Steven Gunawan

Concise One-Pot Preparation of Unique Bis-Pyrrolidinone Tetrazoles

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates.

Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity

1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles.

Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.

Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. Mol Cancer Ther; 16(6); 1054–67. ©2017 AACR.

Synthesis of peptidomimetics, δ- and \({\varepsilon}\)-lactam tetrazoles

A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1′-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to

2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1,3(2H)-dione

{\varepsilon}

2-Propyl 3,3-dibromo-2-hydroxy-pyrrolidine-1-carboxyl-ate.

-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl2 activation to enable lactam formation.

Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation.

Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1–CUL4A–Roc1–RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBNs activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBNs nonprimate sequence variations. With a series of recombinant thalidomide-binding domain (TBD) proteins, we show that CRBN sequence variants retain their drug-binding properties to both classical immunomodulatory drugs and dBET1, a chemical compound and targeting ligand designed to degrade bromodomain-containing 4 (BRD4) via a CRBN-dependent mechanism. We further show that dBET1 stimulates CRBNs E3 ubiquitin–conjugating function and degrades BRD4 in both mouse and human cells. This insight paves the way for studies of CRBN-dependent proteasome-targeting molecules in nonprimate models and provides a new understanding of CRBNs substrate-recruiting function.

Concise preparation of novel tricyclic chemotypes: fused hydantoin–benzodiazepines

The title compound, C21H21N3O2, was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH2 and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.s. deviation 0.075 Å). In the crystal, the compound packs as a twisted chain, which propagates along the b axis by means of an R 1 2(6) motif formed by one of the carbonyl O atoms acting as a bifurcated acceptor in an N—H⋯O and C—H⋯O interaction. No diffraction was observed from the needle-shaped crystals.