Rapamycin - Sirolimus

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

Inhibition of interleukin-2 (IL-2) production or action cyclosporin, tacrolimus, rapamycin (sirolimus). 

Sehgal SN. 2006. Rapamune (RAPA, rapamycin, sirolimus) mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 39 484-489. 

Morris RE, Cao W, Huang X, et al, Rapamycin (Sirolimus) inhibits vascular smooth muscle DNA synthesis in vitro and... 

Therapeutic Function Immunosuppressive, Antifungal Chemical Name Rapamycin Common Name Rapamycin Sirolimus Structural Formula ... 

Rapamycin (sirolimus) is also a natural product, from a soil organism, which is unrelated to cyclosporin but has similar actions, though binding to a different immunophilins. Tacrolimus is a recently introduced macrolide antibiotic similar to cyclosporin, but appears to have a higher incidence of neurotoxicity and nephrotoxicity. 

Rapamycin (Sirolimus) Non-specific Gi/S blockade via mTOR protein Phase I, II human coronary artery Sousa et ah... 

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

Rapamycin (sirolimus 2), isolated from Streptomyces hygroscopicus, is a highly functionalized 31-membered macrolide that exhibits potent antibiotic, cytotoxic, and immunosuppressive activity. FK506 (1) and rapamycin (2) are the structurally related macrolides (Fig. 1) thus, rapamycin possesses an a,p-diketoamide hemi-ketal system, a pipecolic acid moiety, 1,2,4-trisubstituted cyclohexane, and trisub-stituted tetrahydropyran rings, which are similar to those of FK506. In addition to these units, rapamycin (2) includes an ( , , )-triene moiety, two stereochemically complex aldol units, and 15 chiral centers beyond those found in FK506. 

Rapamycin (sirolimus) is another macrolide antibiotic that possesses potent immunosuppressant activity. Rapamycin has a chemical structure partially similar to that of tacrolimus (Fig. 2). It was first isolated from Streptomyces hygro-scopicus strains found in soil obtained on Rapa Nui (Easter Island), hence the name rapamycin [19, 20]. This compound was initially investigated as an antifungal agent and later found to have immunosuppressive activity [21]. Rapamycin also binds to FKBP, but its immunosuppressive mechanisms are distinct from those of tacrolimus and cyclosporin in that it does not act via the calcineurin pathway [22, 23]. The immunosuppressive effects of rapamycin result from its inhibition of T-cell [23, 24] and B-cell [25] proliferation. The key effect on those cells results from the blocking of the signals of several cytokines (IL-2 and IL-4), leading to interruption of the cell cycle from the G, to the S phase. Unlike tacrolimus, the complex of rapamycin and FKBP-12 does not inhibit the dephosphorylase... 

One of the analogues of FK506, rapamycin (sirolimus) produced by Strepto-myces hygroscopicus, is a 31-membered macrocyclic lactone that contains a masked a- and P-diketo amide L-pipecolic acid residue similar to that found in FK506, and a unique triene segment including a distinctive shikimic acid-derived trisubstituted cyclohexane moiety (Fig. 1) [19]. It was originally isolated as an... 

It has been estimated that well over 300,000 secondary metabolites exist, and it s thought that their primary function is to increase the likelihood of an organism s survival by repelling or attracting other organisms. Alkaloids, such as morphine antibiotics, such as erythromycin and the penicillins and immunosuppressive agents, such as rapamycin (sirolimus) prescribed for liver transplant recipients, are examples. 

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