Interleukin ip converting enzyme

Warmus et al. (121) recently reported the multivariate optimization of reaction conditions for the synthesis of a known class of ICE (interleukin-ip converting enzyme) inhibitors, represented by compound 9.70. The structure of the compound and the synthetic route, starting from the key bromide intermediate 9.71, are reported in Fig. 9.29 (the acetylvaline moiety of 9.70 was replaced during the optimization with an Fmoc carbamate). 

The similarities between PCD in plants and animals is corroborated by the detection of highly conserved homologes of ced 2 and 3 (cell death defective) genes [307,308,309] in plant and the ICE (interleukin-iP-converting enzymes) in mammalians cells which represent cysteinproteases [310-313] able to induce cell death [301,314]. 

ICE 1. interleukin- Ip converting-enzyme. 2. street name for methamphetamine. 

Hara H, Friedlander RM, Gagliardini V et al. Inhibition of interleukin ip converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 1997 94 2007-2012. 

Fas, fragment apoptosis stimulator FADD, Fas-associated death domain FLICE, FADD-like Interleukin-Ibeta (IL-ip) converting enzyme. Click for human B-cell lymphoblasts producing constitutively Fas-Ugand (FasL) to kill Fas-receptor positive (FasR CIM" (cluster of differentiation) immune T cells (Klinker MW et al Front Immunol 2014 Apr 4. doi 10.3389/fimmu.2014.00144. 

NEMO kinase (regulatory subunit IKKy), NFkB (nuclear factor kappa B lymphoma) essential modulator, inhibitor of kappa kinase gamma (IKKy). Protein kinase C-interacting protein p62/sequestosome-l, is activated by interleukin IL-IP in sequence, it activates of nuclear factor NFkB in TNFa-stimulated cells (Zotti T et al Mol Immunol 2014 58 27-31). NEMO promotes vFFlP (Fas-associated death domain-like interleukin-1-converting enzyme inhibitory protein) expression by Kaposi sarcoma associated herpesvirus (KSHV) (Tolani B et al J Virol 2014 March 26 PMID 24672029). 

Interleukin-lp converting enzyme (ICE, which converts the M, 33,000 protease form of interleukin-ip to the active M, 17,500 form by cleaving after Asp residues) and other members of the ICE-like family of proteases appear to play a significant role in A. For example, expresrion of CrmA protein (a protease inhibitor that inhibits ICE) potently blocks the A. induced by stimulation of Fas or TNF-1, implying that ICE-type proteases are involved in these suicide pathways. Proteins identified as early targets or death substrates associated with the onset of A. are poly(ADP-ribose) polymerase, lamin Bl, a-fodrin, topoisomerase I, p-actin, and the Af, 70,000 compo nent of the U1 small ribonucleoprotein (Ul-70kD). 

---