Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2

Bcl-2 Family Proteins as Therapeutic Targets

“…Using a diversity-oriented approach, Marcaurelle and co-workers have described a series of molecules based on a pyridone scaffold with weak but selective binding for Bcl-2 (compound (11), Fig. 6) [76]. Similarly, Di Micco and coworkers have recently described the preparation of an extensive library of compounds based on diversity-oriented synthesis (com- Fig.…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

“…In an effort to identify novel inhibitors of Bcl-2, scientists at Infinity Pharmaceuticals designed and prepared a 15,000-member pyridone library (Figure 9a/b), via discovery oriented synthesis (DOS). 182 The design of this library was based on the structure of the nicotinic agonist (−)-cytisine ( 130 ) and previous work describing the total synthesis of this natural product. In particular, the pyridone cyclization step, key transformation for the total synthesis of (−)-cytisine, was exploited for the diversity oriented synthesis of heterocycles 131a and 132a as well as their corresponding enantiomers 131b and 132b , respectively.…”

“…This year’s 18 vignettes include (a) biologically active libraries: HDAC1/HDAC2 inhibitors, 134 H 3 antagonists, 136 glucagon receptor antagonists, 179 purinergic P2Y 12 receptor antagonists, 221 heat shock protein 90 (Hsp90) inhibitors, 41 selective norepinephrine reuptake inhibitors, 73 allosteric modulators of mGluR4 287 and mGluR5 71 Bcl-2 inhibitors via DOS library; 182 (b) molecular probes: Ned-19 340 and DG-041; 338 (c) high throughput chemical methodology: catch and release synthesis of substituted guanidines. 289 and substituted pyrimidines via a 3-component reaction; 158 and (d) fluorous technology: displaceable fluorous dihydropyran 322 and isonnitrile linkers, 327 fluorous synthesis of 1,4-benzodiazepine-2,5-dione, 327 piperazinedion-fulsed tricyclic 328 compound libraries and a fluorous mixture synthesis of natural product resorcyclic acid lactone library.…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…182 Apoptosis, or programmed cell death, is important for normal development, host defense, and suppression of oncogenesis, and disregulation of apoptosis has been implicated in cancer and many other human diseases. The Bcl-2 family proteins are central regulators of apoptosis and comprise anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Mcl-1 and proapoptotic proteins such as Bak, Bax, Bim, Bid, and Bad.…”

“…In an effort to identify novel inhibitors of Bcl-2, scientists at Infinity Pharmaceuticals designed and prepared a 15,000-member pyridone library (Figure 9a/b), via discovery oriented synthesis (DOS). 182 The design of this library was based on the structure of the nicotinic agonist (−)-cytisine (130) and previous work describing the total synthesis of this natural product. In particular, the pyridone cyclization step, key transformation for the total synthesis of (−)-cytisine, was exploited for the diversity oriented synthesis of heterocycles 131a and 132a as well as their corresponding enantiomers 131b and 132b, respectively.…”