Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.

The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity.

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.

Stereoselective syntheses of L-pipecolic acid and (2S,3S)-3-hydroxypipecolic acid from a chiral N-imino-2-phenyl-1,2-dihydropyridine intermediate.

Stereoselective syntheses of L-pipecolic acid and (2S,3S)-3-hydroxypipecolic acid were achieved from a chiral N-imino-2-phenyl-1,2-dihydropyridine intermediate. The 3-hydroxy substituent of the latter amino acid was introduced by hetero-Diels-Alder reaction of singlet oxygen with the 1,2-dihydropyridine.

Total synthesis and biological evaluation of (+)- and (-)-bisanthraquinone antibiotic BE-43472B and related compounds.

The bisanthraquinone antibiotic BE-43472B [(+)-1] was isolated by Rowley and co-workers from a streptomycete strain found in a blue-green algae associated with the ascidian Ecteinascidia turbinata and has shown promising antibacterial activity against clinically derived isolates of methicillin-susceptible, methicillin-resistant, and tetracyclin-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively) and vancomycin-resistant Enterococcus faecalis (VRE). Described herein is the first total synthesis of both enantiomers of this bisanthraquinone antibiotic, the determination of its absolute configuration, and the biological evaluation of these and related compounds. The developed synthesis relies on a highly efficient cascade sequence involving an intermolecular Diels-Alder reaction between diene (R)-61 and dienophile 55, followed by an intramolecular nucleophilic aromatic ipso substitution. Late-stage transformations included a remarkable photochemical alpha,beta-epoxyketone rearrangement [80 --> (+)-1]. Interestingly, the unnatural enantiomer [(-)-1] of antibiotic BE-43472B exhibited antibacterial properties comparable to those of the natural enantiomer [(+)-1].

Stereoselective synthesis of 2,6-disubstituted 3-piperidinols: application to the expedient synthesis of (+)-julifloridine.

[reaction: see text] The asymmetric synthesis of 2,6-disubstituted 3-piperidinols having a 2,3-cis and 2,6-trans relative stereochemistry was accomplished in three steps using the following sequence: stereocontrolled nucleophilic addition of an organomagnesium reagent to a chiral pyridinium salt; monohydrogenation of the resulting 2-substituted 1,2-dihydropyridine; and a one-pot, highly diastereoselective epoxidation-nucleophilic addition with a heteroatom nucleophile or an organometallic reagent. This methodology was applied to the expedient asymmetric synthesis of (+)-julifloridine in four steps.

[4+2] Cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosobenzene: asymmetric synthesis of trans-2-substituted 3-amino-1,2,3,6-tetrahydropyridines.

[reaction: see text] A new methodology for the stereoselective synthesis of trans-2-substituted 3-amino-1,2,3,6-tetrahydropyridines is reported. The preparation of these 3-aminopiperidines is achieved by cycloaddition of nitrosobenzene with 2-substituted 1,2-dihydropyridines followed by chemoselective reduction of the cycloadducts. Enantioenriched 1,2-dihydropyridine derivatives are easily prepared from pyridine and a chiral amide following a previous report from our laboratories. Moreover, the in situ hydrogenation of these cycloadducts over palladium in a solution of hydrogen chloride in methanol led to tetrahydropyrroloimidazoles.

Nucleophilic addition to 3-substituted pyridinium salts: expedient syntheses of (-)-L-733,061 and (-)-CP-99,994.

[reaction: see text] The addition of nucleophiles to 3-substituted pyridinium salts prepared from N-methylbenzamide and various pyridines has been investigated. Good to excellent regioselectivities favoring the 2,3-disubstituted 1,2-dihydropyridines were observed. The resulting 1,2-dihydropyridines led to the corresponding 2,3-disubstituted pyridines upon treatment with Mn(OAc)3/NaIO4. This methodology was also successfully applied to the enantioselective syntheses of (-)-L-733,061 and (-)-CP-99,994, two members of a new class of highly potent, nonpeptide, Substance P antagonists.