt analogs the C-4 epimer ((45)-MeBmt), the C-4 des methyl analog (MeBth), and the C-4 dimethyl (MeBm2t) analog. The immunosuppressive activity of the analogs follows the order MeBmt > MeBm2t > MeBth > (4 )-MeBmt. 

A new generation of antiinflammatory agents having immunosuppressive activity has been developed. The appearance of preclinical and clinical reports suggest that these are near entry to the pharmaceutical market. For example, tenidap (CP-66,248) (12) has been demonstrated to inhibit IL-1 production from human peripheral blood monocytes in culture (55). Clinically, IL-1 in synovial fluids of arthritic patients was reduced following treatment with tenidap. Patients with rheumatoid or osteoarthritis, when treated with tenidap, showed clinical improvement (57,58). In addition to its immunological effects, tenidap also has an antiinflammatory profile similar to the classical NSAIDs (59). Other synthetic inhibitors of IL-1 production are SKF 86002 (20) andE-5110 (21) (55). 

Another natural product, mizoribiae (39), a nucleoside antibiotic produced by the fungus Eupenicillium brefeldianum has cytotoxic and immunosuppressive activity. It has been evaluated for use ia renal transplantation and neoplasia (68). 

Faneti/ole (122) is a biological response modifier with significant immunosuppressant activity It can be synthesized by conversion of 2 phen> lethylamine (120) with ammonium thio cyanate to the corresponding thiourea analogue 121 The synthesis of faneli/ole (122) concludes by thiazole nng formation of 121 by reaction with phenacylbromide Thus its synthesis involves use of the classic Hantzsch procedure in which a bromoacetone analogue and an appropriate thio urea denvative are reacted 143]... 

Figure 8.4b). Some of the early antihistamines were found to exert antidepressant and antipsychotic properties. These led to modem psychopharmaceuticals. The immunosuppressant activity of the fungal agent cyclosporine also was exploited for therapeutic utility. 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

The fungal metabolite (+)-brefeldin A (325) displays potent antitumor, antifungal, antiviral, antimitotic, and immunosuppressive activities. Recently, Romo and Wang described a highly concise total synthesis of 325 by a combined /J-lactone-CM approach (Scheme 63), that again underlines the high tolerance of sensitive functionality exhibited by the second-generation Ru catalysts [ 145]. 

Davis, D. and Safe, S.H. (1990). Immunosuppressive activities of PCBs in C57BL/ 6N mice structure-activity relationships as Ah receptor agonists and partial agonists. Toxicology 63, 97-111. 

Zheng J. Screening of active anti-inflammatory, immunosuppressive and anti-fertility components of Tripterygium wildfordii III. A comparison of the anti-inflammatory and immunosuppressive activities of 7 diterpene lactones epoxides compounds in vivo. Zhongguo Yixue Kexueyuan Xuebao 1991 13 391-397. 

Cyclosporine demonstrates immunosuppressive activity by inhibiting the first phase of T-cell activation. It also inhibits release of inflammatory mediators from mast cells, basophils, and polymorphonuclear cells. It is used in the treatment of both cutaneous and arthritis manifestations of severe psoriasis. The usual dose is between 2.5 and 5 mg/kg/day given in two divided doses. Adverse effects include nephrotoxicity, hypertension, hypomagnesemia, hyperkalemia, alterations in liver function tests, elevations of serum lipids, GI intolerance, paresthesias, hypertrichosis, and gingival hyperplasia. Cumulative treatment for more than 2 years may increase the risk of malignancy, including skin cancers and lymphoproliferative disorders. 

Vos, J.G. and de Roij, T., Immunosuppressive activity of a polychlorinated diphenyl preparation on the humoral immune response in guinea pigs, Toxicol. Appl. Pharmacol., 21, 549, 1972. 

Smialowicz, R.J. et al., Differences between rats and mice in the immunosuppressive activity of 2-methoxyethanol and 2-methoxyacetic acid, Toxicology, 74, 57, 1992. 

FK-506 was isolated105 from Streptomyces trukubaensis, possessing a unique 21-membered macrolide, in particular an unusual a,/ -diketoamide hemiketo system. It shows immunosuppressive activity superior to that of cyclosporin in the inhibition of delayed hypersensitivity response in a variety of allograft transplantation and autoimmunity models. 

In Poland, various 5-cycloaminornetbyl-6-(p-chlorophenyl)-4,5-dihydro-3(2//)-pyridazinones (89, R1 = pyrrolidino, piperidino, morpholino, etc. R2 = H, substituted alkyl, aryl) have been prepared in search of biologically active pyridazines some of these compounds have been reported to exhibit immunosuppressive activity [180, 284, 285]. 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

G. Lhoest, R. K. Verbeeck, N. Maton, P. Muthelet, D. Latinne, The in vivo Immunosuppressive Activity of the C15-Demethylated Metabolite of FK-506 Is Governed by Ring- and Open-Chain Tautomerism Effects , J. Pharmacol. Exp. Ther. 1995, 274, 622 -626. 

As a consequence of their immunosuppressive activity, Tregs may function as a cellular therapeutic agent that ameliorates allergies and autoimmune diseases. This has been proven in several disease models including asthma, inflammatory bowel disease, multiple sclerosis and CHS reactions. Others and we have studied the effects of in vivo applied Tregs as a possible therapeutical means to curb... 

Some of these metabolites are also detectable in plasma, fecal, and urine samples. Glucuronide and sulfate conjugates are not present in any of the biologic matrices. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity. 

In 1994, McAlpine et al. reported the isolation of MLR-52 (320), along with (-i-)-staurosporine (295) (see Scheme 2.74), from the fermentation broth and mycelia of Streptomyces sp. AB 1869R-359. In nature, this isolate was obtained in its optically active form [aJu +68.0 (c 0.093, MeOH). This isolate has shown inhibition of PKC and potent in vitro immunosuppressive activity (305). 

The sesquiterpene pyridine alkaloids have antifeedant and insecticidal activ-ihes. Some alkaloids, such as triptonine B, hypoglaunine B, hyponine B and wilfortrine, have antivirus activity potential. Others, such as emarginatines A-B, E-G and emarginatine, have cytotoxic activity. Ebenifoline and cangorinine have immunosuppressive activity. 

Alkaloids such as vinblastine and vincristine are known to bind to the microtubules of the spindle apparatus. They are active agents that influence DNA synthesis and amino acid metabolism. They are also known to reduce mitosis at metaphase. Vinblastine and vincristine also have some immunosuppressive activity. There are many applications of these alkaloids. They have been used in the treatment of Hodgkin s disease, cancers and blood disorders. Vincristine is a basis for the development of clinic agents used to treat cerebral and pulmonary disorders. Vinblastine and vincristine are well-known anficancer agents. 

Immunosuppressive activity largely affects thymocytes and (im)mature T-cells and thus lymphocyte cultures are a rather straightforward model to assess immunosuppressive activity. Thymocyte cultures are also used, but may be less amenable to routine in vitro testing (Table 18.4). 

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