Although apoptosis (programmed cell death) is an essential part of normal homeostasis, the evasion of apoptosis by cells is one of the defining hallmarks of cancer.1
While advances in cancer chemotherapeutics over the last few years have improved life expectancy in many cases, the onset of intrinsic or acquired resistance remains a major barrier to effective treatment.2
Defective apoptotic signalling by caspases, a family of intracellular proteases, is an underlying cause of resistance to cell death.3
The activity of caspases is suppressed by a number of endogenous proteins, foremost among them being the inhibitor of apoptosis proteins (IAPs).4,5
In humans the IAP family consists of eight members, including X chromosome-linked IAP (XIAP), cellular IAP 1 (cIAP1), cellular IAP 2 (cIAP2), and melanoma IAP (ML-IAP). Each of the IAPs contains regions called baculoviral IAP repeat (BIR) domains which are 70–80 amino acids in length. In XIAP, the BIR2 domain and the linker preceding it inhibit the effector caspases 3 and 7, while BIR3 binds to, and antagonizes, the initiator caspase 9. The second mitochondria-derived activator of caspases (Smac) protein is an endogenous dimeric proapoptotic antagonist of XIAP. Acting through the intrinsic apoptotic pathway, Smac is released into the cytosol from the mitochondrial intermembrane space in response to cellular stress. Specifically, it is the Smac N
-terminal AVPI sequence () that directly binds to a well, defined surface groove created by the BIR domains of each IAP family member and de-represses the actions of caspases, allowing apoptosis to proceed. Thus, the inhibition of IAPs by small molecules, or “inhibiting the inhibitors”, is a highly promising approach for the treatment of cancer.
(A) Previous Smac mimetics from Genentech and S. Wang are based on the crucial N-terminal AVPI binding domain, but suffer from lengthy syntheses. (B) Novel Smac mimetic 1a can be accessed quickly in two chemical steps from dipeptide 2a.
Following initial studies by Fesik and co-workers,6,7
several research groups initiated programs directed at developing IAP antagonists that mimic the AVPI tetrapeptide sequence (). For example, the synthesis and characterization of drug-like bicyclic peptidomimetics were reported separately by Genentech,8
and P. Seneci.10
In addition to being potent IAP antagonists in vitro
and in cells, these compounds exhibited promising drug-like properties, a logical consequence of their reduced peptidic nature compared with AVPI.
While such Smac peptidomimetics appear to be promising targets, previous syntheses of this framework have generally been laborious, requiring numerous (11–19) synthetic steps and purifications. A notable drawback to the reported procedures is their linear nature, in effect creating a bottleneck for rapid lead optimization. We therefore envisaged a scaffold that could mimic the pertinent interactions of AVPI with IAPs, avoid the typical issues associated with peptides as pharmaceutical agents, and yet could also be synthesized rapidly and efficiently in convergent fashion. This led us to hypothesize that peptidomimetic 1a
and its derivatives might be both synthetically accessible and lead to potent, drug-like IAP antagonists.4
Although the [4,3,0]-bicyclic lactam core is known and has been studied for its propensity to adopt a reverse-turn conformation, application of previous methods to assemble 1a
would require a lengthy linear synthesis or necessitate the use of specialized reaction conditions, such as anodic oxidation.11-18
We theorized that use of the Ugi four-component reaction (Ugi 4CR) had the potential to provide rapid access to the desired heterobicyclic structures.19
Utilization of this novel paradigm, if realized, would bring about the formation of six bonds and two stereocenters (one stereoselectively) over two steps. Herein we report the synthesis of novel, potent IAP antagonists via the highly efficient application of the Ugi 4CR.