Immunosuppressive alkaloid

Total synthesis of the immunosuppressive alkaloid (77) (FR901483) bearing the phosphoric acid residue was described by Kerr and Carson and involved the 1,1-cyclopropanediester (76) as the starting material (Scheme 15). ... 

Carson and Kerr in 2009 deployed an intramolecular imine cyclopropane annulation for the total synthesis of the immunosuppressive alkaloid (-)-FR901483 (112, Scheme 41.24), isolated from the fermentation broth of Cladobotryum sp." " The key formal [3+2] cycloaddition was performed by adding the complex cyclopropane gem-diester 108 to a 70°C preheated (to avoid eliminative ringopening of the cyclopropane) dilute solution of excess paraformaldehyde (7 equiv) with a catalytic amount of ytter-bium(lll) triflate (7.5 mol%) in dichloroethane. Pyrrobdine 110 was thus obtained in 67%. It is likely that the mechanism is stepwise opening of the cyclopropane by the nitrogen of the imine 109 followed by intramolecular addition of the formed malonate to the imminium species 111. Finally, monodecarboxylation, Curtius rearrangement, and incorporation of the phosphate moiety provided (-)-FR901483 112. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Drugs that may be affected by indinavir include antiarrhythmics, clarithromycin, dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressant agents, phosphodiesterase type 5 inhibitors, pimozide, saquinavir, trazodone, cisapride, amiodarone, benzodiazepines, ergot alkaloids, fentanyl, rifamycins, ritonavir. 

The following drug classes may have a potential drug interaction with nevirapine Antiarrhythmics, anticonvulsants, antifungals, calcium channel blockers, cancer chemotherapy (cyclophosphamide), ergot alkaloids, immunosuppressants, motility agents, opiate agonists. 

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. 

The sponge Agelas dispar from the Bahamas contained pyridinebetaine B (494) [420]. Echinoclathrines B-C (495-496) are members of a new class of pyridine alkaloids from an Okinawan species of Echinoclathria. They exhibit weak immunosuppressive activity [421]. 

Manzamine-type alkaloids were also reported in another samples of marine sponges, eg., the Okinawan Amphimedon sp. [252-254], Pachypellina sp. [255], and a novel alkaloid called hyrtiomanzamine from Hyrtios erecta, with interesting immunosuppressive activity [256]. From... 

The thiol group can also be found in heterocyclic compounds such as 2-mercaptobenzothiazole (9) and echinoclathrine C (10). Compound 9 was isolated from the symbiont bacterium Micrococcus sp., which was obtained from the sponge Tedania ignis [13]. The pyridine alkaloid echinoclathrine C (10) and its S-acetylated derivative, echinoclathrine B (11), were isolated from the Okinawan sponge Echinoclathria sp. [14]. The position of the hydroxyl and acylamino group on the phenyl ring in echinoclathrines (11 and 10) was recently corrected [15]. Compound 11 showed weak immunosuppressive activity in the mixed lymphocyte reaction assay with an IC50 of 9.7 pg/ml [14]. 

The New Zealand bryozoan Cribicellina cribraria was the source of several P-carboline alkaloids. One of these examples, compound 34, has a unique methylsulfone substituent. Spectroscopic studies identified 34 as 1-ethyl-4-methylsulfone-P-carboline [34]. Hyrtiomanzamine (35) represents the first example of a 6-OH-P-carboline ring associated with a betaine unit to be obtained from a natural source. This compound was isolated from the Red Sea sponge Hyrtios erecta and its structure was determined on the basis of its spectral data [35]. Compound 35 displayed immunosuppressive activity with an ED50 of 2 mg/ml in the B lymphocytes reaction assay. The lack of cytotoxicity against KB cells indicated that the immunosuppressive activity of 35 is specific and not due to a general cytotoxic effect. 

The deep-red colored prodigiosin alkaloids are endowed with potent antibacterial, cytotoxic, and antimalaria properties. Additionally, in a series of recent reports it has been claimed that this family also displays a significant immunosuppressive activity. This finding is particularly noteworthy since the mechanism of action seems to be distinctly different from that of... 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

Bromopyrrole alkaloids are important not only for their ecological role and for chemotaxonomic considerations, but also for the number of interesting pharmacological activities they have been shown to possess. Among them, the cytotoxicity of agelastatin (see below) and the immunosuppressive activity of palau amine (see below) are remarkable. This is probably why the interest of organic chemists in total syntheses of bromopyrrole alkaloids has strongly increased since 2000. 

VINCA ALKALOIDS AZATHIOPRINE t risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis Additive myelotoxic effects Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity Avoid co-administration... 

The solid phase synthesis of many organic molecules utilizes carbodiimide mediated reactions. An example is the synthesis of l,4-benzodiazepine-2,5-dione using EDCCl in NMP in a key synthesis step. Often carbodiimides are used in the synthesis of complex proteins. A recent example is the synthesis of the tripeptide backbone of the novel immunosuppressent sanglifehrin A. In the synthesis of the marine alkaloid, variolin B, the formation of an annelated pyrimidine ring is achieved using a carbodiimide mediated cyclization process. 

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