Immunosuppressive activity alkaloids

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... 

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. 

Wilfomine (65) was isolated from Tripterygium mlfordii roots. The alkaloid was found to have immunosuppressive activity in mice [189],... 

In the course of these research programmes, cytotoxic quinones, polyester sesquiterpenes and pyridine-sesquiterpene alkaloids with antifeedant and/or insecticidal properties have been isolated from Latin American species, in particular those of the Maytenus genus which is extensively used by rural communities and tribes in the Andes and the Amazon basin. Recently some sesquiterpene alkaloids with immunosuppressive activity and sesquiterpenes with antitumoral activity have also been described [3]. 

There are about 20 alkaloids separated from the herb. Most of them are three-ring sesquctcrpcnes linked with a pyridine through two ester groups. Many of these alkaloids have immunosuppressive activities (c.f. table 2 fig. 2) [45-55]. 

In the course of these research programmes, many characteristic bioactive compounds have been reported. Polyester sesquiterpenes and pyridine-sesquiterpene alkaloids with insect antifeedant or insecticidal properties have been isolated from some species and recently sesquiterpene pyridine alkaloids with immunosuppressive or antitumoral activities have also been described. Diterpene triepoxides with potent antileukemic and immunosuppressive activities and triterpenoid quinonemethides, named as celastroloids , with antibiotic and cytostatic activities, have been isolated from species of Celastraceae family. 

C 7H22CIN,02, Mr 419.87, amorphous, [alo-45.2° (CHjOH). Alkaloid from the sponge Stylotella auran-tium with cytotoxic and immunosuppressive activities. The less active 4-bromo and 4,5-dibromo derivatives have also been isolated. 

Their significant bioactivities and daunting structural complexity are good enough reasons for captivating organic chemists who have exerted intensive effort to access those alkaloids. For instance, palau amine 247, a polycyclic alkaloid isolated from Stylotella aurantium, exhibits immunosuppressive activity and moderate cytotoxicity. Indeed,... 

In 2005, Honda et al. pubhshed a first total synthesis of a quinohzidine alkaloid using RCM as one of the key steps, namely, (—)-deoxynupharidine (246) [80]. The alkaloid was isolated from plants of the genus Nuphar and exhibited amongst others immunosuppressive activity. Its synthesis commenced with a stereoselective construction of the enantiopure 5,6-disubstituted piperidinone building block 244 by modification and ring expansion of the protected D-pyroglutamic acid derivative 243 (Scheme 2.53). Subsequent RCM of 244 (catalyst [Ru]-II, benzene, 60°C) afforded quinolizidinone 245 in 96% yield, whereafter three consecutive steps led to the natural product itself... 

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... 

The list of commercial products from natural sources could fill volumes. It must be emphasized that their discoveries range from systematic searches, to tradition to chance favors the prepared mind. The latter is reemphasized in the discovery of the alkaloids from the periwinkle plant (vincristine and vinblastine) which were first screened for their hypoglycemic activity based on reports of their use by local groups in Madagascar. While the hypoglycemic response could not be confirmed under controlled laboratory conditions, an immunosuppressive effect due to... 

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