Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy aryl aldehydes (HAA), selectively inhibit IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a H-bond with Tyr892. Structure activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

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We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

+)-Maritimol (1), a member of the stemodane diterpenoids (1-3), was isolated 1 from Stemodia maritima L. (Scrophulariaceae) and used as a Caribbean folk medicine for treatment of venereal diseases. It represents a long-standing synthetic challenge 2 with its unique tetracyclic stemodane framework and the construction of its seven chiral centers, particularly the two central, adjacent quaternary carbons at positions 9 and 10. Reported in this contribution is the first asymmetric total synthesis of (+)-maritimol, applying the TADA strategy, developed in our laboratory (Scheme 1). 3aFrom a synthetic point of view, the A.B.C[6.6.5] trans-syncis (TSC) ring system of maritimol correlated well 4a with our previous fundamental TADA model studies, having demonstrated the stereospecific transformation of 14-and 15-membered transcis-cis (TCC) macrocyclic trienes to the respective A.B.C[6.6.6] 4b and [6.6.7] 4c TSC-tricycles. It was also shown that even tetrasubstituted dienophiles were tolerated, particularly when they were activated. 4a,c Moreover, a discovery that a stereogenic center on the macrocycle at the maritimol pro-12 position may induce perfect diastereoface selection in the TADA reaction was also made. 4aRetrosynthetic analysis suggests that tetracycle 4, a central advanced intermediate of stemodanes, 2a is available via TSCtricycle 5 corresponding 4 to macrocycle 6 (Scheme 1). This chiral macrocycle, in turn, can be made in a highly convergent manner, starting from tetrasubstituted cis-dienophile 7. Following an introduction of the requisite asymmetry via (S)-N-amino-2-(methoxymethyl)pyrrolidine (SAMP) 5 hydrazone-based alkylation with Z-1,3-diiodo-propene (8), 6 a Stille coupling 7 with stannane 9 8 delivers the ω-functionalized acyclic -ketoester substrate for macrocyclization.The actual synthesis began with aldehyde 10 (Scheme 2), available in two steps (70%) from commercial Hagemann's ester. 9 NaBH 4 reduction and silyl protection provided tetrasubstituted cis-dienophile 12 (70%), which was selectively hydrolyzed to monoacid 13 (93%) and further transformed into Weinreb amide 14 (89%). 10 Parallel reduction (DIBAL-H) of both carbonyls afforded, after a methanol quench, methoxytetrahydropyran 15, which could be easily transformed to SAMP 5 hydrazone 16 (83%).(1) Hufford, C. D.; Guerrero, R. D.; Doorenbos, N. J. J. Pharm. Sci. 1976, 95, 778-780. (2) For a recent review on the synthesis of stemodane diterpenoids, see: (a) Toyota, M.; Ihara, M. Tetrahedron 1999, 55, 5641-5679. See also: (b) Pearson, A. J.; Fang, X. Scheme 2 a a Reagents: (a) NaBH4, MeOH, >73%. (b) Imidazole, TBS-Cl, 95%. (c) NaOH, THF, 5°C, 96%. (d) Carbonyldiimidazole then Et3N and NH(OMe)Me‚HCl, 89%. (e) DIBALH, CH2Cl2, -78°C then MeOH, 89%. (f) SAMP, PTSA (cat.), PhH, 80°C, 93%. (g) Imidazole, TBDPSCl, 100%. (h) LDA, 0°C then 8, THF, -100°C, 83%. (i) Mgmonoperoxyphthalate, MeOH/Et2O, 98%. (j) Py‚HF, THF then 9, PdCl2‚(MeCN)2, DMF, 52%. (k) (Cl3C)2CO, PPh3, CH2Cl2, -78 to 0°C , 94%. (l) Cs2CO3, CsI, MeCN, 80°C, 75%. (m) TBAF, THF, 87%. (n)...