Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure−activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors.

The discovery of ribozymes led to the proposal of an RNA world, where a single type of molecule was supposedly capable of selfreplication and chemical catalysis. We show here that both autocatalysis and organocatalysis can be engineered into a synthetic structure. The compound is shown to selectively accelerate its own formation and catalyze either hydrogenation or nucleophilic addition to α,β-unsaturated aldehydes. The observed reactivity indicates that the components of a purported pre-RNA world conceivably include smaller organic molecules.imidazolidinone catalysis | self-replication | template effects S tudies of prebiotic chemistry raise questions concerning which functions came nearer the origin of life-genetics or metabolism (1). The discovery of the catalytic activity of ribozymes provided an answer in which both functions could be accounted for in an "RNA world" (2). Although no one doubted that RNA could carry genetic information, some 15 years lapsed before an RNA molecule was shown to self-replicate (3), and this type of catalysis has since been developed to an extraordinary level of efficiency (4). Short, self-complementary DNA strands were shown to selfreplicate in 1986 (5), and autocatalysis based on molecular recognition was found in simplified organic molecules (6) and even peptides (7). At the present time, many types of self-replicating structures are known (8). These systems function like their nucleic acid counterparts in that the self-complementary structures operate as templates for their own formation. However, unlike ribozymes, the synthetic self-replicating systems are not known to catalyze other chemical reactions. The wholly synthetic structures act as either organocatalysts or autocatalysts, but published evidence for both activities in a single molecule is limited (9). This research was undertaken to find molecules that could perform in both capacities, and we report here an imidazolidinone-based compound and its properties as a catalyst and autocatalyst. Results and DiscussionTo realize an autocatalytic/organocatalytic molecule, we made modifications in the structure of compound 1, a molecule that bears self-complementary hydrogen-bonding subunits-a diaminotriazine and cyclic imide-that allow for dimerization in noncompeting organic media (Fig. 1). The arrangement of these subunits in 1 was earlier shown to allow its action as an autocatalyst (10): It acts as a template for its own synthesis, gathering two subunits on its surface to facilitate the formation of the amide bond. The insertion of a functional group known to catalyze organic transformations into 1 was a prospect to be explored. We initially inserted a thiourea into the framework of 1 (11). Although the thiourea function is a widely used organocatalyst (12), its applications were limited in the present context: The same hydrogen bonding that accounts for the thiourea's activity requires the use of solvents that also lead to tight dimerization of the template. This effect minimizes the fraction of the monomeric compound t...

A chiral tetraazamacrocycle 9 having four pendant-arms was synthesized by repeating ring opening of an Ns-aziridine with secondary amines, followed by macrocyclization. The structure of 9 has been determined by single crystal X-ray diffraction analysis and NMR studies. Sugar-hybrid molecules 12a-12f were synthesized based on the scaffold 9. NMR study showed that 12a-12f keep the similar conformation as 9 in solution.

Cyclic peptidic RGD models were efficiently synthesized by Pd(P(t-Bu)3)2-catalyzed carbonylative macrolactamization in the presence of 4 A molecular sieves under 10 atm of carbon monoxide.